[go: up one dir, main page]

WO2013037804A1 - Procédé de surveillance des réponses des lymphocytes t cytotoxiques (ctl) par une réaction d'hypersensibilité de type retardée à l'aide d'épitopes viraux de ctl définis - Google Patents

Procédé de surveillance des réponses des lymphocytes t cytotoxiques (ctl) par une réaction d'hypersensibilité de type retardée à l'aide d'épitopes viraux de ctl définis Download PDF

Info

Publication number
WO2013037804A1
WO2013037804A1 PCT/EP2012/067794 EP2012067794W WO2013037804A1 WO 2013037804 A1 WO2013037804 A1 WO 2013037804A1 EP 2012067794 W EP2012067794 W EP 2012067794W WO 2013037804 A1 WO2013037804 A1 WO 2013037804A1
Authority
WO
WIPO (PCT)
Prior art keywords
dth
hla
ctl
peptide
epitope
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.)
Ceased
Application number
PCT/EP2012/067794
Other languages
English (en)
Inventor
Christian Brander
Marta RUIZ RIOL
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.)
Institucio Catalana de Recerca i Estudis Avancats ICREA
IrsiCaixa Institut de Recerca de la Sida
Esteve Pharmaceuticals SA
Original Assignee
Institucio Catalana de Recerca i Estudis Avancats ICREA
IrsiCaixa Institut de Recerca de la Sida
Laboratorios del Dr Esteve SA
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 Institucio Catalana de Recerca i Estudis Avancats ICREA, IrsiCaixa Institut de Recerca de la Sida, Laboratorios del Dr Esteve SA filed Critical Institucio Catalana de Recerca i Estudis Avancats ICREA
Priority to ES201490028A priority Critical patent/ES2490915B1/es
Publication of WO2013037804A1 publication Critical patent/WO2013037804A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0006—Skin tests, e.g. intradermal testing, test strips, delayed hypersensitivity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56972—White blood cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • 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
    • A61K39/12—Viral antigens
    • A61K39/145—Orthomyxoviridae, e.g. influenza virus
    • 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
    • A61K39/12—Viral antigens
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K4/00—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
    • C07K4/02—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof from viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/11—Orthomyxoviridae, e.g. influenza virus

Definitions

  • the present invention relates to an in vivo method for monitoring cytotoxic T lymphocyte (CTL) responses by inducing a delayed-type hypersensitivity (DTH) reaction using defined CTL epitopes.
  • CTL cytotoxic T lymphocyte
  • DTH delayed-type hypersensitivity
  • the invention also relates to a kit containing said 0 defined CTL epitopes.
  • FIG. 1 A) Representative example of DTH response 72h after intradermal delivery of PBS, Candida, influenza-GL9 peptide, HIV-SL9 peptide and tetanus toxo ' id (TT). B) Extend of DTH (determined as the diameter of induration (mm)) is shown for all HLA-A2 expressing subjects included in the study. Black symbols indicate HIV uninfected subjects, white symbols represent HIV infected patients.
  • FIG. 1 A) Representative example of gating strategy with dextramer positive (middle) and negative (right) staining for SL9 and GL9 specific T cells populations.
  • the right hand panel shows the direct comparison of the frequency of central memory cells among SL9 and GL9 positive cells.
  • MFI mean fluorescence intensity
  • FIG. 3 A) CLA expression differences among epitope specific populations, shown as percentages of all epitope-specific cells (left panels) and MFI levels (right panels Y) for both, the pre-epitope injection and 72h post injection time points.
  • the present invention refers to an in vivo method for monitoring the cytotoxic T lymphocyte (CTL) response against a virus in a subject.
  • the method comprises the steps of i) administering a HLA-A2 restricted epitope of a viral antigen to the subject, and ii) determining if a cutaneous DTH reaction occurs, wherein a positive DTH reaction is indicative that the subject can mount an effective CTL response against the virus.
  • the method involves administering the antigen epitope intradermally to the subject and observing if induration and erythema ensues after 48-72 hours post- injection.
  • a positive response means that the subject has been exposed to the antigen at least 4 to 6 weeks before the administration and that his cell-mediated immunity mechanism is effective in recognizing and responding to the antigen.
  • the lack of a DTH response to the antigen may be regarded as an evidence of anergy. In the absence of underlying diseases, anergy may indicate primary or secondary T cell immunodeficiency.
  • the invention relates to kit or composition comprising a HLA- A2 restricted epitope of the invention for assaying the CTL immune response in subject.
  • the induction CTLs is believed to be an important defense mechanism against viral infections.
  • their in vivo effectiveness may vary in different infections.
  • their in vitro, functional assessment often relies on surrogate markers, such as single cytokine release, that may be physiologically quite irrelevant.
  • surrogate markers such as single cytokine release
  • the present invention demonstrates that local DTH reactions can be elicited by short CTL epitopes alone and that differences in dermal migration markers between HIV and influenza-specific CTL could reflect the impaired in vivo functionality of HIV-specific CTL. These data may help to establish "CTL-DTH" as a simple, cheap and sensitive immune monitoring tool for large-scale vaccine trials for HIV and other viral pathogens. More specifically, the present invention relates to an in vivo method for monitoring the CTL response against virus by administering to a subject a HLA-A2 restricted CTL epitope of a viral antigen and observing if a DTH response is induced.
  • HLA-A2 restricted CTL epitopes from influenza GL9, GILGFVFTL
  • HIV SL9, SLYNTVATL
  • the epitopes were administered to the subject intradermally and the appearance of induration and erythema was observed.
  • the GL9 was able induce such a DTH reaction exclusively in HLA-A2 expressing individuals.
  • Neither magnitude of the epitope-specific responses, HIV infection status, HIV viral loads or CD4 counts were predictive of the extent of DTH reactions.
  • AIDS refers to the symptomatic phase of HIV infection, and includes both Acquired Immune Deficiency Syndrome (commonly known as AIDS) and "ARC,” or AIDS-Related Complex. See Adler M, et al, Brit. Med. J. 1987; 294: 1145-1147.
  • the immunological and clinical manifestations of AIDS are known in the art and include, for example, opportunistic infections and cancers resulting from immune deficiency.
  • adjuvant refers to a substance that enhances, augments or potentiates the host's immune response to a vaccine antigen either by contributing to presenting the vaccine antigen to the immune system or by non-specifically stimulating directly different components of the immune system,
  • B cell refers to any member of a diverse population of morphologically similar cell types that develop in the bone marrow and that mediate the humoral immune response of the adaptive immune system.
  • B cells are characterized by the presence of a B cell receptor able to bind specifically an antigen. Their principal functions are to make antibodies against antigens, perform the role of antigen- presenting cells (APCs) and eventually develop into memory B cells after activation by antigen interaction.
  • APCs antigen- presenting cells
  • BLT1 refers to the leukotriene B4 receptor 1, a protein encoded by the LTB4R gene in humans (UniProt accession no. Q 15722).
  • CCR7 refers to the cluster of differentiation 197, the C-C chemokine receptor type 7 protein. CCR7 is expressed in various lymphoid tissues and activates B and T cells. It has been shown to control the migration of memory T cells home to secondary lymphatic organs, such as the lymphatic, as well as stimulate dendritic cell maturation (UniProt accession no. P32248).
  • CD3 refers to the cluster of differentiation 3, a protein complex composed of four distinct chains. In mammals, the complex contains a CD3y chain, a CD35 chain, and two CD3s chains. These chains associate with a molecule known as the T cell receptor (TCR) and the ⁇ -chain to generate an activation signal in T lymphocytes.
  • TCR T cell receptor
  • CD8 refers to the cluster of differentiation 8, a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR) expressed in the cytotoxic T cells (CTL). CTLs are implicated in the rejection of transplants and the destruction of tumor and virally infected cells (UniProt accession no. PI 0966).
  • CD27 refers to cluster of differentiation 27, a tumor necrosis factor receptor member of the TNF-receptor superfamily. This receptor is required for generation and long-term maintenance of T cell immunity. It binds to ligand CD70, and plays a key role in regulating B cell activation and immunoglobulin synthesis. The receptor transduces signals that lead to the activation of NF- ⁇ and MAPK8/JNK. Adaptor proteins TRAF2 and TRAF5 have been shown to mediate the signaling process of this receptor (HGNC identification no. 11922).
  • CD45RA refers to isoform RA of the cluster of differentiation 45, or protein tyrosine phosphatase, receptor type, C (PTPRC). CD45RA is expressed by na ' ive T cells (UniProt accession no. P08575).
  • CD103 refers to cluster of differentiation 103, or integrin E (ITGAE). CD 103 binds integrin ⁇ 7 to form the complete heterodimeric integrin molecule ⁇ 7 (UniProt accession no. P38570).
  • CLA refers to the cutaneous lymphocyte-associated antigen, a skin-homing receptor that facilitates the targeting of T cells to inflamed skin.
  • CLA is defined by its reactivity towards the HECA-452 monoclonal antibody and its activity as a ligand for E-selectin. See Fuhlbrigge R, et ah, Nature 1997; 389(6654):978- 981.
  • CTL Cytotoxic T Lymphocyte
  • Ag processed antigen
  • cytotoxic T lymphocyte (CTL) response is used to refer to the primary immune response mediated by CTL cells.
  • This specific immune response can be e.g. the production of specific cytokines such as IFN-gamma (IFN- gamma., IFN- ⁇ ) (measured e.g. by ELISPOT or intracellular FACS), degranulation (measured e.g. by a granzyme-b specific ELISPOT), or cytolytic activity (e.g. measured by a 51 Cr-release assay).
  • IFN-gamma IFN-gamma
  • IFN- ⁇ immunofluory-gamma
  • ELISPOT intracellular FACS
  • degranulation measured e.g. by a granzyme-b specific ELISPOT
  • cytolytic activity e.g. measured by a 51 Cr-release assay.
  • the antigen specific CD8+ cell can be detected directly by e.g. the use of tetramers.
  • CXCR1 or "CD181", as used d herein, refers to cluster of differentiation 181, also known as interleukin 8 receptor a (ILRA).
  • CXCR1 is a chemokine receptor with high affinity for interleukin 8 (IL8).
  • the protein encoded by the CXCR1 gene is a member of the G-protein-coupled receptor family (UniProt accession no. P25024).
  • DTH yed-typed hypersensitivity
  • helper T cells recognize the antigen in a complex with class 2 HLA complex.
  • the antigen-presenting cells in this case are macrophages that secrete IL-12, which further stimulates the proliferation of CD4+ Thl cells.
  • CD4+ T cells secrete IL-2 and interferon gamma, inducing the release of other Thl cytokines, thus mediating the immune response.
  • Activated CD8+ T cells destroy target cells on contact, whereas activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells.
  • diagnosis is used herein to refer to the identification of a molecular or pathological state, disease or condition or to refer to identification of a patient who may benefit from a particular treatment regimen. As will be understood by those skilled in the art, such an assessment is usually not intended to be correct for all (i.e. 100 percent) of the subjects to be identified. The term, however, requires that a statistically significant portion of subjects can be identified (e.g. a cohort in a cohort study). Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann- Whitney test etc..
  • Preferred confidence intervals are at least 90 percent, at least 95 percent, at least 97 percent, at least 98 percent or at least 99 percent.
  • the p- values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001. More preferably, at least 60 percent, at least 70 percent, at least 80 percent or at least 90 percent of the subjects of a population can be properly identified by the method of the present invention.
  • HLA-A2 refers to the HLA-A2 type containing the subtypes, examples of which include, but are not limited to, HLA-A*0201, HLA-A*0202, HLA- A*0203, HLA-A*0204, HLA-A*0205, HLA-A*0206, HLA-A*0207, HLA-A*0210, HLA-A*0211, HLA-A*0213, HLA-A*0216, HLA-A*0218, HLA-A*0219, HLA- A*0228 and HLA-A*0250.
  • HLA-A2 restricted peptide shall refer to any polypeptide comprising an epitope that is capable of, or predicted to be capable of, being bound by a human leukocyte antigen molecule of HLA class II.
  • the binding of the HLA-A2 restricted peptide to the HLA class II molecule occurs with an IC 50 lower than 1000 nM.
  • the "HLA-A2 restricted peptide is about 8 to about 13 amino acids, or about 8, 9, 10 or 11 amino acids in length.
  • one or more of said HLA-A2 restricted peptides are provided together in the form of a polyepitope peptide or construct.
  • the polyepitope construct of the present invention preferably includes 2 or more, 5 or more, 10 or more, 13 or more, 15 or more, 20 or more, or 25 or more CTL epitopes. More specific, the polyepitope construct comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60 or more CTL epitopes.
  • the "HLA-A2 restricted peptide may be of any size, including but not limited to having a size of less than 100,000 Dalton in molecular weight, less than 50,000 Dalton in molecular weight, less than 10,000 Dalton in molecular weight, less than 5,000 Dalton in molecular weight, less than 2,500 Dalton in molecular weight, or from about 1000 to 2000 Dalton in molecular weight.
  • the HLA-A2 restricted peptide derives from an influenza virus antigen.
  • a suitable influenza antigen can be a surface antigen, such as hemagglutinin (HA), neuraminidase (NA), M2, or a fragment thereof (e.g., one or more HTL or CTL epitopes).
  • Suitable influenza antigens include Ml, NP, NS1, NS2, PA, PB1, and PB2, or fragments thereof.
  • Suitable HLA-A2 restricted peptides derived from Ml include GILGFVFTL (SEQ ID NO: l), LLTEVETYV (SEQ ID NO:2), ILGFVFTLTV (SEQ ID NO:3) and RMGTVTTEV (SEQ ID NO:4).
  • Suitable HLA-A2 restricted peptide derived from HA include, without limitation GLFGAIAGFI (SEQ ID NO:5), FLDIWTYNA (SEQ ID NO:6), ALSTLCLLI (SEQ ID NO:7) and HLECRTFFL (SEQ ID NO: 8).
  • Suitable HLA-A2 restricted peptides derived from NP include KSCLPACVY (SEQ ID NO:9), CLPACVYGL (SEQ ID NO: 10), LQNSQVFSL (SEQ ID NO: l 1) and FQGRGVFEL (SEQ ID NO: 12).
  • Suitable HLA-A2 restricted peptide derived from NS1 include, without limitation, FQVDCFLWHV (SEQ ID NO: 13), QVDCFLWHV (SEQ ID NO: 14), FLWHVRKQV (SEQ ID NO: 15), and IILKANFSV (SEQ ID NO: 16).
  • Suitable HLA-A2 restricted peptide derived from NS2 include, without limitation, FMQALQLLL (SEQ ID NO: 17), MQALQLLLEV (SEQ ID NO: 18) and MITQFESLK (SEQ ID NO: 19).
  • Suitable HLA-A2 restricted peptide derived from PA include, without limitation, FMYSDFHFI (SEQ ID NO:20), ALLKHRFEI (SEQ ID NO:21), MAWTVVNSI (SEQ ID NO:22), LLMDALKLSI (SEQ ID NO:23), LLAWKQVLA (SEQ ID NO:24) and YINTALLNA (SEQ ID NO:25).
  • Suitable HLA-A2 restricted peptide derived from PA include, without limitation, AQTDCVLEA (SEQ ID NO:26), CVLEAMAFL (SEQ ID NO:27), RLIDFLKDV (SEQ ID NO:28), QIRGFVYFV (SEQ ID NO:29), FVYFVETLA (SEQ ID NO:30), RMFLAMITYI (SEQ ID NO:31), LLIDGTASL (SEQ ID NO:32), NMLSTVLGV (SEQ ID NO:33), FVANFSMEL (SEQ ID NO:34), AQMALQLFI (SEQ ID NO:35), and RLCNPLNPFV (SEQ ID NO:36).
  • AQTDCVLEA SEQ ID NO:26
  • CVLEAMAFL SEQ ID NO:27
  • RLIDFLKDV SEQ ID NO:28
  • QIRGFVYFV SEQ ID NO:29
  • FVYFVETLA SEQ ID NO:30
  • RMFLAMITYI SEQ ID NO
  • Suitable HLA-A2 restricted peptide derived from PA include, without limitation, LQDCKIAPL (SEQ ID NO:37), FQNWGIEHI (SEQ ID NO:38), FQNWGIEPI (SEQ ID NO:39) and RMQFSSLTV (SEQ ID NO:40).
  • HIV include HIV-1 and HIV-2 and SIV.
  • HIV- 1 means the human immunodeficiency virus type-1. HIV-1 includes, but is not limited to, extracellular virus particles and the forms of HIV-1 associated with HIV-1 infected cells. The HIV-1 virus may represent any of the known major subtypes (Classes A, B, C, D E, F, G and H) or outlying subtype (Group O) including laboratory strains and primary isolates.
  • HIV-2 means the human immunodeficiency virus type-2. HIV-2 includes, but is not limited to, extracellular virus particles and the forms of HIV-2 associated with HIV-2 infected cells.
  • SIV refers to simian immunodeficiency virus which is an HIV-like virus that infects monkeys, chimpanzees, and other nonhuman primates. SIV includes, but is not limited to, extracellular virus particles and the forms of SIV associated with SIV infected cells.
  • influenza refers to a virus which can cause influenza, and includes, but is not limited to, A type, B type, and C type influenza viruses.
  • Representative strains that are associated with disease in man, swine, and/or birds including H1N1 strains (e.g., A/Wilson-Smith/33, A/New Calcdonia/20/99, A/Swine Korea/S 10/2004, A/Brevig Mission/1/1918, A Pureto Rico/8/34/Mount Yale, A California/7/2009, A California/20172009, A California/08/2009, A Texas/04/2009, A swine/Saskatchewan/18789/02, A mallard/Alberta/130/2003, A mallard/Alberta/2001, A swine/Cotes d * Armor/1482/99, A swine/Betzig/2/2001, and/or A turkey/Germany/3/91), H3N2 strains (e.g., A/Wilson
  • kit refers to a product containing the different reagents necessary for carrying out the methods of the invention packed so as to allow their transport and storage.
  • Materials suitable for packing the components of the kit include crystal, plastic (e.g. polyethylene, polypropylene, polycarbonate), bottles, vials, paper, or envelopes.
  • subject refers to an individual, plant or animal, such as a human beings, a non-human primate (e.g. chimpanzees and other apes and monkey species), a farm animal (e.g. birds, fish, cattle, sheep, pigs, goats and horses), a domestic mammal (e.g. dogs and cats), or a laboratory animal (e.g. rodents, such as mice, rats and guinea pigs.
  • farm animal e.g. birds, fish, cattle, sheep, pigs, goats and horses
  • a domestic mammal e.g. dogs and cats
  • laboratory animal e.g. rodents, such as mice, rats and guinea pigs.
  • subject encompasses an embryo and a fetus.
  • T cell refers to any member of a diverse population of morphologically similar lymphocytes types that develop in the thymus and that mediate the cellular immune response of the adaptive immune system. They are characterized by the presence of a T cell receptor on the cell surface. There are several subsets of T cells, each with a distinct function (i.e. helper, memory, regulatory, natural killer). See Alberts, 2008, supra, pp. 1364-1374, 1392-1409.
  • Treg refers to a T cell that expresses the CD4 or CD25 marker at least and which is capable of reducing or suppressing the activity of a T cell.
  • This term includes T cells producing low levels of IL-2, IL-4, IL-5, and IL-1, and which suppress the activation of the immune system.
  • Regulatory T cells suppress actively the proliferation and cytokine production of TEL , T3 ⁇ 4, or naive T cells which have been stimulated in culture with an activating signal (e.g. antigen and antigen presenting cells or with a signal that mimics antigen in the context of HLA, such as, for instance, an anti-CD3 antibody plus an anti-CD28 antibody).
  • Treg cells may express the FoxP3 marker.
  • the invention relates to an in vivo method for determining whether a subject is capable of mounting am effective cytotoxic T lymphocyte (CTL) response against a virus comprising:
  • DTH delayed-type hypersensitivity
  • a peptide comprising an HLA-A2 restricted epitope of an antigen from said virus is administered to the subject.
  • the peptide is administered intradermally, typically in a similar manner to the Mantoux test.
  • the peptide can be administered epidermally.
  • the peptide is typically administered by needle, such as by injection, but can be administered by other methods such as ballistics, for example the ballistics techniques which have been used to deliver nucleic acids.
  • Published EPC Application No. EP-A- 0693119 describes techniques which can typically be used to administer the peptide.
  • a polynucleotide capable of expressing the polypeptide can be administered.
  • the polynucleotide typically has any of the characteristics of the polynucleotide which is discussed below.
  • Polypeptide is expressed from the polynucleotide in vivo and recognition of the peptide in vivo may be measured.
  • 0.001 to 1000 ⁇ g for example from 0.01 to 100 ⁇ g or 0.1 to 10 ⁇ of polynucleotide is administered.
  • the peptide is administered without adjuvant.
  • the HLA-A2 restricted epitope is derived from influenza.
  • the HLA-A2 restricted epitope is derived from the influenza matrix protein 1.
  • the HLA-A2 restricted epitope is GILGFVFTL (SEQ ID NO: 1).
  • the subject is human.
  • the subject has been previously infected by the virus and/or immunized with an immunogen comprising the viral antigen.
  • the method comprises determining if a delayed-type hypersensitivity (DTH) reaction occurs.
  • the determination of the delayed-type hypersensitivity (DTH) reaction comprises determining the appearance of a cutaneous DTH reaction.
  • the cutaneous DTH reaction is determined by determining the presence of induration and/or erythema of an area surrounding a site of antigen exposure.
  • the determination of the delayed-type hypersensitivity (DTH) reaction comprises determining the increase in the number of CLA+ epitope- specific CTL and/or the increase in the number of CD 103+ epitope-specific CTL.
  • the increase in the number of CLA+ epitope-specific CTL and/or the increase in the number of CD 103+ epitope-specific CTL is usually determined with respect to a reference value.
  • the reference value correspond to the number of number of CLA+ epitope-specific CTL or the number of CD 103+ epitope-specific CTL in a subject who has not been treated or in a subject who has been treated with a peptide which does not comprise an HLA-A2 restricted epitope of an antigen from the virus.
  • the invention relates to a method for the diagnosis of an infection by a virus in a subject comprising i) administering a peptide comprising a HLA-A2 restricted epitope of an antigen from said virus to the subject, and
  • DTH delayed-type hypersensitivity
  • a peptide comprising an HLA-A2 restricted epitope of an antigen from said virus is administered to the subject.
  • the peptide is administered intradermally, typically in a similar manner to the Mantoux test.
  • the peptide can be administered epidermally.
  • the peptide is typically administered by needle, such as by injection, but can be administered by other methods such as ballistics, for example the ballistics techniques which have been used to deliver nucleic acids.
  • Published EPC Application No. EP-A- 0693119 describes techniques which can typically be used to administer the peptide.
  • a polynucleotide capable of expressing the polypeptide can be administered.
  • the polynucleotide typically has any of the characteristics of the polynucleotide which is discussed below.
  • Polypeptide is expressed from the polynucleotide in vivo and recognition of the peptide in vivo may be measured.
  • the HLA-A2 restricted epitope is derived from influenza.
  • the HLA-A2 restricted epitope is derived from the influenza matrix protein 1. .
  • the HLA-A2 restricted epitope is GILGFVFTL (SEQ ID NO: 1).
  • HLA-A2 restricted epitope is derived from influenza include, without limitation, the epitopes GILGFVFTL (SEQ ID NO: 1), LLTEVETYV (SEQ ID NO: 2), ILGFVFTLTV (SEQ ID NO: 3) and RMGTVTTEV (SEQ ID NO:4).
  • the subject is human.
  • the subject has been previously infected by the virus and/or immunized with an immunogen comprising the viral antigen.
  • the method comprises determining if a delayed-type hypersensitivity (DTH) reaction occurs.
  • the determination of the delayed-type hypersensitivity (DTH) reaction comprises determining the appearance of a cutaneous DTH reaction.
  • the cutaneous DTH reaction is determined by determining the presence of induration and/or erythema of an area surrounding a site of antigen exposure.
  • the determination of the delayed-type hypersensitivity (DTH) reaction comprises determining the increase in the number of CLA+ epitope- specific CTL and/or the increase in the number of CD 103+ epitope-specific CTL.
  • the increase in the number of CLA+ epitope-specific CTL and/or the increase in the number of CD 103+ epitope-specific CTL is usually determined with respect to a reference value.
  • the reference value correspond to the number of number of CLA+ epitope-specific CTL or the number of CD 103+ epitope-specific CTL in a subject who has not been treated or in a subject who has been treated with a peptide which does not comprise an HLA-A2 restricted epitope of an antigen from the virus.
  • the invention relates to a peptide comprising at least one HLA-A2 restricted epitope of the invention.
  • the invention relates to a kit comprising a peptide according to the invention.
  • Control injections included standard intradermal injections of PBS, tetanus toxo ' id and Candida antigens. Cutaneous reaction at sites of injections was measured 72h after injection by palpating skin indurations and by measuring the diameter (mm) of erythema extension. Blood samples were obtained before injection and 72h thereafter, T cells isolated by density gradient centrifugation (Lymphoprep®, Axis-Shield pic, Dundee, Scotland, GB) and cryopreserved until use. 2. Flow cytometry analysis
  • thawed cells (1 million of PBMCs) were stained with 10 of PE-couple HLA-A2/GL9 dextramer (Immudex AS, Copenhagen, DK) and 10 ⁇ APC-couple HLA-A2/SL9 dextramer (Immudex AS, Copenhagen, DK) at room temperature for 20 minutes.
  • PE-couple HLA-A2/GL9 dextramer Immudex AS, Copenhagen, DK
  • APC-couple HLA-A2/SL9 dextramer Immudex AS, Copenhagen, DK
  • the reduced extent of GL9 DTH reactions in HIV infected individuals compared to HIV uninfected subjects is in line with the diminished DTH reactivities in HIV infected subjects to antigens such as BCG. See Johnson M, et al, J. Infect. Dis. 1992; 166(1): 194-198 and Costa N, et al, Rev. Soc. Bras. Med. Trop. 2011; 44(5):542-545.
  • CLA cutaneous lymphocyte associated antigen
  • CD 103 ⁇ 7 integrin
  • BLT1 leukotriene B4 receptor
  • IL8 receptor alpha also known as CXCR1.
  • CLA has been shown to be present on more than 80% of T cells infiltrating inflamed skin lesions, while only 5-20% of total T cells in peripheral blood are CLA+.
  • CLA expression is typically increased in individuals with diverse inflammatory and skin diseases. See Ogg G, et al, J. Exp. Med. 1998; 188(6): 1203-1208, Dworzak M, et al, J. Allergy Clin. Immunol. 1999; 103(5Ptl):901-906, Borowitz M, et al, Leukemia 1993; 7(6):859-863, Seneviratne S, et al, QJM 2007; 100(1): 19-27, Antelo D, et al, Photodermatol.
  • CLA expression was selectively increased in the GL9 specific CTL (both, by %> positive cells as well as by the intensity of expression per cell; SL9 median 23.32%> and GL9 85.77% p-value ⁇ 0.0001, Mann-Whitney; SL9 median 976 MFI and GL9 3537.5 MFI, p-value ⁇ 0.0001, Mann- Whitney). This difference was consistent for both, at the time when the antigen was injected and at the 72h follow-up point. See Figure 3 A.
  • the higher levels of CLA in the influenza specific CD8 cells suggest that this marker could be responsible, or at least required for the observed DTH reactions seen against GL9 but not SL9.
  • the ⁇ 7 integrin (CD 103) was initially described in intraepithelial T cells residing in the gut and other epithelial compartments such as skin and lung as well as the tonsils and, with its expression biased towards CD8+ T cells.
  • CD 103 is upregulated by exposure to TGFp, IL4 and with streptococcal pyrogenic superantigen stimulation partly co-expressed with CLA. See Woodberry T. et al, J. Immunol. 2005; 175(7):4355-4362, Sigmundsdottir H, et al, Clin. Immunol. 2004; 111(1): 119-125, and Seneviratne S, et al, Clin Exp Immunol 2005; 141(1): 107-115.
  • the HIV infected subjects showed comparable results (GL9 median: 100% vs SL9 median: 99.95%; p- value: 0.7622 Mann- Whitney), but the expression level was significantly higher on GL9-specific CTL (GL9 median: 7116.5 MFI vs SL9 median: 2388 MFI; p-value ⁇ 0.0001 Mann- Whitney). See Figure 3B. While CD103 is not necessarily considered a homing marker, its increased expression on GL9 specific cells may allow to retain these cells within epithelial layers, facilitating a rapid DTH reaction.
  • leukotriene B4, leukotriene B4 receptor (BLT1) and CXCR1 (IL8 receptor a) have been observed in various inflammatory diseases, such as asthma, allergic disease, and atopic dermatitis, characterized by a Th2-like cytokine microenvironment.
  • BLT1 leukotriene B4 receptor
  • CXCR1 IL8 receptor a
  • BLT1 is mainly expressed on CD8+ effector T cells while the CD8+ T cells with CM phenotype express lower levels BLT1.
  • CXCR1 expression is largely restricted to terminally differentiated effector memory T cells, with increased perforin, granzyme B and IFN- ⁇ expression and high cytotoxic potential. See Takata H, et al, J. Immunol. 2004; 173(4):2231-2235.
  • Elevated CXCR1 expression has been detected on HlV-specific CD8 T cells from patients that control HIV replication during structured treatment interruptions and identifies cells with strong cytolytic activity and ability to be recruitment rapidly to sites of innate immune system activation. See Hess C, et al, Blood 2004; 104(12):3463-3471.
  • the BLT1 and CXCR1 markers were also assessed on HIV SL9 and influenza GL9 specific CTL.
  • both markers were found to be elevated on the HIV SL9-specific cells compared to the GL9 specific CTL population (for BLT1 expression: GL9 median: 56.9% vs SL9 median: 88.45%; p-value: 0.0001; for CXCR1 : GL9 median: 12.97 % vs SL9 median: 32.27%; p-value ⁇ 0.0001, Mann- Whitney). See Figure 3C.
  • CLA and CD 103 the expression of these inflammatory tissue homing markers was not modulated between time of antigen injection and the 72h post-injection time point, suggesting that the large fraction of PBMC -derived GL9 and SL9 were either not stimulated by the intradermal antigen injection or that the SL9 specific cells express constitutively more BLT1 and CXCR1 than the GL9 specific CTL.
  • BLT1 or CXCR1 may be involved in promoting the migration to or retention of GL9 specific CTL at the dermal antigen injection site.
  • the absence of both of these markers on HIV SL9 specific cells is consistent with the lack of DTH reactivity to this antigen and may indicate differential effector function profiles of CTL directed against these viral infections.
  • Immudex AS Copenhagen, DK
  • BD Biosciences Corp Franklin Lakes, NJ, US

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Cell Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Virology (AREA)
  • Pathology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Zoology (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne un procédé in vivo de surveillance des réponses des lymphocytes T cytotoxiques (CTL) par induction d'une réaction d'hypersensibilité de type retardée (DTH) en utilisant des épitopes de CTL définis. La présente invention concerne en outre les épitopes et les kits les comprenant.
PCT/EP2012/067794 2011-09-12 2012-09-12 Procédé de surveillance des réponses des lymphocytes t cytotoxiques (ctl) par une réaction d'hypersensibilité de type retardée à l'aide d'épitopes viraux de ctl définis Ceased WO2013037804A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
ES201490028A ES2490915B1 (es) 2011-09-12 2012-09-12 Método para monitorizar las respuestas de linfocitos T citotóxicos (LTC) mediante una reacción de hipersensibilidad de tipo retardado usando epítopos de LTC definidos

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161533476P 2011-09-12 2011-09-12
US61/533,476 2011-09-12

Publications (1)

Publication Number Publication Date
WO2013037804A1 true WO2013037804A1 (fr) 2013-03-21

Family

ID=46832400

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/067794 Ceased WO2013037804A1 (fr) 2011-09-12 2012-09-12 Procédé de surveillance des réponses des lymphocytes t cytotoxiques (ctl) par une réaction d'hypersensibilité de type retardée à l'aide d'épitopes viraux de ctl définis

Country Status (2)

Country Link
ES (1) ES2490915B1 (fr)
WO (1) WO2013037804A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015033137A1 (fr) 2013-09-04 2015-03-12 Imperial Innovations Limited Procédés biologiques et matériaux utilisables dans le cadre desdits procédés
WO2017071467A1 (fr) * 2015-10-26 2017-05-04 复旦大学 Kit de test immunologique cellulaire pour évaluer l'efficacité immunologique cellulaire, et procédé de conservation associé
EP4019042A1 (fr) * 2020-12-23 2022-06-29 De La Cuesta Roldán, Carlos Procédé permettant de déterminer si une réponse immunitaire s'est produite chez des sujets infectés par le coronavirus ou ayant été vaccinés

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0693119A1 (fr) 1993-04-08 1996-01-24 Oxford Biosciences Ltd Seringue sans aiguille permettant d'administrer des particules a l'aide d'un jet de gaz supersonique
WO1998050423A2 (fr) * 1997-05-07 1998-11-12 Centre National De La Recherche Scientifique Analogues peptidiques et leurs utilisations notamment dans des compositions pharmaceutiques et pour le diagnostic
WO2009016639A2 (fr) * 2007-08-02 2009-02-05 Biondvax Pharmaceuticals Ltd. Vaccins contre la grippe à multiples épitopes multimères

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0693119A1 (fr) 1993-04-08 1996-01-24 Oxford Biosciences Ltd Seringue sans aiguille permettant d'administrer des particules a l'aide d'un jet de gaz supersonique
WO1998050423A2 (fr) * 1997-05-07 1998-11-12 Centre National De La Recherche Scientifique Analogues peptidiques et leurs utilisations notamment dans des compositions pharmaceutiques et pour le diagnostic
WO2009016639A2 (fr) * 2007-08-02 2009-02-05 Biondvax Pharmaceuticals Ltd. Vaccins contre la grippe à multiples épitopes multimères

Non-Patent Citations (42)

* Cited by examiner, † Cited by third party
Title
12 September 2011 (2011-09-12), Retrieved from the Internet <URL:http://www.vaccineenterprise.org/conference/2011/sites/default/files/RuizRiol%20etal_Bangkok2011.pdf> [retrieved on 20121116] *
ADLER M ET AL., BRIT. MED. J., vol. 294, 1987, pages 1145 - 1147
ALBERTS B ET AL.: "Molecular Biology of the Cell", 2008, GARLAND PUBLISHING INC., pages: 1363 - 1391
ANTELO D ET AL., PHOTODERMATOL. PHOTOIMMUNOL. PHOTOMED., vol. 27, no. 1, 2011, pages 40 - 44
APPAY V ET AL., CYTOMETRY A, vol. 73, no. 11, 2008, pages 975 - 983
APPAY V. ET AL., NAT. MED., vol. 8, no. 4, 2002, pages 379 - 385
ASJO B ET AL: "Phase I trial of a therapeutic HIV type 1 vaccine, Vacc-4x, in HIV type 1-infected individuals with or without antiretroviral therapy", AIDS RESEARCH AND HUMAN RETROVIRUSES 2002 US, vol. 18, no. 18, 2002, pages 1357 - 1365, XP002687385, ISSN: 0889-2229 *
BIRX D ET AL., J. ACQUIR. IMMUNE DEFIC. SYNDR., vol. 6, no. 11, 1993, pages 1248 - 1257
BOROWITZ M ET AL., LEUKEMIA, vol. 7, no. 6, 1993, pages 859 - 863
BRANDER C ET AL., EUR. J. IMMUNOL., vol. 23, no. 12, 1993, pages 3217 - 3223
BRANDER C ET AL., J. CLIN. INVEST., vol. 101, no. 11, 1998, pages 2559 - 2566
BRANDER C ET AL., J. IMMUNOL., vol. 155, no. 5, 1995, pages 2670 - 2678
CHEN Q ET AL., CANCER IMMUN., vol. 5, 2005, pages 5
COSTA N ET AL., REV. SOC. BRAS. MED. TROP., vol. 44, no. 5, 2011, pages 542 - 545
DOWDY; WEARDEN: "Statistics for Research", 1983, JOHN WILEY AND SONS
DWORZAK M ET AL., J. ALLERGY CLIN. IMMUNOL., vol. 103, 1999, pages 901 - 906
FRANCIS J ET AL., J. IMMUNOL., vol. 172, no. 1, 2004, pages 268 - 273
FUHLBRIGGE R C ET AL: "Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells", NATURE: INTERNATIONAL WEEKLY JOURNAL OF SCIENCE, NATURE PUBLISHING GROUP, UNITED KINGDOM, vol. 389, 30 October 1997 (1997-10-30), pages 978 - 981, XP002975219, ISSN: 0028-0836, DOI: 10.1038/40166 *
FUHLBRIGGE R ET AL., NATURE, vol. 389, no. 6654, 1997, pages 978 - 981
GOODARZI K ET AL., NAT. IMMUNOL., vol. 4, no. 10, 2003, pages 965 - 973
HESS C ET AL., BLOOD, vol. 104, no. 12, 2004, pages 3463 - 3471
HLADIK F ET AL., J. IMMUNOL., vol. 166, no. 5, 2001, pages 3580 - 3588
JOHNSON M ET AL., J. INFECT. DIS., vol. 166, no. 1, 1992, pages 194 - 198
KOELLE D ET AL., J. CLIN. INVEST., vol. 110, no. 4, 2002, pages 537 - 548
KOELLE D ET AL., J. VIROL., vol. 80, no. 6, 2006, pages 2863 - 2872
KOUP R ET AL., PLOS ONE, vol. 5, no. 2, 2010, pages E9015
KRAN ANNE-MARTE B ET AL: "HLA- and dose-dependent immunogenicity of a peptide-based HIV-1 immunotherapy candidate (Vacc-4x).", AIDS (LONDON, ENGLAND) 24 SEP 2004, vol. 18, no. 14, 24 September 2004 (2004-09-24), pages 1875 - 1883, XP008157948, ISSN: 0269-9370 *
KUNDIG T ET AL., PROC. NATL. ACAD. SCI. USA, vol. 89, no. 16, 1992, pages 7757 - 7761
OGG G ET AL., J. EXP. MED., vol. 188, no. 6, 1998, pages 1203 - 1208
OHNISHI H ET AL., ALLERGOL. INT., vol. 57, no. 4, 2008, pages 291 - 298
PALMER D ET AL., J. INFECT. DIS., vol. 130, no. 2, 1974, pages 132 - 137
PALMER D ET AL., J. INFECT. DIS., vol. 130, no. 2, 1974, pages 138 - 143
PRADO J ET AL., CURR. MED. CHEM., vol. 18, no. 26, 2011, pages 3963 - 3970
RUIZ-RIOL M ET AL: "Delayed-Type Hypersensitivity (DTH) Elicited by Defined Cytotoxic T Lymphocyte (CTL) Epitopes as a Potential Immune Read-out for Vaccine Trials", AIDS RESEARCH AND HUMAN RETROVIRUSES, vol. 27, no. 10, October 2011 (2011-10-01), & CONFERENCE ON AIDS VACCINE; BANGKOK, THAILAND; SEPTEMBER 12 -15, 2011, pages A94, XP002687388 *
SENEVIRATNE S ET AL., CLIN EXP IMMUNOL, vol. 141, no. 1, 2005, pages 107 - 115
SENEVIRATNE S ET AL., QJM, vol. 100, no. 1, 2007, pages 19 - 27
SIGMUNDSDOTTIR H ET AL., CLIN. EXP. IMMUNOL., vol. 126, no. 2, 2001, pages 365 - 369
SIGMUNDSDOTTIR H ET AL., CLIN. IMMUNOL., vol. 111, no. 1, 2004, pages 119 - 125
STEMMLER S ET AL., GENES IMMUN., vol. 6, no. 3, 2005, pages 225 - 230
TAKATA H ET AL., J. IMMUNOL., vol. 173, no. 4, 2004, pages 2231 - 2235
WOODBERRY T. ET AL., J. IMMUNOL., vol. 175, no. 7, 2005, pages 4355 - 4362
YANG O ET AL., TRENDS IMMUNOL., vol. 24, no. 2, 2003, pages 67 - 72

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015033137A1 (fr) 2013-09-04 2015-03-12 Imperial Innovations Limited Procédés biologiques et matériaux utilisables dans le cadre desdits procédés
WO2017071467A1 (fr) * 2015-10-26 2017-05-04 复旦大学 Kit de test immunologique cellulaire pour évaluer l'efficacité immunologique cellulaire, et procédé de conservation associé
EP4019042A1 (fr) * 2020-12-23 2022-06-29 De La Cuesta Roldán, Carlos Procédé permettant de déterminer si une réponse immunitaire s'est produite chez des sujets infectés par le coronavirus ou ayant été vaccinés
WO2022136628A1 (fr) * 2020-12-23 2022-06-30 Dermocovid Llc Procédé pour déterminer si une réponse immunitaire s'est produite chez des sujets qui ont été infectés par le coronavirus ou vaccinés contre celui-ci

Also Published As

Publication number Publication date
ES2490915A2 (es) 2014-09-04
ES2490915R1 (es) 2015-01-02
ES2490915B1 (es) 2015-09-17

Similar Documents

Publication Publication Date Title
Clute et al. Cross-reactive influenza virus–specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus–associated infectious mononucleosis
Varga et al. The attachment (G) glycoprotein of respiratory syncytial virus contains a single immunodominant epitope that elicits both Th1 and Th2 CD4+ T cell responses
Fan et al. Characterization of SARS-CoV-specific memory T cells from recovered individuals 4 years after infection
Cornberg et al. CD8 T cell cross-reactivity networks mediate heterologous immunity in human EBV and murine vaccinia virus infections
Raziorrouh et al. Inhibitory molecules that regulate expansion and restoration of HCV-specific CD4+ T cells in patients with chronic infection
Sridhar et al. Predominance of heterosubtypic IFN‐γ‐only‐secreting effector memory T cells in pandemic H 1 N 1 naive adults
Paillot et al. ISCOM-matrix-based equine influenza (EIV) vaccine stimulates cell-mediated immunity in the horse
US10179174B2 (en) Method for inducing an immune response and formulations thereof
CN101795705A (zh) 皮内hpv肽接种
WO2022023727A1 (fr) Panels de polypeptides et leurs utilisations associées
US20230138095A1 (en) Scaffolds with stabilized mhc molecules for immune-cell manipulation
WO2013037804A1 (fr) Procédé de surveillance des réponses des lymphocytes t cytotoxiques (ctl) par une réaction d&#39;hypersensibilité de type retardée à l&#39;aide d&#39;épitopes viraux de ctl définis
Powell et al. Identification of H5N1-specific T-cell responses in a high-risk cohort in vietnam indicates the existence of potential asymptomatic infections
Koelle et al. Phase I dose-escalation study of a monovalent heat shock protein 70-herpes simplex virus type 2 (HSV-2) peptide-based vaccine designed to prime or boost CD8 T-cell responses in HSV-naive and HSV-2-infected subjects
US20120288850A1 (en) Methods for diagnosis of immune responses against viruses
Singh et al. Avian influenza viral nucleocapsid and hemagglutinin proteins induce chicken CD8+ memory T lymphocytes
Chen et al. Induction of cell surface human leukocyte antigen–G expression in pandemic H1N1 2009 and seasonal H1N1 influenza virus–infected patients
Liu et al. The determination of in vivo envelope-specific cell-mediated immune responses in equine infectious anemia virus-infected ponies
Ishmukhametov et al. Safety and immunogenicity of inactivated whole virion vaccine CoviVac against COVID-19: a multicenter, randomized, double-blind, placebo-controlled phase I/II clinical trial
Davey et al. Identification of a MHC I-restricted epitope of DsRed in C57BL/6 mice
Srivastava et al. Phenotypic and functional signatures of Herpes Simplex virus–specific effector Memory CD73+ CD45RAhighCCR7lowCD8+ TEMRA and CD73+ CD45RAlowCCR7lowCD8+ TEM cells are associated with asymptomatic ocular Herpes
Kopp et al. Herpes Simplex Virus‐2 Glycoprotein Interaction with HVEM Influences Virus‐Specific Recall Cellular Responses at the Mucosa
Liu et al. IL-2–Engineered nano-APC Effectively Activates Viral Antigen-Mediated T Cell Responses from Chronic Hepatitis B Virus-Infected Patients
Manca et al. Recognition of human T-leukemia virus (HTLV-1) envelope by human CD4+ T-cell lines from HTLV-1 seronegative individuals: specificity and clonal heterogeneity
Layton et al. Development of an anti-ferret CD4 monoclonal antibody for the characterisation of ferret T lymphocytes

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: 12758473

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: P201490028

Country of ref document: ES

122 Ep: pct application non-entry in european phase

Ref document number: 12758473

Country of ref document: EP

Kind code of ref document: A1