[Immunosuppressive effect of CTLA-4 blockade and regulatory role of CD8 T cells in Th2-mediated humoral immune responses].
CTLA-4 is a negative regulator for T cell activation and plays an important role in down-regulating immune responses and the maintenance of peripheral tolerance. The effect of initial treatment with anti-CTLA-4 mAb on murine acute and chronic graft-versus-host diseases (GVHD) induced by transfer of either C57BL/6 or BALB/c splenocytes into F1 recipient mice has been investigated. The treatment with anti-CTLA-4 mAb exacerbated the lethality of acute GVHD. Surprisingly, in a chronic GVHD model, the similar treatment with anti-CTLA-4 mAb significantly reduced serum IgE and IL-4 expression and ameliorated the manifestation of chronic GVHD. Analysis of the splenic phenotype revealed that blockade of CTLA-4 greatly enhanced donor T cell expansion, especially within the CD8 subset. The transfer of CD8-depleted splenocytes did not exhibit the inhibitory effect by the anti-CTLA-4 mAb treatment, suggesting that CD8 T cells are required for an inhibitory effect of anti-CTLA-4 mAb. The regulatory roles of CD8 T cells and CTLA-4 pathway blockade in Th2-mediated immune responses were further confirmed by in vitro experiments using BALB/c T cell responses to allo-antigen. The immunosuppressive effect of CTLA-4 blockade and the regulatory function of CD8 T cells in Th2-mediated immune responses were demonstrated.
Second Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tokyo Medical and Dental University.
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Sakurai
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000917:Antibody Formation / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D060908:CTLA-4 Antigen; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy; D018796:Immunoconjugates; D007073:Immunoglobulin E / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D015847:Interleukin-4; D007073:Immunoglobulin E; D000069594:Abatacept; D007371:Interferon-gamma