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WO2004006950A2 - Utilisation de cd152 pour le traitement de maladies auto-immunes et d'inflammations - Google Patents

Utilisation de cd152 pour le traitement de maladies auto-immunes et d'inflammations Download PDF

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Publication number
WO2004006950A2
WO2004006950A2 PCT/EP2003/007665 EP0307665W WO2004006950A2 WO 2004006950 A2 WO2004006950 A2 WO 2004006950A2 EP 0307665 W EP0307665 W EP 0307665W WO 2004006950 A2 WO2004006950 A2 WO 2004006950A2
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Prior art keywords
cells
use according
disease
inflammation
autoimmune
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PCT/EP2003/007665
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German (de)
English (en)
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WO2004006950A3 (fr
Inventor
Monika Brunner-Weinzierl
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Charite Universitaetsmedizin Berlin
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Universitatsklinikum Charite Berlin
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Priority to DE10392933T priority Critical patent/DE10392933B4/de
Priority to AU2003250958A priority patent/AU2003250958A1/en
Publication of WO2004006950A2 publication Critical patent/WO2004006950A2/fr
Publication of WO2004006950A3 publication Critical patent/WO2004006950A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • CD152 for the treatment of autoimmune diseases and inflammation
  • the invention relates to the use of inhibitory coreceptors on T cells, PD-1, BTLA and CD152, in particular CD152 or CTLA-4
  • autoimmune diseases or autoaggressive diseases are diseases in which autoantibodies directed against the body's own substances or specifically sensitized lymphocytes occur in the
  • Pathogenesis play an essential role.
  • the cause of autoimmunization is the abolition of the immune tolerance to the body's own tissues as a result of disorders of self-recognition or the control and regulation mechanisms of the immune system.
  • the autoimmune diseases can be divided into organ-specific, non-organ-specific and mixed or transitional forms. organ-specific organ-specific
  • Autoimmune diseases affect, for example, the thyroid (e.g. Hashimoto's thyroiditis), the stomach (e.g. pernicious anemia) or the pancreas (e.g. juvenile diabetes mellitus).
  • Non-organ-specific autoimmune diseases affect, for example, the joints (e.g. rheumatoid arthritis) or the muscles (e.g. dermatomyositis).
  • Mixed or transitional forms of autoimmune diseases include Werlhof disease, Goodpasture syndrome or autoimmune hemolytic anemia.
  • Autoimmune diseases often require substitution treatment, possibly a transplant. If the disease is in its early stages, it is possible to replace the function of the organs damaged by the autoimmune lesions in such a way that hormones are given; In the case of hypothyroidism, the missing thyroid hormone is replaced with thyroxine.
  • the invention lies. therefore the task of providing means that can be used for the efficient treatment of autoimmune diseases, inflammation and unwanted immune responses.
  • the invention solves this problem by using CD152 for the treatment of autoimmune diseases and inflammation (Fig.e 1-9).
  • CD152 or the B7 receptor CTLA-4 is an opponent to the CD28-B7 receptor molecule and therefore takes on a "master switch function" in the immunological process of T-cell activation and Proliferation.
  • Other important molecules that counteract, ie inhibit, the stimulation and activation of T cells are PD-1 (or programmed cell death 1) and BTLA (or B and T lymphocyte attenuator), which can be expressed by T cells.
  • PD-1 or programmed cell death 1
  • BTLA or B and T lymphocyte attenuator
  • BTLA is mainly expressed on Thl cells.
  • BTLA deficient T cells show increased cell division.
  • T cell activation Most immune responses in the specific immune system are dependent on T cell activation. Any activation of these cells necessarily requires at least two signals, which must be transmitted by the antigen-presenting cell. The first is through the binding of the antigen presented on an MHC molecule to a specific T cell receptor. The second - the so-called costimulation - results from a second contact between the two cells involved via the B7 molecule on the antigen-presenting cell and CD28 - a B7 receptor - on the T cell.
  • CTLA-4 or CD152 is also a B7 receptor molecule and at the same time a direct opponent to CD28. It is a lymphocyte-specific marker that is expressed by cell activation on the surface and accumulated intracellularly. Due to the 20-fold higher affinity for B7 - compared to CD28 - it largely prevents the absolutely necessary costimulation.
  • the "master switch" function of CD152 results from the control of the immune response: hyperergy - normergy - anergy. Mice without genetic information for CD152 develop lymphoproliferative disease very quickly. There is evidence of a connection between the course of infectious diseases and the expression of CTLA-4, for example HIV infection is influenced by CD152. It is known that, in particular, the T cells of HIV patients have an increased expression of CTLA-4. There is also a clear connection with chemokine receptor expression and thus the spread of the infection in the organism. There were therefore considerations to lower the level of CD152 or to block the interaction with CD152 with its ligands in order to have a positive influence on the course of the disease, for example in the case of bacterial sepsis.
  • CD152 preferably CD152 + T cells or of PD-1 or BTLA
  • CD152Ig CTL-4Ig
  • the CD152 + T cells prevent the activation and stimulation of other, preferably inflammatory, T cells; they inhibit activation, cytokine secretion, proliferation and / or the migration.
  • the CD 152+ T cells produce no or less inflammatory cytokines, the cell division is reduced and the inflammation is stopped. Switching off in the sense of the invention relates to all biological or chemical processes which can lead to other T cells having a lower activity. Such an operation is different from blocking a CD 152 receptor by CTLA-41g.
  • the invention is therefore based on the surprising teaching that autoimmune diseases or inflammations, in particular chronic ones, can be treated by the administration of CD152 (FIGS. 1-9).
  • CD152 can be administered directly or in such a way that cells are used on or in which CD152 (FIG. 9) occurs.
  • PD-1, BTLA, but in particular CD152 or the cells comprising CD152 to be produced a medicine used to treat autoimmune diseases or inflammation and unwanted immune responses.
  • T cells In chronic inflammation or a significant part of autoimmune diseases, T cells, which should be limited in their activity by regulating mechanisms, are permanently activated. This maintains the inflammatory process. With the use of CD152 according to the invention, it is possible for the first time to specifically reduce or switch off this process of inflammation or autoimmunity.
  • PDl or BTLA can first be prepared in vitro or immediately in vivo in the patient.
  • PD-1 or BTLA-expressed cells can be used and to introduce them into the patient that were previously generated outside the patient.
  • the cells can be harvested from the patient's focus of inflammation, isolated, and multiplied for use or from another source; for example, it can be immunocompetent cells, such as inflammatory cells; which are treated in such a way that PD1 or / and BTLA are induced on them or transfected into them.
  • the induction of CD152 on T cells takes place in particular with TRAIL, TGFb, IL -10, Cystation, vitamin D and its derivatives, IL-15 or anti-PD-1 antibodies.
  • CD152 can first be prepared in vitro or immediately in vivo in the patient (FIG. 9). For example, it is possible to use CD152-expressed cells and to introduce them into the patient, which were previously generated outside the patient.
  • the cells can be harvested from the patient's focus of inflammation, isolated, and multiplied for use or from another source; for example, it can be immunocompetent cells, such as inflammatory cells; they are treated so that CD152 is induced on them or transfected into them. It is of course also possible to provide a context in vivo which leads to an expansion of CD152 + cells or to an induction of “.CD152.
  • the induction of CD152 on T cells takes place in particular with TRAIL, TGFb, IL-10, Cystation, VitaminD and its derivatives, statins, IL-15 or anti-PD-1 antibodies.
  • CD152 + T cells from immune responses that are already running in order to return them to the patient after in vitro enrichment (FIGS. 1, 2, 4 and 5).
  • Autologous T cells can be stimulated in vitro alone or in combination with other cells or taken ex vivo from an inflammation site on the patient, then enriched in vitro and returned to the patient.
  • the autoimmune disease or inflammation in particular chronic inflammation, or also chronic immune response, is an atiglomerular basement membrane disease, autoimmune diseases of the nervous system, a systemic lupus erythematosus, an Addison's disease, an antiphospholipid syndrome, an IgA glomerulononephritis, a good Syndrome, ' a Lambert-Eaton myasthenia syndrome, a bullous pemphigoid, a thrombocytopenic, idiopathic purpura, an autoimmune thyroiditis, a rheumatoid arthritis, an insulin-dependent diabetes mellitus, a pemphigus, an inflammatory bowel disease, an inflammation, a collagen an undesirable immune reaction such as sepsis, autoimmune hemolytic anemia, dermatitis herpetiformis Duhring, membranous glomerulonephritis, Graves disease, sympathetic ophthalmia.... an autoimmune polyendocrinopathy
  • the disease or inflammation is a disease associated with rheumatism, in particular rheumatoid arthritis.
  • rheumatism in particular rheumatoid arthritis.
  • Preference is furthermore given to the treatment of inflammatory bowel diseases such as Crohn's disease and / or ulcerative colitis, of collagenoses such as sclerodomy and / or Sjörgen's syndrome, of inflammations such as chronic hepatitis C and / or of rheumatic diseases
  • MS multiple sclerosis
  • thrombocytopenia is also preferred
  • the CD152 is used as a CD152 + cell, preferably as a CD152 + T cell (FIG. 9). It could be shown according to the invention that isolated CD152 + T cells advantageously keep CD152 on their surface (FIG. 1).
  • the cell can in particular be a cell expressing surface CD152.
  • the CD152 + T cell can advantageously be cells which have been isolated from an inflammatory focus of the patient (FIG. 5) or cells which have been generated by in vitro stimulation of PBMCs (FIGS. 1, 2, 4) and 6).
  • the cells obtained in this way can advantageously be enriched so that they can then be used directly or for the production of an agent for the treatment of autoimmune diseases or inflammations.
  • CD152 + T cells are able to inactivate other cells, especially immune-associated cells (FIGS. 2, 6 and 7).
  • CD4 + CD25 + regulatory cells are present in the periphery and can prevent autoimmunity.
  • the CD152 + T cells which arise from the CD4 + CD25 + T cells advantageously do not have to use CD152 exclusively for their inhibitory function; here it is in particular a marker, whereby it can be used for the inhibitory function.
  • direct cell-cell contact is particularly important Target cell required (Fig. 7 and 8); Soluble factors such as pleiotropic cytokines can be excluded as a primary mechanism.
  • CD25 + T reg cells express CD152 and keep it on the surface for a long time after activation. This property advantageously makes it possible to separate regulatory T cells from inflammatory T cells during an already established immune response.
  • the separated and isolated cells can be applied to the patient especially in the event of relapse, and the same applies to other molecules from the group of inhibitory molecules: PD-1 and BTLA.
  • CD152 is induced in immunocompetent cells, preferably inflammatory T cells, the induction preferably being carried out ex vivo. Induction can take place by transfection of immunocompetent cells, in particular with TRAIL, TGFb, IL-10, statins, cystation, vitamin D and / or its derivatives, IL-15 or anti-PD-1 antibodies.
  • the CD152 + T cells are isolated directly ex vivo from a patient's focus of inflammation, expanded in vitro and returned to an inflammatory focus. It may be advantageous to isolate the CD152 + T cells in vitro from autologous PBMCs, the PBMCs containing 0.05 ⁇ g / ml - 10 ⁇ g / ml anti-CD3, 0.05 ⁇ g / ml - 10 ⁇ g / ml SEB or 0.05 ⁇ g / ml - 10 ⁇ g / ml anti-CD3 / 0.05 ⁇ g / ml - 10 ⁇ g / ml anti-CD28.
  • ⁇ g / ml anti-CD3, 1 ⁇ g / ml SEB and / or 1 ⁇ g / ml anti-CD28 is very particularly preferred to use more than 1 ⁇ g / ml anti-CD3, 1 ⁇ g / ml SEB and / or 1 ⁇ g / ml anti-CD28.
  • the amount can be determined by a person skilled in the art through routine tests. For example, by taking samples or aliquots at regular or irregular intervals and determining the desired parameters therein.
  • the CD152 + T cells are isolated after 48 h to 7 days, preferably after 2 to 3 days.
  • CD152 is of course also possible to generate or induce CD152, PD-1 and BTLA by transfection in the cells, CD152 being particularly preferred.
  • the transfection can take place physically, chemically and / or biologically.
  • the physical transfection can take place in particular by means of electroporation.
  • the DNA encoded for CD152 is injected subcutaneously in an inflammatory focus and the electrical impulse is applied to the skin via a clip.
  • the chemical transfection of CD152 plasmid constructs is mediated in particular by the presence of DEAE dextran, sodium phosphate or dendrimers.
  • the biological transfection of plasmids, cosmids or other vectors comprising CD152 ' or CD152 - including gold particles - is advantageously possible via receptor-mediated gene transfer, lipotection or retrovival transfection or other viral uptake mechanisms. The same applies to other molecules from the group of inhibitory molecules: PD-1 and BTLA.
  • the invention further relates to compositions for therapeutic, prophylactic or diagnostic purposes comprising at least one CD152 T cell, preferably CD 152+ T cell, PD-1 and / or BTLA in a suitable, in particular a pharmaceutically suitable form or composition.
  • the pharmaceutical composition includes in particular additional substances and substances, for example medical and / or pharmaceutical auxiliary substances.
  • additional substances and substances for example medical and / or pharmaceutical auxiliary substances.
  • these compositions for ex vivo diagnostics which can contain additional substances and substances.
  • Medicaments or pharmaceutical compositions which are used synonymously in the present case are substances and preparations made of substances which are intended, by application to or in the human body, to cure, alleviate or prevent illnesses, physical damage or pathological complaints.
  • medical auxiliaries are substances which are used for production as active ingredients of pharmaceuticals.
  • Pharmaceutical-technical auxiliaries serve for the suitable formulation of the medicament or the pharmaceutical composition and can even, if they are only required during the production process, be subsequently removed or can be part of the pharmaceutical composition as a pharmaceutically acceptable carrier.
  • the pharmaceutical formulation or formulation of the pharmaceutical composition is optionally carried out in combination with an pharmaceutically acceptable carrier and / or diluent.
  • Suitable pharmaceutically acceptable carriers include, for example, phosphate-buffered saline solutions, water, emulsions such as, for example, oil / water emulsions, various types of detergents, sterile solutions, etc.
  • Medicaments or pharmaceutical compositions which comprise such carriers can be formulated using known conventional methods. These drugs or pharmaceutical compositions can be administered to an individual in a suitable dose, for example in a range from 0.01 ⁇ g to 10 g, or 0.05 ⁇ g / ml-10 ⁇ g / ml of CD152, preferably CD152 T cells, PD- 1 and / or BTLA per day and patient. Doses of 1 mg to 1 g are preferred.
  • the administration can take place in various ways, for example intravenously, intraperitoneally, intrarectally, intragastrointestinally, intranodally, intramuscularly, locally, for example in the focus of inflammation, but also subcutaneously, intradermally or on the skin or via the mucous membranes.
  • the administration can of course take the form of gene therapy, for example via vectors.
  • the type of dosage and route of administration can be determined by the attending physician in accordance with the clinical factors. It is known to the person skilled in the art that the type of dosage depends on various factors, such as, for example Size, body surface area, age, gender, or general health of the patient, but also the particular agent being administered, the duration and mode of administration, and other drugs that may be administered in parallel.
  • the pharmaceutical compositions or the medicament in particular comprises a pharmacological substance which contains one or more CD152, PD-1 and / or BTLA molecules and / or nucleic acid molecules encoding them in a suitable solution or administration form. These can either be administered alone with the corresponding auxiliaries described under medicaments or pharmaceutical compositions or in combination with another suitable substance for enhancing the action. These are mixed in known methods with CD152, PD-1 and / or BTLA molecules and administered in a suitable formulation and dosage. Formulations, dosages and suitable components are known to the person skilled in the art.
  • the pharmaceutical composition or the medicament can of course also be a combination of 2 or more of the pharmaceutical compositions or medicaments according to the invention, as well as a combination with others Anti-inflammatory drugs that are administered or applied in a suitable manner over time or separately.
  • the pharmaceuticals or pharmaceutical compositions are prepared by methods known per se.
  • the invention also relates to a kit which comprises a pharmaceutical composition according to the invention.
  • This kit can be used, for example, for the prophylaxis, diagnosis and / or therapy of autoimmune diseases or inflammation, the disease preferably being selected from the group comprising antiglomerular basement membrane disease, autoimmune diseases of the nervous system, systemic lupus erythematosus, an Addison disease, an antiphospholipid syndrome , IgA glomerulonephritis, Goodpasture syndrome, Lambert-Eaton myasthenia syndrome, bullous pemphigoid, thrombocytopenic, idiopathic
  • Purpura an autoimmune thyroiditis, rheumatoid arthritis, insulin-dependent diabetes mellitus, pemphigus, inflammatory bowel disease, collagenosis, inflammation, an undesirable immune reaction such as sepsis, autoimmune hamolytic anemia, dermatitis herpetiformis duhromeric diarrhea, a diaphragm Disease, sympathetic ophthalmia, autoimmune polyendocrinopathies and / or Reiter's disease, especially multiple sclerosis and
  • the disease or inflammation is a disease associated with rheumatism, especially rheumatic arthritis.
  • the kit may include instructions or information on pharmaceutical delivery or therapeutic treatment procedures.
  • the information can be, for example, an instruction leaflet or another medium which gives the user information about the therapeutic method or scheme with which the substances mentioned, ie in particular CD152 + T cells or the pharmaceutical agent according to the invention, are to be used.
  • the package insert contains in particular detailed and / or essential information about the healing process. Of course, it is not absolutely necessary for this information to be formulated on a package insert, it is also possible for this information to be communicated, for example, via the Internet.
  • CD152-expressing cells For the first time, it has been possible according to the invention to display individual, CD152-expressing cells also cytometrically and to isolate them for functional examinations. With the help of a sensitive staining method could be shown, among other things, that during an antigen-specific stimulation cell membrane-bound CD152 is only expressed on a subpopulation of activated cells (CD152 + T cells). In contrast to activated CD152 " T cells, isolated, activated CD152 + T cells were inhibited in their proliferation upon restimulation (FIG. 4). This heterogeneous expression of CD152 on activated T cells ensures the diversity of a clonal T cell response (FIG. 3).
  • T cells with different effector functions is a fundamental property of the adaptive immune response, and the data also show that CD152 is indeed able to inhibit already activated individual T cells (Fig. 3). CD152 can therefore very well also be established regulate "ongoing" immune responses, and the same can be said for the PDI and BTLA molecules.
  • CD152 + T cells act autoregulatory. Furthermore, human CD152 + T cells have an suppressive effect shown on other T cell responses (IL production after 24 hours) (Fig. 2). In addition, a suppressive effect on other immune responses has been confirmed with human CD152 + T cells (IFNg production after 3 days) (FIG. 6). Sereological blockade of CD152 during mitogen stimulation of PBMCs from patients with rheumatoid arthritis revealed that the CD152 molecule is functional in patients. CD152 + T cells are found in the focus of inflammation of rheumatoid arthritis (RA) in the synovium (Fig. 5). In detail:
  • CD152 remains expressed longer on a fraction of the T cells.
  • Human PBMCs (2 l0 5 / ml) were stimulated with 1.5 ⁇ g / ml SEB and the CD152 + T. Cells were isolated after 48 hours. Cultured with syngeneic PBMCs and with or without 1.5 ⁇ g / ml SEB, CD152 was again measured cytometrically on the surface of the T cells 62 hours later. The Y axis shows in% the number of CD152 + T cells of all CD4 + T cells. Black columns: CD152 + or CD152- T cells that were added to PBMCs and still express CD152 after 62 hours (proportionate to all added cells), white columns show the CD152 + T cells that were newly created in the PBMCs after restimulation.
  • CD152 + T cells were ind CD152-T cells were added to the PBMCs in cocultures.
  • Activated, isolated CD152 + T cells inhibit the stimulation of other T cells.
  • IL-2 was measured in the culture supernatant. Either CD152 + T cells were added (columns 3 and 4) or CD152- (columns 5 and 6) or no cells were added to the PBMCs (columns 1 and 2). Gray columns 1, 3 and 5 show cocultures that have no further stimulus after restimulation, black columns 2, 4 and 6 have 1.5 ⁇ g / ml SEB.
  • the bar below the figure shows that CD152 + T cells had 170% mRNA for the inhibitory cytokine TGFbeta before addition to the co-structures, CD152- however only 100%. In the presence of CD152 + T cells, almost no IL-2 could be measured. IL-2 production stands here as a parameter for general inhibition of stimulation.
  • a CD152 signal leads to the inactivation of a subpopulation of activated T cells.
  • Murine T cells were stimulated with fixed-phase coupled anti-CD3 / anti-CD28 for 48 hours, then restimulated with antibody-coupled latex beads, either (1) with 0 aCD3 + aCD28 + control antibody or (2) aCD3 + aCD28 + aCD152.
  • the cells were labeled with CFSE. The decrease in intensity indicates the division of the cell. With CD152 cross-linking, more cells remain in the slowest generation 5 than without cross-linking.
  • individual CD152 + T cells are refractory to antigen-specific restimulation.
  • PBMCs were activated with soluble anti-CD3 25 for 48 hours and labeled for CD152, cytometric and isolated.
  • the CD152 +, CD152- and unsorted CD4 cells were added to fresh PBMCs. Two days later, the proliferation of the fractions was detected using the CFSE staining.
  • CD152 + T cells 30 (CD4 + mCD152 +, gray curve) did not proliferate, or less than CD4 + or CD4 + CD152- T cells. From what is shown it follows that CD152 already activated T cells can be switched off. Ml marks the proportion of proliferating cells. Meanfluorescenceintensity (%): CD4 +: 2200 (61%), CD4 + CD152 + 3000 (36%), CD4 + CD152- (1800) 74%.
  • SEB Staphylococcus aureus B
  • IL-2 Interleukin 2
  • mCD152 membrane-bound CD152.
  • Activated, isolated CD152 + T cells inhibit the stimulation of other T cells, using the proinflammatory cytokine IFNgamma as an example.
  • PBMCs were stimulated for 48 h with anti-CD3 and anti-CD28 coupled to latex particles and then CD152 + and CD152-CD4 + T cells were separated. These cells became fresh PBMCs given. Then it was restimulated for 48 hours with either SEB, anti-CD3 or anti-CD3 / anti-CD28. Either no further cells (white), CD152 + T cells (black column) or CD152- (gray column) were added and IFNgamma im Culture supernatant measured by ELISA. In the presence of CD152 4 " T cells, almost no more IFNgamma could be measured. IFNgamma production stands here as an inflammation parameter for general inhibition of stimulation (FIG. 2). The different stimulation conditions stand for different and differently strong stimulation conditions for the T cells, all of them lead to the same result:
  • IFNgamma is greatly reduced in cocultures.
  • Activated, isolated CD152 + T cells inhibit the proliferation of other T cells (T).
  • CD152 + T cells (E) were added to the PBMCs (T are the CD4 cells of the PBMCs). In the presence of CD152 + T cells, almost no proliferation of the CD4 target cells (T) could be measured on the basis of decreasing CFSE staining intensity. Proliferation stands here as a parameter for general inhibition of stimulation and chronic Inflammatory process.
  • the supernatants from the left experiment (1) were taken and applied to anti-CD3-stimulated PBMCs.
  • the proliferation of the CD4 cells of the PBMCs was measured after 3 days.
  • the CFSE staining of the CD4 cells served as a parameter
  • CD152-T cells are identified by white squares. C (white diamond) represents 1 in 1
  • PBMCs were stimulated with anti-CD3 (A) or isolated directly from the focus of inflammation so that a fraction of CD152 is expressed on the surface (top row of cells). 1) These cells produce little or no IL-2 or IFNgamma and are limited in their proliferation (2). Under cell-cell contact, these CD152 + T cells can continue to switch off cells in their proliferation and inhibition of pro-inflammatory cytokines. The inflammation . is stopped. The lower cells show inflammatory T cells that keep the inflammation going.
  • PBMCs are stimulated to obtain CD152 + T cells (or CD152 + T cells are derived from the
  • Inflammatory T cells can also be reprogrammed by CD152 by inducing or transfecting CD152. Then the cells are expanded in vitro and returned to the patient. The ignition is switched off (Fig. 9, bottom right).

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Abstract

L'invention concerne l'utilisation de cellules T CD152, de préférence CD152+ pour le traitement de maladies auto-immunes et d'inflammations, en particulier de maladies associées aux rhumatismes.
PCT/EP2003/007665 2002-07-15 2003-07-15 Utilisation de cd152 pour le traitement de maladies auto-immunes et d'inflammations Ceased WO2004006950A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE10392933T DE10392933B4 (de) 2002-07-15 2003-07-15 Verwendung von CD152+ T Zellen zur Behandlung von Krankheiten des rheumatischen Formenkreises
AU2003250958A AU2003250958A1 (en) 2002-07-15 2003-07-15 Use of cd152 for treating autoimmune diseases and inflammations

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DE10232697A DE10232697A1 (de) 2002-07-15 2002-07-15 Verwendung von CD152 zur Behandlung von Autoimmunkrankheiten und Entzündungen
DE10232697.5 2002-07-15

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WO2004006950A2 true WO2004006950A2 (fr) 2004-01-22
WO2004006950A3 WO2004006950A3 (fr) 2004-06-10

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US8475790B2 (en) 2008-10-06 2013-07-02 Bristol-Myers Squibb Company Combination of CD137 antibody and CTLA-4 antibody for the treatment of proliferative diseases

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DE10392933D2 (de) 2005-07-14
DE10232697A1 (de) 2004-02-05

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