[go: up one dir, main page]

WO2024213794A1 - Utilisation de donneurs de pentylamine pour le traitement de troubles auto-immuns - Google Patents

Utilisation de donneurs de pentylamine pour le traitement de troubles auto-immuns Download PDF

Info

Publication number
WO2024213794A1
WO2024213794A1 PCT/EP2024/060179 EP2024060179W WO2024213794A1 WO 2024213794 A1 WO2024213794 A1 WO 2024213794A1 EP 2024060179 W EP2024060179 W EP 2024060179W WO 2024213794 A1 WO2024213794 A1 WO 2024213794A1
Authority
WO
WIPO (PCT)
Prior art keywords
cells
subject
pentylamine
trp
expression
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/060179
Other languages
English (en)
Inventor
Latif RACHDI
Raphaël SCHARFMANN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Cite
Original Assignee
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Cite
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Institut National de la Sante et de la Recherche Medicale INSERM, Universite Paris Cite filed Critical Centre National de la Recherche Scientifique CNRS
Publication of WO2024213794A1 publication Critical patent/WO2024213794A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A61K35/39—Pancreas; Islets of Langerhans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0676—Pancreatic cells

Definitions

  • the present invention is in the field of medicine, in particular autoimmune diseases as diabetes.
  • the immune checkpoint protein Programmed cell Death Ligand 1 (PD-L1), also known as B7- H1/CD274, is expressed at the cell surface in response to inflammation 1 .
  • PD-L1 interacts with its receptor Programmed cell Death 1 (PD-1) on T cells to inhibit T-cell activation and cytokine production.
  • PD-L1 is found on the surface of placental syncytiotrophob lasts, where it induces materno-fetal immune tolerance 2 4 .
  • PD-L1 is also expressed by cancer cells that evade from immune surveillance 2,4 ’ 5 , and immune checkpoint blockade has provided innovative cancer immunotherapies based on PD-1/PD-L1 blocking antibodies 6
  • these new therapies have autoimmune side effects, and some patients develop type 1 diabetes (T1D) 9 .
  • Type 1 diabetes is a chronic autoimmune disease in which insulin-secreting P cells located in pancreatic islets are destroyed by autoreactive T cells 10 l3 . Although its etiology is not fully understood, a genetic predisposition and environmental factors are involved in its initiation, development and progression. Gradual lymphocytic infiltration known as insulitis is detected in islets from T1D patients, where P-cell antigen-reactive CD8+ T cells, mostly recognizing preproinsulin 14 , initiate progressive islet destruction.
  • T cells act through T- cell receptors (TCRs) that recognize P-cell epitopes presented by HLA class I (HLA-I) molecules, leading to their production of cytokines, such as interferon-y (IFN-y).
  • IFN-y induces expression by P cells of HLA-I and chemokines, such as CXCL10, thus amplifying the homing and activation of T cells in the islets’ 1 13 .
  • IFN-y interferon-y
  • CXCL10 interferon-y
  • This progressive destruction leads to insulin deficiency and hyperglycemia 10 .
  • PD-L1 has been proposed to limit the autoimmune attack by CD8+ cytotoxic T cells 9 .
  • PD-L1 over-expression in human P-like cells produced in vitro from stem cells protects them from destruction 15 .
  • NID Non-Obese Diabetic mice
  • megakaryocyte progenitor cells overexpressing PD-L1 suppress the activity of islet-reactive T cells, protecting p cells from their attack 16 .
  • PD- Ll-treated islets grafted into NOD mice are protected from destruction 17 .
  • PD-L1 expression is controlled by a number of signaling pathways 18 .
  • IFN-a and IFN-y are the main PD-L1 inducers through the JAK/STAT1/IRF1 pathway 19 .
  • Transforming growth factor-P TGF-P
  • pathogens such as coxsackieviruses induce PD-L1 expression through toll-like receptor 3 signaling21.
  • PD-L1 expression can also be induced through the RAS/MEK/ERK (MAPK) and PI3K/AKT/mT0R pathways 22 26 .
  • AhR aryl hydrocarbon receptor pathway 27 .
  • AhR is a transcription factor that controls genes, such as CYP1A1, which protect cells by oxidation of various aromatic hydrocarbons 28 .
  • AhR has historically been studied in the context of the dioxin compound 2, 3,7,8- Tetrachlorodibenzodioxin (TCDD) 29 .
  • TRP tryptophan
  • kynurenic acid 30 indole-3 -pyruvic acid 31
  • UV photoproducts 6-formylindolo 3,2b carbazole (FICZ) 32 or TRP itself 33 ’ 34 have been identified as endogenous AhR ligands.
  • TRP tryptophan
  • the present invention is defined by the claims.
  • the present invention relates to use of pentylamine donors for the treatment of autoimmune diseases.
  • TRP tryptophan
  • TRP could induce immune tolerance to P cells by promoting their immune evasion through HLA-I downregulation and PD-Ll upregulation. They furthermore confirm the induction of PD-L1 via TRP in thyroid cell and intestinal epithelium cell (i.e colonocyte).
  • T1D type 1 diabetes
  • the first object of the present invention relates to a method for increasing the expression of PDL1 on cells of a subject, comprising administering to the subject a therapeutically effective amount of at least one pentylamine donor.
  • the cell is selected from the group consisting in pancreatic P-cells, keratinocytes, intestinal epithelium cell, melanocytes and/or thyroid cells
  • the cell is pancreatic P-cell.
  • pancreatic p-cell has its general meaning in the art and refers to a type of cell found in pancreatic islets that synthesize and secrete insulin. Beta cells make up 50-70% of the cells in human islets.
  • pancreatic p-cell function refers to the biological activity that is used to describe a mammalian (e.g., human) pancreatic P-cell (e.g., an activity that is specifically unique to a pancreatic P-cell).
  • pancreatic P-cell function include the synthesis and secretion of insulin, the synthesis and secretion of islet amyloid polypeptide (IAPP), and the synthesis and section of C-peptide.
  • IAPP islet amyloid polypeptide
  • Methods for detecting the synthesis and secretion of insulin, IAPP, and C-peptide are known in the art.
  • Pancreatic P-cell function can also be detected indirectly using the methods described herein, as well as methods known in the art (e.g., determining blood glucose levels and determining glycated hemoglobin A1C levels).
  • pancreatic p-cell mass refers to the total number of viable insulinsecreting pancreatic P-cells in a mammal (e.g., a human). Methods for indirectly determining the pancreatic P-cell mass in a subject are described herein. Additional methods for indirectly determining the pancreatic P-cell mass in a subject are known in the art (e.g., determining blood glucose levels and determining glycated hemoglobin A1C levels).
  • the pancreatic P-cell mass may represent the total number of endogenous viable pancreatic P-cells in a subject or may represent the sum of the number of endogenous viable pancreatic P-cells in a subject plus the number of viable pancreatic P-cells transplanted into the subject (e.g., autograft, homograft, or xenografted viable pancreatic P-cells).
  • keratinocyte has its general meaning in the art and refers to the major type of cell found in epidermis that play an essential role in protection against environmental damage by heat, UV radiation, water loss, pathogenic bacteria, fungi, parasites, and viruses. Keratinocyte constitute 90% of epidermal skin cells. Loss of integrity of the keratinocyte, caused by autoantibodies against proteins in the desmosomes, plays a key pathogenic role in pemphigus.
  • melanocyte has its general meaning in the art and refers to melaninproducing neural crest-derived cells. Melanocytes are well known for their role in skin pigmentation, and their ability to produce and distribute melanin. They are also able to secrete a wide range of signal molecules, including cytokines, POMC peptides, catecholamines, and NO in response to UV irradiation and other stimulus. Extensive melanocyte destruction caused vitiligo.
  • thyroid cell has its general meaning in the art and refers to cell located in the thyroid gland, which trap and concentrate iodine and use it to make thyroid hormone. Thyroid cell include two major type of cell : follicular and parafollicular thyroid cell.
  • follicular thyroid cell also known as thyroid epithelial cells or thyrocytes, has its general meaning in the art and refers to the major cell type in the thyroid gland, and are responsible for the production and secretion of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).
  • a monolayer of follicular thyroid cell organizes follicles into honeycomb-like structures that produce thyroglobulin (TG), which is modified with iodine into thyroid hormone.
  • TG thyroglobulin
  • parafollicular thyroid cell has its general meaning in the art and refers to neuroendocrine cells located in the thyroid. Their primary function is to secrete calcitonin (thyrocalcitonin). Hashimoto's disease is characterised by the loss of follicular thyroid cells.
  • epithelial intestinal cell has its general meaning in the art and refers to cell layer that form the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract, where they play important roles in the digestion of food, absorption of nutrients, and protection of the human body from microbial infections, and others.
  • epithelial cells In addition to the well-established role of epithelial cells in ion transport, these cells appear to function as an integral component of the mucosal immune system.
  • Human epithelial intestinal cell an process and present antigens to T cells in vitro, and can be stimulated to express HLA class II and intercellular adhesion molecules in vivo. Loss of integrity of the intestinal epithelium, caused by autoantibodies against intestinal epithelial cells, plays a key pathogenic role in inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the epithelial intestinal cell is colonic intestinal cell.
  • PDL1 has its general meaning in the art and refers to the programmed death-ligand 1 also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1).
  • PDL1 is a 40kDa type 1 transmembrane protein that in humans is encoded by the CD274 gene.
  • the binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM). This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).
  • An exemplary amino acid sequence for PDL1 is represented by SEQ ID NO: 1.
  • the expression “increasing the expression” refers to an improvement or enhancement of 1%, 5%, 10%, 25% 50%, 75%, 100%, or greater than 100% of the expression of the protein.
  • the pentylamine donor does not increase the expression of MHC class I molecules on pancreatic P-cells, keratinocytes, intestinal epithelium cell, melanocytes or thyroid cells.
  • the pentylamine donor does synergize with interferon-gamma (INF-y) and/or interferon-alpha (INF-a) to increase the expression of PDL-1 on pancreatic P-cells, keratinocytes, intestinal epithelium cell, melanocytes or thyroid cells.
  • INF-y interferon-gamma
  • INF-a interferon-alpha
  • the pentylamine donor does impair interferon-gamma (INF-y) and/or interferon-alpha (INF-a) to induce the expression of pro inflammatory gene as CXCL9, CXCL10, CXCL11, HLA-A2, B2M or IL7 on pancreatic P- cells, keratinocytes, intestinal epithelium cell, melanocytes or thyroid cells.
  • INF-y interferon-gamma
  • INF-a interferon-alpha
  • MHC major histocompatibility complex
  • HLA human leucocyte antigens
  • the a-3 domain and P-2m are relatively conserved and show amino-acid sequence homology to immunoglobulin constant domains.
  • the polymorphic a-1 and a-2 domains show no significant sequence homology to immunoglobulin constant or variable region, but do have weak sequence homology to each other.
  • the membrane-distal polymorphic a-1 (approximately 90 amino acids) and a-2 (approximately 92 amino acids) domains each include four anti-parallel, P -pleated sheets bordered by one a-helical regions, (the first from the a-1 and the second from the a-2 domain).
  • the a-2 domain is attached to the less-polymorphic, membrane-proximal a-3 (approximately 92 amino acids) domain which is followed by a conserved transmembrane (25 amino acids) and an intra-cytoplasmic (approximately 30 amino acids) segment.
  • a conserved transmembrane 25 amino acids
  • an intra-cytoplasmic approximately 30 amino acids
  • the classical class I gene family includes the highly polymorphic human class T molecules HLA- A, -B, and -C, and murine class I (i.e., H-2) molecules D, K, and L.
  • a series of structural relatives has been found in humans (e.g., HLA-E, -F, -G, -H, -I, and -J; and GDI) and mice (Q, T, M, and GDI) (Shawar et al., 1994, Annu. Rev. Immunol., 12:839-880).
  • Exemplary MHC Class I molecules include, for example, molecules that are encoded by human leukocyte antigen (HLA)-A, HLA-B, HLA-C, HLA-E, HLA-F, or HLA-G loci. More particularly, the HLA class I MHC antigen molecules include but are not limited to HLA-A*0201, HLA-A*0101, HLA-A*0301, HLA-A*1101, HLA-A*2402, HLA-A*3303, HLA-C*0701, HLA-C*0702, HLA-C*0401, HLA-B*0702, HLA-B*4402, and HLA-B*3501.
  • HLA-A*0201 HLA-A*0101
  • HLA-A*0301 HLA-A*1101, HLA-A*2402, HLA-A*3303, HLA-C*0701, HLA-C*0702, HLA-C*0401, HLA-B*0702, HLA-B*440
  • interferon-gamma As used herein, the term “interferon-gamma” or “INF-y” has its general meaning in the art and refers to type II class of interferon proteins that help regulate the activity of the immune system. IFN-y, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral, some bacterial and protozoan infections. IFN-y is an important activator of macrophages and inducer of major histocompatibility complex class II molecule expression.
  • IFN-alpha As used herein, the term “interferon-alpha” or “IFN-a” has its general meaning in the art and refers to proteins produced mainly by plasmacytoid dendritic cells (pDCs). IFN-a is mainly involved in innate immunity against viral infection.
  • pentylamine donor refers to an agent containing one or more amines that when catabolized give rise to pentylamine.
  • catabolism has its general meaning in the art and is the part of the metabolism responsible for breaking complex molecules down into smaller molecules. During the catabolism energy is released from the bonds of the large molecules being broken down.
  • Pentylamine has its general meaning in the art and refers to a compound having the formula of formula CFFfCFE ⁇ NFE. Pentylamine exhibits reactions typical of other simple alkyl amines, i.e. protonation, alkylation, acylation, condensation with carbonyls.
  • the pentylamine donor is able to inhibit the translation of STAT1 and IRF1.
  • the pentylamine donor inhibits the STAT1 and IRFl.
  • STAT1 also known as “Signal transducer and activator of transcription 1” refers to a signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors.
  • IFNs interferons
  • Type I interferons IFN-a, IFN-B
  • IFN-a, IFN-B Type I interferons bind to receptors, cause signaling via kinases, phosphorylate and activate the Jak kinases TYK2 and JAK1 and also STAT1 and STAT2.
  • IFN-a, IFN-B Type I interferons bind to receptors, cause signaling via kinases, phosphorylate and activate the Jak kinases TYK2 and
  • IRF1 also known as “Interferon regulatory factor 1” refers to the first member of the interferon regulatory transcription factor (IRF) family identified. IRF1 regulates the transcription of genes that play essential roles in viral infection, tumor immune surveillance, pro-inflammatory injury, and immunity system development. Its Entrez reference is 3659 and its UniProt reference is P10914.
  • the pentylamine donor is tryptophan.
  • the pentylamine donor is tryptamine.
  • the pentylamine donor is isopentylamine.
  • tryptophan has its general meaning in the art and refers to the compound having the formula of:
  • tryptamine has its general meaning in the art and refers to the compound having the formula of:
  • isopentylamine or “isoamylamine” has its general meaning in the art and refers to the compound having the formula of:
  • the present invention relates to a method for increasing the expression of PDL1 on cells of a subject, comprising administering to the subject a therapeutically effective amount of tryptophan.
  • the term “subject” refers to any mammals, such as a rodent, a feline, a canine, and a primate.
  • the subject is a human afflicted with or susceptible to be afflicted with autoimmune diseases.
  • the subject is a human afflicted with or susceptible to be afflicted with disease associated with hashimoto’s thyroiditis, inflammatory bowel disease or type 1 diabetes.
  • the subject is susceptible to be afflicted with autoimmune diseases, such as type 1 diabetes, and thus the pentylamine donor is used for preventing of said autoimmune disease.
  • the subject suffers from autoimmune diseases, such as type 1 diabetes and thus the pentylamine donor is used for the treatment of said autoimmune disease.
  • autoimmune diseases such as type 1 diabetes and thus the pentylamine donor is used for the treatment of said autoimmune disease.
  • a further object of the present invention relates to a method of treating autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one pentylamine donor.
  • the present invention relates to a method of treating autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of tryptophan.
  • autoimmune disease has its general meaning in the art and refers to an abnormal immune response against functioning body part, i.e against a substance that does not normally elicit an immune response in a healthy subject. The causes of autoimmune disorders are not well understood and many have no cure.
  • autoimmune diseases include but are not limited to: Acute disseminated encephalomyelitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Axonal & neuronal neuropathy (AMAN), Behcet's disease, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg -Strauss, Cicatricial pemphigoid/benign mucosal pemphigoid, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocardi
  • the autoimmune disease is type 1 diabetes (T1D), rheumatoid arthritis, systemic lupus erythematosus (lupus), pemphigus, vitiligo, psoriasis and psoriatic arthritis, dermatomyositis, alopecia areata, multiple sclerosis, inflammatory bowel disease such as Crohn’s disease and ulcerative colitis, celiac disease or hashimoto’s thyroiditis.
  • the autoimmune disease is hashimoto’s thyroiditis, inflammatory bowel disease or type 1 diabetes.
  • HT Hashimoto thyroiditis
  • autoimmune thyroiditis has its general meaning in the art and results from a dysregulation of the immune system leading to an immune attack on the thyroid, characterized by lymphocytic infiltration of the thyroid parenchyma leading to thyroid cell death.
  • Hashimoto's thyroiditis causes hypothyroidism.
  • Immune-mediated thyroiditis can be caused by PD-L1 inhibitors in cancer patients treated with PD-L1 inhibitors 35 .
  • Clinical diagnosis of HT is based on the presence of diffuse goiter, antithyroid peroxidase antibodies, anti-thyroglobuline (anti-Tg) antibodies or lymphocytic infiltration on cytological examination.
  • inflammatory bowel disease has its general meaning in the art and refers to any inflammatory disease that affects the bowel.
  • the term includes but is not limited to ulcerative colitis (UC), Crohn’s disease (CD), especially Crohn’s disease in a state that affect specifically the colon with or without ileitis, microscopic colitis (lymphocytic colitis and collagenous colitis), infectious colitis caused by bacteria or by virus, radiation colitis, ischemic colitis, pediatric colitis, pouchitis, celiac disease, undetermined colitis, and functional bowel disorders (described symptoms without evident anatomical abnormalities).
  • UC ulcerative colitis
  • CD Crohn’s disease
  • CD Crohn’s disease in a state that affect specifically the colon with or without ileitis
  • microscopic colitis lymphocytic colitis and collagenous colitis
  • infectious colitis caused by bacteria or by virus
  • radiation colitis ischemic colitis
  • pediatric colitis pouchitis
  • celiac disease undetermined colitis
  • CD and UC are chronic inflammatory diseases, and are not medically curable except for the use of surgery, although this may not eliminate extra-intestinal symptoms, and for CD, this does not preclude relapses.
  • Previous study suggests that the decrease in surface PD-L1 on the epithelial intestinal cell contributes to increasing immune responses in CD 36 .
  • vitiligo has its general meaning in the art and refers to the disease characterized by the autoimmune destruction of the melanocytes causing patches of skin to lose pigment or color.
  • autoreactive CD8+ T cells play a pivotal role in melanocyte destruction in autoimmune vitiligo.
  • type 1 diabetes or “T1D” is also known as “insulin-dependent diabetes mellitus” or “type I diabetes mellitus” has its general meaning in the art and refers to the disease characterized by the autoimmune destruction of the P cells in the pancreatic islets of Langerhans.
  • the autoimmune disease is type 1 diabetes.
  • treatment or “treating a subject” is defined as the application or administration of a therapeutic agent to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient, who has a disease, a symptom of disease or a predisposition toward a disease.
  • the terms “treating” or “treatment” refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment. Treatment can slow, cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease, the symptoms of disease or the predisposition toward disease.
  • treatment of a subject can slow, improve, or stop the ongoing autoimmunity, such as a reaction against pancreatic P-cells, in a subject before, during, or after the clinical onset of autoimmune disease, such as type 1 diabetes.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase "induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • the method of the invention can prevent vitiligo, or prevent or delay loss of melanocyte mass, providing a re-coloring of the skin and/or delaying the onset of vitiligo.
  • the present invention is particular suitable for treating vitiligo.
  • the method of the invention can prevent hashimoto thyroiditis (HT), or prevent or delay death of thyroid cell (which produces thyroid hormones necessary to regulates metabolism) and/or delaying the onset of hashimoto thyroiditis.
  • HT hashimoto thyroiditis
  • the method of the invention can prevent diabetes mellitus, or prevent or delay loss of residual P-cell mass, providing a longer remission period reducing short term complications and/or delaying the onset of diabetes-related complications at a later stage of the life.
  • the present invention is particular suitable for treating T1D.
  • the onset of T1D may be delayed by the method as described herein such that insulin is not needed by the subject for a longer length of time.
  • the present method may extend the “honeymoon phase” in an already diabetic subject.
  • the honeymoon phase is where insulin is secreted by the pancreas, causing high blood sugar levels to subside, and resulting in normal or near normal glucose levels due to responses to insulin injections and treatment.
  • the method of the present invention is also used to arrest the autoimmune destruction of tissue, such as pancreatic P-cells, thyroid cell or melanocyte.
  • tissue such as pancreatic P-cells, thyroid cell or melanocyte.
  • the method of the present invention is suitable to arrest the autoimmune destruction, even at a late stage. For example, at the time of clinical onset of type 1 diabetes mellitus, significant number of insulin producing P-cells are destroyed but around 15% maybe as much as 40% are still capable of insulin production. If the autoimmune process can be arrested even in this late stage, these cells can be preserved.
  • the P- cells have some limited capacity to replicate and precursors may form new P-cells.
  • the expression “delaying the progression” as used herein in the context of delaying the progression of autoimmune disorders, such as diabetes mellitus, vitiligo, IBD and hashimoto’ s thyroiditis means that the loss of functional cells (such as pancreatic P-cell, melanocytes, keratinocytes, thyroid cells and epithelial intestinal cells).
  • the expression “delaying the progression” in the context of delaying the progression of diabetes mellitus means that the loss of functional residual P-cell mass, after the clinical onset of Type 1 diabetes is delayed.
  • the delayed progression of T1D can be measured, for example, by measuring C- peptide production.
  • the subject was early diagnosed with autoimmune disease.
  • the subject was early diagnosed with T1D.
  • the expression "early diagnosis of T1D” or “early diagnosed T1D” refers to the patient in whom T1D has either been recently or newly diagnosed, e.g. wherein the patient has been diagnosed with T1D within about 3 months of initial treatment, and/or wherein the patient's T1D is in early stages or is not advanced, e.g. wherein the patient is determined to have functioning beta cells, for instance as determined by a blood test such as C-peptide in which a detectable level of C-peptide (e.g.
  • MMTT mixed-meal tolerance test
  • stage can also include two stages where stage 1 is defined as the presence of P-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic and stage 2 as the presence of P-cell autoimmunity with dysglycemia and is presymptomatic.
  • the subject has been newly been detected to have self-autoantibodies associated with T1D.
  • the expression “has newly been detected” or “recently been diagnosed” refers to patients has been diagnosed with T1D for less than 6 months, and more particularly less than 3 month, and/or wherein the patient's T1D is in early stages (i.e stage 1 or 2 as described above) or is not advanced.
  • the four autoantibodies that are markers of beta cell autoimmunity in type 1 diabetes are: islet cell antibodies (ICA, against cytoplasmic proteins in the beta cell), antibodies to glutamic acid decarboxylase (GAD-65), insulin autoantibodies (IAA), and IA-2A, to protein tyrosine phosphatase.
  • ICA islet cell antibodies
  • GAD 65 antibodies to glutamic acid decarboxylase
  • IAA insulin autoantibodies
  • IA-2A protein tyrosine phosphatase.
  • Autoantibodies against GAD 65 are found in 80% of type 1 diabetics at clinical presentation. Presence of ICA and IA-2A at diagnosis for type 1 diabetes range from 69-90% and 54-75%, respectively. IAA prevalence correlates inversely with age at onset of diabetes; it is usually the first marker in young children at risk for diabetes and found in approximately 70% of young children at time of diagnosis.
  • Type 1 diabetes is a chronic autoimmune disease with both genetic and environmental contributions.
  • the disorder represents a disease continuum that begins prior to its symptomatic manifestations.
  • the risk of developing symptomatic type 1 diabetes can be identified and quantified before the onset of clinical symptoms (such as hyperglycaemia).
  • subject can be diagnosed by detecting to have self-autoantibodies associated with T1D as described above while being asymptomatic.
  • the subject is not yet symptomatic for T1D (i.e. hyperglycaemia).
  • the method of the present invention is thus particularly suitable for delaying the onset of hyperglycaemia for such an individual.
  • hypoglycemia or “high blood sugar” is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/1 (200 mg/dl), but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/1 (250-300 mg/dl).
  • a subject with a consistent range between 5.6 and 7 mmol/1 (100-126 mg/dl) (American Diabetes Association guidelines) is considered hyperglycemic, while above 7 mmol/1 (126 mg/dl) is generally held to have diabetes.
  • the subject has blood sugar below 11.1 mmol/1 (200 mg/dl). In another embodiment, the blood sugar below 15 mmol/1 ( ⁇ 250 mg/dl) or below 20 mmol/1 300 mg/dl).
  • the subject is not yet symptomatic for auto-immune HT (i.e. hypothyroidism).
  • auto-immune HT i.e. hypothyroidism
  • the method of the present invention is thus particularly suitable for delaying the onset of hypothyroidism for such an individual.
  • hypothyroidism has its general meaning in the art and refers to a condition characterized by an elevated serum thyroid-stimulating hormone (TSH) level along with a low level of thyroxine T4and triiodothyronine T3.
  • TSH serum thyroid-stimulating hormone
  • RAIU radioactive iodine uptake
  • the pentylamine donor as described herein is administered in combination with a therapeutic compound used to treat autoimmune diseases.
  • the terms “combined treatment”, “combined therapy” or “therapy combination” refer to a treatment that uses more than one medication.
  • the combined therapy may be dual therapy, bi-therapy or tri-therapy.
  • the medications used in the combined treatment according to the invention are administered to the subject simultaneously, separately or sequentially.
  • the pentylamine donor as described herein is administered in combination with a CTLA4 molecule.
  • CTLA4 molecule is a molecule comprising a cytotoxic T- lymphocyte-associated antigen 4 (CTLA4) extracellular domain.
  • CTLA4 molecule is an isolated and purified CTLA4 molecule.
  • the CTLA4 molecule is Abatacept.
  • Abatacept is a soluble fusion protein that consists of the extracellular domain of human CTLA-4 linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgGl).
  • the pentylamine donor is used in combination with a GABA receptor agonist.
  • receptor agonist refers to the native ligand of that receptor (e.g., a GABA receptor) to analogues thereof or other ligands that similarly “activate” the receptor, and/or to a positive allosteric modulator of the receptor.
  • GABA refers to gamma-amino butyric acid of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof as well as mixtures thereof
  • GABAA receptor specific agonist refers to an agent that has agonistic activity at the GABAA receptor and substantially no agonist activity at the GAB AB.
  • GABAA receptor preferential agonist refers to an agent that has greater agonistic activity at the GABAA receptor than at the GAB AB.
  • the GABAA receptor preferential agonist has at least 1.2-fold, more preferably at least 1.5 fold still more preferably at least 2 fold, and most preferably at least 3 -fold, at least 5 -fold, or at least 10-fold greater activity at the GABAA receptor than at the GAB AB and as determined using an conventional assay for agonist activity at a GABA receptor.
  • GABAB receptor specific agonist refers to an agent that has agonistic activity at the GABAB receptor and substantially no agonist activity at the GABAA.
  • GABAB receptor preferential agonist refers to an agent that has greater agonistic activity at the GABAB receptor than at the GABAA.
  • the GABAB receptor preferential agonist has at least 1.2-fold, more preferably at least 1.5 fold still more preferably at least 2 fold, and most preferably at least 3 -fold, at least 5 -fold, or at least 10-fold greater activity at the GAB AB receptor than at the GABAA as determined using an conventional assay for agonist activity at a GABA receptor.
  • Illustrative GABA receptor agonists include, but are not limited to, certain barbiturates (e.g., thiopental, thiamylal, pentobarbital, secobarbital, hexobarbital, butobarbital, amobarbital, barbital, mephobarbital, phenobarbital, primidone, and the like), certain benzodiazepines (e.g., midazolam, triazolam, lometazepam, flutazolam, nitrazepam, fluritrazepam, nimetazepam, diazepam, medazepam, oxazolam, prazeam, tofisopam, rilmazafonoe, lorazepam, temazepam, oxazepam, fluidazepam, chlordizaepoxide, cloxazolam, flutoprazepam, alprazolam, est
  • the GABA receptor agonist is selected from the group consisting of muscimol, THIP/gaboxadol, isoguvacine, kojic amine, homotaurine, homohypotaurine, trans- aminocy cl opentane-3 -carboxylic acid, trans-amino-4-crotonic acid, P-guanidinopropionic acid, homo-P -proline, isonipecotic acid, 3- ((aminoiminomethyl)thio)-2-propenoic acid (ZAPA), imidazoleacetic acid, and piperidine- 4-sulfonic acid (P4S).
  • pentylamine donor herein described is used in combination with, for example, any known therapeutic agent or method for treating T1D.
  • known therapeutics for treating T1D include insulin, insulin analogs, islet transplantation, stem cell therapy including PROCHYMAL®, non-insulin therapies such as IL-lbeta inhibitors including (Anakinra, Kineret®), Diamyd, alefacept (Ameviv®), anti-CD3 antibodies such as Otelixizumab, DiaPep277 (Hsp60 derived peptide), Alpha 1- Antitrypsin, Prednisone, azathioprine, Ciclosporin, El-INT (an injectable islet neogenesis therapy comprising an epidermal growth factor analog and a gastrin analog), statins including Zocor®, Simlup®, Simcard®, Simvacor®, Sitagliptin (dipeptidyl peptidase
  • the pentylamine donor as described herein is used in combination with an agent known for meaning and/or increasing the pancreatic P-cell mass of a subject suffering from type 1 diabetes.
  • the pentylamine donor is used in combination with a GABA receptor agonist.
  • pentylamine donor herein described is used in combination with, for example, any known therapeutic agent or method for treating Hashimoto’s thyroiditis.
  • Non-limiting examples of such known therapeutics for treating HT include synthetic thyroxine (T4) hormone such as levothyroxine, synthetic triiodothyronine (T3) hormone such as cytomel or a synthetic T4 and T3 combination.
  • T4 hormone such as levothyroxine
  • T3 hormone such as cytomel or a synthetic T4 and T3 combination.
  • pentylamine donor herein described is used in combination with, for example, any known therapeutic agent or method for treating IBD.
  • known therapeutics for treating IBD include anti- TNF alpha compounds such as etanercept, infliximab and adalimumab; golimumab; certolizumab; vedolizumab; ustekinumab; onercept and CDP571 anti-inflammatory drugs such as corticosteroids, aminosalicylayes, mesalazines, balsalazide and olsalazine; immunosuppressant drugs such as azathioprine, mercaptopurine and methotrexate; antioxidants such as ascorbic acid, vitamin A, vitamin E; and antibiotics.
  • anti- TNF alpha compounds such as etanercept, infliximab and adalimumab; golimumab; certolizumab; vedolizumab; ustekinum
  • the pentylamine donor of the present invention is also particularly suitable for preventing the autoimmune destruction of a population of cells that is engrafted in a subject suffering from autoimmune disease, wherein the population of cells is selected among pancreatic P-cells, keratinocytes, intestinal epithelium cell, melanocytes or thyroid cells.
  • the pentylamine donor of the present invention is also particularly suitable for preventing the autoimmune destruction of a population of thyroid cells that is engrafted in a subject suffering from hashimoto’s disease.
  • a further object of the present relates to a method of treating hashimoto’s disease in a subject in need thereof comprising the steps of i) providing a population of thyroid cells ii) contacting the population of thyroid cells with an effective amount of at least one pentylamine donor for a sufficient time for allowing the expression of PDL1 and iii) engrafting the population of thyroid cells at step ii) into the subject.
  • the population of thyroid cells is contacted with an effective amount of at least one pentylamine donor in combination with an effective amount of interferon-gamma (INF-y) and/or interferon-alpha (INF-a).
  • INF-y interferon-gamma
  • INF-a interferon-alpha
  • the present relates to a method of treating hashimoto’s disease in a subject in need thereof comprising the steps of i) providing a population of thyroid cells ii) contacting the population of thyroid cells with an effective amount of at least one pentylamine donor for a sufficient time for allowing the expression of PDL1 with with interferon-gamma (INF-y) and/or interferonalpha (INF-a) and iii) engrafting the population of thyroid cells at step ii) into the subject.
  • INF-y interferon-gamma
  • INF-a interferonalpha
  • the pentylamine donor of the present invention is also particularly suitable for preventing the autoimmune destruction of a population of pancreatic beta-cells that is engrafted in a subject suffering from type 1 diabetes.
  • a further object of the present relates to a method of treating type 1 diabetes in a subject in need thereof comprising the steps of i) providing a population of pancreatic beta-cells ii) contacting the population of pancreatic beta-cells with an effective amount of at least one pentylamine donor for a sufficient time for allowing the expression of PDL1 and iii) engrafting the population of pancreatic beta-cells at step ii) into the subject.
  • the population of thyroid cells is contacted with an effective amount of at least one pentylamine donor in combination with interferon-gamma (INF-y) and/or interferon-alpha (INF-a).
  • INF-y interferon-gamma
  • INF-a interferon-alpha
  • the present relates to a method of treating treating type 1 diabetes in a subject in need thereof comprising the steps of i) providing a population of pancreatic beta-cells ii) contacting the population of pancreatic beta-cells with an effective amount of at least one pentylamine donor for a sufficient time for allowing the expression of PDL1 with interferon-gamma (INF- y) and/or interferon-alpha (INF-a) and iii) engrafting the population of thyroid cells at step ii) into the subject.
  • INF- y interferon-gamma
  • INF-a interferon-alpha
  • a further object of the present relates to a method of treating autoimmune disease in a subject in need thereof comprising the steps of i) providing a population of cells, selected among pancreatic P-cells, keratinocytes, intestinal epithelium cell, melanocytes or thyroid cells ii) engrafting the population of cells at step ii) into the subject and iii) administering to the subject a therapeutically effective amount of at least one pentylamine donor thereby preventing the autoimmune destruction of the engrafted population of cells.
  • a further object of the present relates to a method of treating hashimoto’s disease in a subject in need thereof comprising the steps of i) providing a population of thyroid cells ii) engrafting the population of thyroid cells at step ii) into the subject and iii) administering to the subject a therapeutically effective amount of at least one pentylamine donor thereby preventing the autoimmune destruction of the engrafted population of pancreatic beta-cells.
  • a further object of the present relates to a method of treating type 1 diabetes in a subject in need thereof comprising the steps of i) providing a population of pancreatic beta-cells ii) engrafting the population of pancreatic beta-cells at step ii) into the subject and iii) administering to the subject a therapeutically effective amount of at least one pentylamine donor thereby preventing the autoimmune destruction of the engrafted population of pancreatic beta-cells.
  • the expression "therapeutically effective amount” is meant a sufficient amount of the active ingredient (e.g. pentylamine donor) for treating or reducing the symptoms at reasonable benefit/risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with the active ingredients; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, typically from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the active ingredient of the present invention e.g. pentylamine donor
  • pharmaceutically acceptable excipients e.g. pentylamine donor
  • sustained-release matrices such as biodegradable polymers
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the active ingredients of the invention can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the invention refers to a pharmaceutical composition comprising at least one pentylamine donor.
  • the invention refers to a pharmaceutical composition comprising at least one pentylamine donor for use for treating autoimmune disease.
  • the pentylamine donor is tryptophan. In some embodiments, the pentylamine donor is tryptamine. In some embodiments, the pentylamine donor is isopentylamine. In some embodiments, the autoimmune disease is type 1 diabetes.
  • FIGURES are a diagrammatic representation of FIGURES.
  • C Dose response effect of TRP on PD-L1 expression measured by RT-qPCR in ECN90 cells (12 h treatment).
  • D-E Effects of AHR inhibitors StemRegenin (1 pM) and CH 223191 (1 pM) on CYP1A1 (D) and PD-L1 (E) measured by RT-qPCR in ECN90 cells treated for 12 h with TRP.
  • MFI Mean fluorescence intensity
  • TRP is the only AA that robustly induces PD-L1 in ECN90 cells.
  • A ECN90 cells were treated with or without amino acids (10 mM/each) for 12 h and analyzed for PD-L1 expression by RT-qPCR.
  • B ECN90 cells were depleted of TRP for 48 h and then treated with IFN-y (25 ng/ml) for 12 h. PD-L1 was analyzed by RT-qPCR.
  • ECN90 cells were treated with TRP or its catabolites from (A) the kynurenine (KYN 200 pM, KA 200 pM), (B) serotonin (5-HTP 1 mM, 5-HT 1 mM), (C) indole (I3PA 1 mM, 13 A 1 mM) pathways, (D-E) TRY (5 mM) and ISO (10 pM) catabolites.
  • ECN90 cells were treated with TRP (10 mM), IFNy (25 ng/ml) or both.
  • A PD-L1 expression was measured by RT-qPCR (12 h treatment);
  • B-C PD-L1 was analyzed and quantified by Western blot (48 h treatment);
  • D-E flow cytometry plots and mean fluorescence intensity (MFI) of PD-L1 and HLA-A2 (48 h treatment).
  • G-H HLA-ABC, HLA-E and CXCL10 measured by RT-qPCR (12 h treatment).
  • N 3-9).
  • I-L ECN90 cells were treated with TRP (10 mM), IFNa (25 ng/ml) or both.
  • HLA-ABC, PD-L1 and CXCL10 measured by RT-qPCR (12 h treatment).
  • Islets were prepared from 12-week-old C57BL/6 male mice and treated with TRP (10 mM), IFNy (250 pg/ml) or both.
  • A Pd-11 gene expression was measured by RT-qPCR (12 h treatment).
  • B-C Pd-11 was analyzed and quantified by Western blot (48 h treatment);
  • D h2(DLBlQl) was measured by RT-qPCR (12 h treatment).
  • E Flow cytometry plots of Pd-11 and MHC Class I and mean fluorescence intensity (MFI) on p cells from dispersed islet cells treated for 48 h as above. Gate on p cells was defined as CD71+CD49f+ among live Lin-EpCam+CD241ow cells.
  • FIG. 7 Effects of TRP on human islets.
  • FIG. 8 PD-L1 induction by TRP is AKT-dependent.
  • ECN90 cells were treated for 12 h with TRP (10 mM) with or without cycloheximide (50 pg/mL) or rapamycin (50 nM). PD-L1 was measured by RT-qPCR.
  • C Western blot of pSTATl, STAT1 and pAKT and
  • D pAKT/TUBULIN quantification in ECN90 cells treated with TRP, IFN-y or both for 12 h.
  • E, F PD-L1 was measured by RT-qPCR in ECN90 cells treated for 12 h with TRP (10 mM), with or without (E) the Akt inhibitor 10-DEBC (30 pM) or (F) the AKT activator PS48 (30 pM) or IGF-LR3 (100 ng/ml).
  • G-H Mean fluorescence intensity (MFI) ofPD-Ll and HLA-A2.
  • FIG. 9 TRP-treated ECN90 p cells downregulate activation and PD-1 expression of TCR-transduced Jurkat T cells.
  • B-C Percent positive cells expressing the indicated markers in non-transduced or anti-PPI TCR transduced Jurkat T cells.
  • N 10-15.
  • D Percent positive cells expressing the indicated markers in antiviral TCR transduced Jurkat T cells cultured with ECN90 cells pulsed or not with the viral peptide. **P ⁇ 0.01; ***P ⁇ 0.005.
  • gate is on TCR-transduced Jurkat cells (no gate for parental non-transduced cells shown in panel B, left).
  • Figure 10 Translation of STAT1 et IRF1 is inhibited by TRP treatment.
  • Figure 11 Insulin in pancreas after treatment by gavage of NOD mice.
  • NOD mice was treated with tryptophan at 0,5mg TRP/g mouse (TRP) or not (CT) for 1 week. Mice also received one dose of gavage per day.
  • A Absolute P cell mass in Non-Obese Diabetic (NOD, a T1D model) mice treated or not with TRP. Data are shown as mean ⁇ SEM of at least 3 independent experiments. **P ⁇ 0.01.
  • the human pancreatic P cell line ECN9036 (HLA-I haplotype: HLA-A*02:01/03:01, - B*40:01/49:01, -C*03:04/07:01) was cultured on plates coated with 1.2% Matrigel and 3 pg/ml fibronectin (both from Sigma- Aldrich) at 37°C in 5% CO2 in Advanced DMEM/F12 medium (Thermo Fisher Scientific) supplemented with 2% bovine serum albumin fraction V (Roche), 6.7 ng/ml sodium selenite, 10 mM nicotinamide (Calbiochem), 50 pM P-mercaptoethanol (Sigma- Aldrich), 100 U/ml penicillin and 100 pg/ml streptomycin (Thermo Fisher Scientific).
  • Human islets were provided by the Human islet core facility of St. Louis Hospital (APHP, France). They were obtained from pancreata of 8 brain-dead donors (mean age 35.5 ⁇ 10.75 years; BMI 27.5 ⁇ 2.05 kg/m2) with signed informed consents according to the procedures approved by the French Agency of Biomedicine. Donor and islet characteristics are presented in Supplemental Table 1. Islets were isolated, handpicked and cultured 48 h in 12-well plates (50-100 islets per well) in CMRL medium (Thermo Fisher Scientific) supplemented with 10% fetal calf serum, Hepes and penicillin/streptomycin (all from Thermo Fisher Scientific).
  • CMRL medium Thermo Fisher Scientific
  • RNA isolation, reverse transcription, and RT-qPCR RNA isolation, reverse transcription, and RT-qPCR.
  • Species-specific HRP -linked secondary antibodies were used for detection and visualization was performed on an ImageQuant LAS 4000 following ECL exposure (GE Healthcare). The blots were quantified using the Image J software and signal intensities were normalized to that of a-TUBULIN or P-ACTIN.
  • ECN90 cells were trypsinized, washed thrice in HBSS/1% BSA and incubated at 4 °C for 15 min in the dark with the antibodies diluted in HBSS medium/1% BSA (Gibco/Roche Diagnostics); PD-L1 (1/100, 329714, Biolegend), HLA-A2 (1/100, 3114410, Biolegend). Only fluorochrome-conjugated primary antibodies were used. Following rinsing in HBSS/1% BSA and incubation with FACS medium containing propidium iodide (1/4,000, Sigma-Aldrich), analysis was carried out using a FACS Aria III (BD Biosciences, San Jose, CA, USA). Dead cells (positive for propidium iodide) were excluded from analyses. Data were analyzed using FlowJo 10.7 software (RRID:SCR_008520). Results are expressed in mean fluorescence intensities fold changes relative to the control condition.
  • P-cells were prepared from 12-week-old mouse pancreatic islets as described51. Briefly, islets were isolated from C57BL/6JRj mouse pancreata by collagenase-P treatment, cultured overnight in RPMI 1640 medium, supplemented with 10% FCS and dispersed in a single cell suspension by incubation in 0.025% trypsin-EDTA (Thermo Fisher Scientific) at 37°C for 3 min. Cells were then incubated with antibodies in FACS medium (HBSS + 2% FCS) at 4°C for 15 min in the dark, rinsed and resuspended in FACS medium containing propidium iodide (1/4,000, Sigma-Aldrich).
  • FACS medium HBSS + 2% FCS
  • TCR-/- triple parameter TCR signaling reporter Jurkat cells were generated as described57,81. They were transduced with lentiviral vectors (Takara Bio) encoding human CD8 and TCRs recognizing HLA-A*02:01-restricted PPH5-2358 or HLA-A*03:01-restricted Coxsackievirus Bl 1356-1364 peptide. Transduction was obtained by spinoculation with ultracentrifugeconcentrated viral particles produced in 293T-HEK-TN cells (System Biosciences). Transduced cells were stained with anti-mouse TCRP antibody (RRID:AB_2738023), followed by FACS sorting of TCR+ cells.
  • TCR-transduced Jurkat T cells were co-cultured for 6 h with preconditioned ECN90 > cells at a 1 :2 Jurkat:ECN90 ratio, then collected, washed, and stained with PE-conjugated anti-human PD-1 antibody (RRID:AB_940483) and BV711 -conjugated anti-mouse TCRP antibody (RRID:AB_2738023). Cells were acquired on a BD FACS Fortessa cytometer and analyzed by Flowjo vl0.8.
  • TRP induces PD-L1 but not HLA-I expression in human p cells, thyroid cells and colonocyte cells.
  • Nthy-ori 3.124 an immortalized human primary thyroid follicular epithelial cell line named Nthy-ori 3.124 to test the effect of TRP. 12 hours TRP treatment of Nthy-ori 3.1 with TRP induced PD-L1 expression tested by RT-qPCR (Fig. II). We furthermore confirm the induction of PD-L1 via TRP in intestinal epithelium cell (i.e colonocyte) ( Figure 2A). Our results suggest at least an ubiquitous endodermic response to TRP activating PD-L1 expression.
  • TRP induces PD-L1 expression in human P-cells in an AhR-independent manner, to a similar extent to IFN-y, but, unlike IFN-y it does not upregulate HLA-I expression.
  • TRP is the only amino acid that robustly induces PD-L1 expression in human P-cells.
  • TRP -mediated PD-L1 induction could simply reflect a cellular stress status by testing osmotic (NaCl), oxidative (H2O2), corticoid (betamethazone) and endoplasmic reticulum (thapsigargin) stressors, but we did not observe any PD-L1 induction (data not shown).
  • TRP was required for PD-L1 induction by IFN-y by pre-incubating ECN90 P-cells with or without TRP for 24 h, followed by a 12 h IFN-y treatment.
  • TRP depletion did not impede IFN-y-induced PD- L1 expression (Fig. 3B).
  • TRP is the only AA that induces PD-L1 expression in cells in a stress-inpdependent manner.
  • TRP- derived amines induce PD-L1 expression.
  • TRP can be metabolized into a multitude of bioactive molecules through the kynurenine (KYN), serotonin (5-HT), and indole pathways (Data not shown). While the first two pathways are active in mammalian cells, the third one is mainly confined to the gut microbiota, leading to the production of most of the endogenous AhR agonists that exhibit local immunomodulatory effects.
  • KYN kynurenine
  • HT serotonin
  • indole pathways Data not shown.
  • the third one is mainly confined to the gut microbiota, leading to the production of most of the endogenous AhR agonists that exhibit local immunomodulatory effects.
  • DDC DOPA Decarboxylase
  • TRY indol-amine tryptamine
  • ISO Isopentylamine
  • Fig. 4E induced PD-L1
  • CYP1 Al CYP1 Al
  • TRP modulates P-cell responses and Caco2 cells to IFN-y
  • TRP either alone or in combination with IFN-y
  • HLA-E Fig. 5G
  • Fig. 5G a non-classical class lb molecule inhibiting NK- and T-cell cytotoxicity48.
  • IFN-y-induced the expression of CXCL10 a proinflammatory chemokine promoting the homing of immune cells to the islets
  • TRP co-treatment Fig. 5H
  • Similar effects were obtained with TRP in combination with IFN-a ( Figure 51- J). Similar effects were obtained with TRY (data not shown) and ISO (data not shown).
  • TRP TRP induced PD-L1 expression and synergized with IFN-y, at both the gene (Fig. 6A) and protein level (Fig. 6B-C).
  • Fig. 6A the gene of the gene
  • Fig. 6B-C protein level
  • TRP did not induce the HLA-I ortholog h2 in mouse islets, although it did not repress IFN-y-driven induction (Fig. 6D).
  • TRP induced Pd-11 presentation at the P-cell surface, an effect that was additive to that observed with IFN-y (Fig. 6E).
  • TRP repressed CxcllO induction by IFN-y (Fig. 6F).
  • PD-L1 induction by TRP is dependent on AKT activation.
  • PD-L1 induction by TRP did not require intermediate protein translation, since treatment of ECN90 cells with cycloheximide, a protein synthesis inhibitor, did not block this effect (Fig. 8A).
  • Fig. 8B We further ruled out the implication of the AA-sensing mTOR pathway, as treatment with the mTOR inhibitor rapamycin did not abrogate PD-L1 induction by TRP (Fig. 8B).
  • the STAT1 and AKT pathways are involved in PD-L1 expression.
  • Western blot analyses indicated that, while IFN-y induced STAT1 phosphorylation, TRP did not. Rather, TRP induced AKT phosphorylation (Fig. 8C-D) and the AKT inhibitor 10-DEBC53 blocked PD-L1 induction by TRP (Fig. 8E).
  • two AKT activators PS4854 (a PDK1 activator that induces AKT phosphorylation at Thr30855), and insulin-like growth factor- 1 long arginine 3 (IGF1-LR3) induced PD-L1 gene expression (Fig. 8F).
  • TRP protects ECN90 [!- cells from autoimmune T-cell recognition.
  • TCR T-cell receptor
  • NF AT eGFP reporter
  • CFP NF-KB
  • AP-1 AP-1
  • TCR recognizing either an HLA-A2 -restricted preproinsulin (PPI)i5-24 peptide (1E6 clone) or a viral HLA- A3 -restricted Coxsackievirus Bii356-i364 peptide as negative control.
  • PPI preproinsulin
  • Bii356-i364 peptide a viral HLA- A3 -restricted Coxsackievirus Bii356-i364 peptide
  • ECN90 P cells were preliminarily treated with TRP and IFN-y, alone or in combination, leading to synergistic PD-L1 induction and inhibition of IFN-y-induced HLA-I upregulation when combined (Fig. 9B), as previously observed.
  • TRP pre-treatment decreased NF AT, NF-KB and AP-1 activation as compared to untreated P cells.
  • the T-cell inhibitory effect of TRP was also evident in the presence of IFN-y.
  • PD-1 expression on Jurkat T cells also decreased upon exposure to TRP -treated ECN90 p cells.
  • Control parental non-transduced Jurkat T cells did not display any activation reporter signal nor PD-1 expression. The same was observed for control viral TCR-transduced Jurkat T cells (Fig. 9D), unless the cognate peptide was exogenously added. In this latter case, the T-cell inhibitory effect of TRP pre-treatment was similar to that observed with PPL 5-24 TCR-transduced Jurkat T cells.
  • TRP induces PD-L1 expression in human pancreatic P cells.
  • This AhR-independent effect relies on AKT signaling and is mimicked by catabolites of the TRY pathway.
  • TRP synergizes with IFN-y to induce PD-L1 and HLA-E, while inhibiting IFN-y-induced HLA-A2 and CXCL10 expression.
  • the two opposing effects of IFN-y namely the immunostimulatory induction of HLA-A2 and CXCL10 and the immune inhibitory upregulation of PD-L1 and HLA-E, can be skewed by TRP treatment toward a more therapeutically attractive immunoregulatory balance.
  • Most of these effects were reproduced in both mouse and human primary islets.
  • TRP shields P cells from autoimmune T- cell recognition we provide evidence that TRP shields P cells from autoimmune T- cell recognition.
  • TRP is the least abundant of all essential AA.
  • TRP an aromatic AA
  • GPR142 is a ligand for GPR142, a Gaq-coupled receptor. Through this receptor, TRP potentiates glucose-induced insulin secretion, promotes P-cell proliferation and protects from stress-induced apoptosis in mouse and human islets.
  • GPR142 is one of the most highly expressed GPCR.
  • PHE another aromatic AA that also signals through GPR142 did not mimic the effects of TRP on PD-L1 expression, suggesting that in our experiments, GPR142 was not engaged in PD-L1 induction.
  • TRP might thus enter P cells through LAT1 (SLC7A5) and its cofactor 4f2 Heavy Chain (SLC3A2/4f2HC), that are expressed in ECN90 P -cells, forming the heterodimer L-type AA transporter CD98.
  • LAT1 SLC7A5
  • SLC3A2/4f2HC cofactor 4f2 Heavy Chain
  • TRP undergoes an extensive metabolism along several pathways, giving rise to many metabolites that significantly affect physiological homeostasis. TRP metabolism in p cells is not fully defined, and we systematically screened for TRP pathways/metabolites that could activate PD-L1. Tryptamin (TRY) mimicked the effects of TRP. TRY is an indolamine produced through DOPA decarboxylase (DCC), an enzyme expressed by P cells that decarboxylates aromatic AA. TRY attenuates pro-inflammatory responses in murine macrophages in an AhR-dependent manner. Our data indicate major similarities between TRP and TRY. They both activate PD-L1 in an AhR-independent manner. We thus propose that TRP activates PD-L1 through TRY.
  • DCC DOPA decarboxylase
  • TRY was recently shown to signal through trace amine- associated receptor 1 (TAAR1) a Gas-coupled receptor expressed in p cells to increase glucosedependent insulin secretion.
  • TAAR1 trace amine- associated receptor 1
  • IFN of both type I (IFN-a) and II (IFN-y) are canonic inducers of PD-L1. They signal through the JAK/STAT1 pathway, inducing translation of interferon regulatory factor 1 (IRF1). STAT1 and IRF1 next synergize to increase the transcription of PD-L173.
  • IRF1 and IRF1 next synergize to increase the transcription of PD-L173.
  • TRP and IFN-y act through different signals, namely the AKT and STAT1 pathways, respectively.
  • PD-L1 has previously been shown to be induced by the PI3K/AKT/mTOR signaling. For example, in human glioma, activation of PI3K/AKT by down-regulating its inhibitor PTEN induces PD-L1.
  • AKT/mTOR pathway is associated with cell proliferation and survival.
  • AKT activators such as IGF-I and PS48 replicate the TRP effect on PD-L1 induction.
  • IGF-I and PS48 replicate the TRP effect on PD-L1 induction.
  • TRP in addition to its induction of PD-L1, induced the expression of HLA-E, a non-polymorphic HLA-I molecules, known to inhibit NK and T-cell cell-mediated lysis.
  • TRP blunted the upregulation of HLA-I by IFN-y This effect resembles the one observed following loss of IRF2 in cancers that decreased HLA-I, while increasing PD-L1 expression.
  • TRP repressed IFN-y induction of the chemokine CXCL10 which may decrease the homing of CD8+ T cells to the islets. All these effects could potentially synergize to inhibit autoimmune responses.
  • NOD mice non-obsese diabetic mice, a well-known T1D mouse model.
  • NOD Mice was treated with tryptophan at 0,5mg TRP/g mouse (TRP) or not (CT) for 1 week. Mice also received one dose of gavage per day.
  • TRP TRP/g mouse
  • CT CT
  • mice all the mice show insulitis and 95 % of the mice will be diabetic at 16 weeks.
  • TRP treatment at 15 weeks, we observed first a protection of the beta cell mass (Figure 11 A).
  • Figure 1 IB We also observed a clear limitation of the development of the insulitis in islet. No mice under TRP treatment were diabetic.
  • Trophoblast CD274 (B7-H1) is differentially expressed across gestation: influence of oxygen concentration. Biol Reprod 74, 352-358 (2006).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Organic Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Biochemistry (AREA)
  • Virology (AREA)
  • Mycology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Malgré la progression significative qui a été faite dans son traitement, le diabète auto-immun constitue une charge grave sur les individus affectés ainsi que sur la société. L'arrêt ou même le ralentissement d'une destruction plus avancée des cellules β peut conduire à une période de rémission prolongée et à retarder les complications liées au diabète. Le système PD-1-PDL1 est crucial pour la préservation de la tolérance aux antigènes de cellules bêta pancréatiques et, s'il est rompu, la perte de cellules bêta à médiation immunitaire peut se poursuivre plus rapidement chez les individus génétiquement prédisposés. En conséquence, l'augmentation de l'expression de PDL1 sur des cellules β pancréatiques peut constituer une stratégie appropriée pour le traitement du diabète de type 1. Les inventeurs démontrent maintenant que des donneurs de pentylamine tels que le tryptophane peuvent augmenter l'expression de PDL1 sur des cellules β pancréatiques sans augmenter l'expression de molécules de classe I du CMH. Ils confirment ces observations dans les îlots humains. En conséquence, la présente invention concerne l'utilisation de donneurs de pentylamine pour le traitement du diabète de type 1.
PCT/EP2024/060179 2023-04-14 2024-04-15 Utilisation de donneurs de pentylamine pour le traitement de troubles auto-immuns Pending WO2024213794A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23305576.3 2023-04-14
EP23305576 2023-04-14

Publications (1)

Publication Number Publication Date
WO2024213794A1 true WO2024213794A1 (fr) 2024-10-17

Family

ID=86382879

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/060179 Pending WO2024213794A1 (fr) 2023-04-14 2024-04-15 Utilisation de donneurs de pentylamine pour le traitement de troubles auto-immuns

Country Status (1)

Country Link
WO (1) WO2024213794A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009067349A2 (fr) * 2007-11-20 2009-05-28 The Brigham And Women's Hospital, Inc. Modulation de la réponse immunitaire
US20120129783A1 (en) * 2002-08-09 2012-05-24 Anthony Cincotta Therapeutic process for the treatment of the metabolic syndrome and associated metabolic disorders
US20150139994A1 (en) * 2013-11-12 2015-05-21 The Regents Of The University Of California Compositions and methods for preventing allogeneic immune rejection
WO2019118641A1 (fr) * 2017-12-12 2019-06-20 The Regents Of The University Of California Conservation de greffes d'îlots pancréatiques dans l'espace extrahépatique
WO2019175381A1 (fr) * 2018-03-16 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Peptides antigéniques dérivés de pcsk2 et leurs utilisations pour le diagnostic et le traitement du diabète de type 1

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120129783A1 (en) * 2002-08-09 2012-05-24 Anthony Cincotta Therapeutic process for the treatment of the metabolic syndrome and associated metabolic disorders
WO2009067349A2 (fr) * 2007-11-20 2009-05-28 The Brigham And Women's Hospital, Inc. Modulation de la réponse immunitaire
US20150139994A1 (en) * 2013-11-12 2015-05-21 The Regents Of The University Of California Compositions and methods for preventing allogeneic immune rejection
WO2019118641A1 (fr) * 2017-12-12 2019-06-20 The Regents Of The University Of California Conservation de greffes d'îlots pancréatiques dans l'espace extrahépatique
WO2019175381A1 (fr) * 2018-03-16 2019-09-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Peptides antigéniques dérivés de pcsk2 et leurs utilisations pour le diagnostic et le traitement du diabète de type 1

Non-Patent Citations (56)

* Cited by examiner, † Cited by third party
Title
AGHAZADEH YASAMAN ET AL: "Cell Therapy for Type 1 Diabetes: Current and Future Strategies", CURRENT DIABETES REPORTS, CURRENT SCIENCE, PHILADELPHIA, VA, US, vol. 17, no. 6, 21 April 2017 (2017-04-21), pages 1 - 9, XP036240592, ISSN: 1534-4827, [retrieved on 20170421], DOI: 10.1007/S11892-017-0863-6 *
AGHAZADEH YNOSTRO MC: "Cell Therapy for Type 1 Diabetes: Current and Future Strategies", CURR DIAB REP., vol. 17, no. 6, 2017, pages 37, XP036240592, DOI: 10.1007/s11892-017-0863-6
AGUIRRE JEBESWICK EJGRIM CURIBE GTAFOYA MCHACON PALMA GSAMEDI VMCKEE RVILLEGER RFOFANOV Y: "Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn's disease and regulate Thl/Thl7 cell responses", INT IMMUNOL., vol. 32, no. 1, 9 January 2020 (2020-01-09), pages 57 - 68
ANDERSON, A. M. ET AL.: "Human islet T cells are highly reactive to preproinsulin in type 1 diabetes", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 118, 2021, pages e2107208118, XP055966301, DOI: 10.1073/pnas.2107208118
ARANA MKUMAR AASHWATHNARAYAN AATARI MBARAJAS M: "Type 1 Diabetes Treatments Based on Stem Cells", CURR DIABETES REV., vol. 14, no. 1, 2018, pages 14 - 23
BATRA, L. ET AL.: "PD-L1-engineered pancreatic islet grafts overcome rejection in allogeneic recipients", THE JOURNAL OF IMMUNOLOGY, vol. 200, 2018
BITTINGER, M. A.NGUYEN, L. P.BRADFIELD, C. A.: "Aspartate aminotransferase generates proagonists of the aryl hydrocarbon receptor", MOLPHARMACOL, vol. 64, 2003, pages 550 - 556
BJORKMANPARHAM, ANNU. REV. BIOCHEM., vol. 59, 1990, pages 253 - 288
BONELLI, M.DALWIGK, K.PLATZER, A. ET AL.: "IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes", EXP MOL MED, vol. 51, 2019, pages 1 - 11
BRAHMER, J. R. ET AL.: "Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates", J CLIN ONCOL, vol. 28, 2010, pages 3167 - 3175, XP055124332, DOI: 10.1200/JCO.2009.26.7609
CARRE, A.RICHARDSON, S. J.LARGER, E.MALLONE, R.: "Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset?", DIABETOLOGIA, vol. 64, 2021, pages 15 - 25, XP037311139, DOI: 10.1007/s00125-020-05298-y
COELHO, M. A. ET AL.: "Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA", IMMUNITY, vol. 47, 2017, pages 1083 - 1099
COPPIETERS, K. T. ET AL.: "Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients", J EXP MED, vol. 209, 2012, pages 51 - 60, XP093118660, DOI: 10.1084/jem.20111187
DIMEGLIO, L. A.EVANS-MOLINA, C.ORAM, R. A.: "Type 1 diabetes", THE LANCET, vol. 391, 2018, pages 2449 - 2462
DINATALE, B. C. ET AL.: "Kynurenic Acid Is a Potent Endogenous Aryl Hydrocarbon Receptor Ligand that Synergistically Induces Interleukin-6 in the Presence of Inflammatory Signaling", TOXICOL SCI, vol. 115, 2010, pages 89 - 97
DONG, H. ET AL.: "Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion", NAT MED, vol. 8, 2002, pages 793 - 800, XP002397368, DOI: 10.1038/nm730
EL KHATIB M M ET AL: "[beta]-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection", GENE THERAPY, NATURE PUBLISHING GROUP, LONDON, GB, vol. 22, no. 5, 19 March 2015 (2015-03-19), pages 430 - 438, XP036974083, ISSN: 0969-7128, [retrieved on 20150319], DOI: 10.1038/GT.2015.18 *
FAROOQ TREHMAN KHAMEED AAKASH MSH: "Stem Cell Therapy and Type 1 Diabetes Mellitus: Treatment Strategies and Future Perspectives", ADV EXP MED BIOL., vol. 1084, 2019, pages 95 - 107
GARCIA-DIAZ, A. ET AL.: "Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression", CELL REP, vol. 19, 2017, pages 1189 - 1201, XP055848328, DOI: 10.1016/j.celrep.2017.04.031
GERMAIN, CELL, vol. 76, 1994, pages 287 - 299
GULERIA, I. ET AL.: "A critical role for the programmed death ligand 1 in fetomaternal tolerance", J EXP MEDIAL, 2005, pages 231 - 237
HABICHT, A. ET AL.: "A link between PDL1 and T regulatory cells in fetomaternal tolerance", J IMMUNOL, vol. 179, 2007, pages 5211 - 5219
HEATH-PAGLIUSO, S. ET AL.: "Activation of the Ah receptor by tryptophan and tryptophan metabolites", BIOCHEMISTRY, vol. 37, 1998, pages 11508 - 11515
HOLETS, L. M.HUNT, J. S.PETROFF, M. G.: "Trophoblast CD274 (B7-H1) is differentially expressed across gestation: influence of oxygen concentration", BIOL REPROD, vol. 74, 2006, pages 352 - 358
HU, X.LI, J.FU, M. ET AL.: "The JAK/STAT signaling pathway: from bench to clinic", SIG TRANSDUCT TARGET THER, vol. 6, 2021, pages 402, XP055925222, DOI: 10.1038/s41392-021-00791-1
INSEL RADUNNE JLATKINSON MACHIANG JLDABELEA DGOTTLIEB PAGREENBAUM CJHEROLD KCKRISCHER JPLERNMARK A: "Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association", DIABETES CARE, vol. 38, no. 10, October 2015 (2015-10-01), pages 1964 - 74, XP093020124, DOI: 10.2337/dc15-1419
IWAI, Y. ET AL.: "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade", PROC NATL ACAD SCI U S A, vol. 99, 2002, pages 12293 - 12297, XP055572034, DOI: 10.1073/pnas.192461099
KOTWAL AKOTTSCHADE LRYDER M: "PD-L1 Inhibitor-Induced Thyroiditis Is Associated with Better Overall Survival in Cancer Patients", THYROID, vol. 30, no. 2, February 2020 (2020-02-01), pages 177 - 184, XP055860678, DOI: 10.1089/thy.2019.0250
LASTWIKA, K. J. ET AL.: "Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer", CANCER RES, vol. 76, 2016, pages 227 - 238, XP055600222, DOI: 10.1158/0008-5472.CAN-14-3362
M. J. I. ANSARI ET AL: "The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice", JOURNAL OF EXPERIMENTAL MEDICINE, vol. 198, no. 1, 30 June 2003 (2003-06-30), pages 63 - 69, XP055188563, ISSN: 0022-1007, DOI: 10.1084/jem.20022125 *
MA RLATIF RDAVIES TF: "Human embryonic stem cells form functional thyroid follicles", THYROID, vol. 25, no. 4, April 2015 (2015-04-01), pages 455 - 61, XP055924378, DOI: 10.1089/thy.2014.0537
MAIKEL L. COLLI ET AL: "PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-? and-? via IRF1 induction", EBIOMEDICINE, vol. 36, 1 October 2018 (2018-10-01), NL, pages 367 - 375, XP055757710, ISSN: 2352-3964, DOI: 10.1016/j.ebiom.2018.09.040 *
MATSUMURA ET AL., SCIENCE, vol. 257, 1992, pages 927 - 934
MATTA BSONG SLI DBARNES BJ: "Interferon regulatory factor signaling in autoimmune disease", CYTOKINE, vol. 98, October 2017 (2017-10-01), pages 15 - 26, XP085186616, DOI: 10.1016/j.cyto.2017.02.006
MILLER, C. A.: "Expression of the human aryl hydrocarbon receptor complex in yeast. Activation of transcription by indole compounds", JBIOL CHEM, vol. 272, 1997, pages 32824 - 32829
MITTENDORF, E. A. ET AL.: "PD-L1 expression in triple-negative breast cancer", CANCER IMMUNOL RES, vol. 2, 2014, pages 361 - 370, XP002756567, DOI: 10.1158/2326-6066.CIR-13-0127
OGUNDIPE ILMLGROEN AHHOSPER ANAGLE PWKHESS JFABER HJELLEMA ALBAANSTRA MLINKS TPUNGER K: "Generation and Differentiation of Adult Tissue-Derived Human Thyroid Organoids", STEM CELL REPORTS, vol. 16, no. 4, 13 April 2021 (2021-04-13), pages 913 - 925, XP055925418, DOI: 10.1016/j.stemcr.2021.02.011
OSTRAND-ROSENBERG, S.HORN, L. A.HAILE, S. T.: "The Programmed Death-1 Immune Suppressive Pathway: Barrier to Anti-Tumor Immunity", J IMMUNOL, vol. 193, 2014, pages 3835 - 3841
PARSA, A. T. ET AL.: "Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma", NAT MED, vol. 13, 2007, pages 84 - 88
PELLEGRINI SPIEMONTI LSORDI V.: "Pluripotent stem cell replacement approaches to treat type 1 diabetes", CURR OPIN PHARMACOL., vol. 43, 2018, pages 20 - 26, XP085555109, DOI: 10.1016/j.coph.2018.07.007
PETROFF, M. G.CHEN, L.PHILLIPS, T. A.HUNT, J. S.: "B7 family molecules: novel immunomodulators at the maternal-fetal interface", PLACENTA, vol. 23, 2002, pages 95 - 101
POLAND, A.GLOVER, E.KENDE, A. S.: "Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 251, 1976, pages 4936 - 4946
POSABELLA AALBER ABUNDEUTSCH HJDROESER RAHOLLENBERG ANIKONOMOU LKOTTON DN: "Derivation of Thyroid Follicular Cells From Pluripotent Stem Cells: Insights From Development and Implications for Regenerative Medicine", FRONT ENDOCRINOL (LAUSANNE), vol. 12, 20 April 2021 (2021-04-20), pages 666565
PUGLIESE, A.: "Autoreactive T cells in type 1 diabetes", J CLIN INVEST, vol. 127, 2017, pages 2881 - 2891, XP093063718, DOI: 10.1172/JCI94549
PULKO, V. ET AL.: "TLR3-stimulated dendritic cells up-regulate B7-H1 expression and influence the magnitude of CD8 T cell responses to tumor vaccination", J IMMUNOL, vol. 183, 2009, pages 3634 - 3641
RACHDI LATIF ET AL: "Tryptophan metabolism promotes immune evasion in human pancreatic [beta] cells", EBIOMEDICINE, vol. 95, 1 September 2023 (2023-09-01), NL, pages 104740, XP093079025, ISSN: 2352-3964, DOI: 10.1016/j.ebiom.2023.104740 *
SHAWAR ET AL., ANNU. REV. IMMUNOL., vol. 12, 1994, pages 839 - 880
STAMATOULI, A. M. ET AL.: "Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors", DIABETES, vol. 67, 2018, pages 1471 - 1480
TUKEY, R. H., HANNAH, R. R., NEGISHI, M., NEBERT, D. W. & EISEN, H. J.: "correlation of intranuclear appearance of inducer-receptor complex with induction of cytochrome P1-450 mRNA", CELL, vol. 31, 1982, pages 275 - 284, XP023912023, DOI: 10.1016/0092-8674(82)90427-5
WANG, G.-Z. ET AL.: "The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy", NAT COMMUN, vol. 10, 2019, pages 1125
WEI, Y. D.BERGANDER, L.RANNUG, U.RANNUG, A.: "Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo[3,2-b]carbazole", ARCH BIOCHEM BIOPHYS, vol. 383, 2000, pages 99 - 107
XU, C. ET AL.: "Loss of Lkb 1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated PD-L1 Expression", CANCER CELL, vol. 25, 2014, pages 590 - 604, XP055203792, DOI: 10.1016/j.ccr.2014.03.033
XUE, V. W. ET AL.: "Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity", CANCERS (BASEL), vol. 12, 2020, pages 3099
YAMAGUCHI, H.HSU, J.-M.YANG, W.-H.HUNG, M.-C.: "Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics", NAT REV CLIN ONCOL, vol. 19, 2022, pages 287 - 305, XP037807475, DOI: 10.1038/s41571-022-00601-9
YOSHIHARA, E. ET AL.: "Immune-evasive human islet-like organoids ameliorate diabetes", NATURE, vol. 586, 2020, pages 606 - 611, XP037277118, DOI: 10.1038/s41586-020-2631-z
ZHANG, X. ET AL.: "Engineered PD-L1-Expressing Platelets Reverse New-Onset Type 1 Diabetes", ADV MATER, vol. 32, 2020, pages 1907692

Similar Documents

Publication Publication Date Title
AU2018389346B2 (en) Artificial antigen presenting cells and methods of use
US9018006B2 (en) Stable Tregs and related materials and methods
ES2693645T3 (es) Uso de IL-2 a baja dosis para tratar la diabetes tipo 1
ES2811624T3 (es) Régimen de dosificación de IL-2 para tratar lupus eritematoso sistémico
Podojil et al. Targeting the B7 family of co-stimulatory molecules: successes and challenges
Lerret et al. Donor-specific CD8+ Foxp3+ T cells protect skin allografts and facilitate induction of conventional CD4+ Foxp3+ regulatory T cells
Mandrup-Poulsen et al. Cytokines as immune effector molecules in autoimmune endocrine diseases with special reference to insulin-dependent diabetes mellitus
Jung et al. Induction of IL-10 in rat peritoneal macrophages and dendritic cells by glatiramer acetate
JP2547162B2 (ja) 哺乳動物における異系移植片拒否反応を抑制するための方法と組成物
Rachdi et al. Tryptophan metabolism promotes immune evasion in human pancreatic β cells
Corrigall et al. Binding immunoglobulin protein‐treated peripheral blood monocyte‐derived dendritic cells are refractory to maturation and induce regulatory T‐cell development
Lu et al. Dextran sulfate protects pancreatic β-cells, reduces autoimmunity, and ameliorates type 1 diabetes
Dalle et al. Receptors and signaling pathways controlling beta-cell function and survival as targets for anti-diabetic therapeutic strategies
Barra et al. Localized cytotoxic T cell–associated antigen 4 and antioxidant islet encapsulation alters macrophage signaling and induces regulatory and anergic T cells to enhance allograft survival
Ruiz-Pablos et al. Hypocortisolemic ASIA: a vaccine-and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis
WO2024213794A1 (fr) Utilisation de donneurs de pentylamine pour le traitement de troubles auto-immuns
US20210322476A1 (en) Compositions and methods for immunosuppression
US20240226168A1 (en) Engineered nk cells and uses thereof
US20200354678A1 (en) T-REG Cell Expansion
US20230107770A1 (en) Method of enhancing immunotherapy using er stress pathway inhibitors
Ye et al. Indoleamine 2, 3-dioxygenase and inducible nitric oxide synthase mediate immune tolerance induced by CTLA4Ig and anti-CD154 hematopoietic stem cell transplantation in a sensitized mouse model
Faustman TNF, BCG, and the proteasome in autoimmunity: an overview of the pathways & results of a Phase I study in type 1 diabetes
Kalovidouris Mechanisms of inflammation and histopathology in inflammatory myopathy
CA3174673A1 (fr) Inhibiteurs de monoamine oxydase en tant que modificateurs de la vulnerabilite des cellules beta dans le diabete de type 1
EP3958887B1 (fr) Procédures médicales d'induction ou de récupération de la tolérance immunitaire

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24717245

Country of ref document: EP

Kind code of ref document: A1