Human anti-porcine T cell response: blocking with anti-class I antibody leads to hyporesponsiveness and a switch in cytokine production.
Intervention in the molecular interactions that lead to an immune response is possible at various stages of Ag recognition and T cell activation. Perturbation of the interaction of the TCR with the MHC/peptide ligand complex is one approach that has shown promise for autoimmunity and graft rejection in blocking T cell-activated responses. In this study, we investigated the effect of altering the target MHC class I molecule by blocking with Abs. We established a system that analyzed the human T cell response against MHC class I+/class II- porcine stimulatory cell targets. The primary human response against porcine smooth muscle cells was CD8+ T cell dependent. In the presence of F(ab')2 fragments of the MHC class I-reactive Ab, PT-85, the proliferative response was inhibited and production of IL-2 and IFN-gamma was blocked. Moreover, in a secondary response, proliferation was reduced and type 1 cytokine levels were inhibited. In contrast, levels of IL-10 and IL-4 were sustained or slightly increased. These findings indicate that Ab against MHC class I blocked the recognition of porcine cells by the human CD8+ T cells and altered the cytokine secretion profile. Thus, a single treatment with PT-85 F(ab')2 directed against the MHC class I molecule provides an attractive approach to the induction of T cell tolerance that may provide long-term graft survival in porcine-to-human cell transplantation.
DerSimonian
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H
Department of Molecular and Cellular Biology, Diacrin, Inc., Charlestown, MA 02129, USA. harout@diacrin.com
Pan
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Yatko
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C
Rodrigue-Way
A
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Johnson
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Edge
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D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019138:Antibodies, Blocking / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000918:Antibody Specificity; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D015847:Interleukin-4 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D013552:Swine / Q000276:immunology*; D013556:Swine, Miniature; D013601:T-Lymphocytes / Q000276:immunology*
D000906:Antibodies; D019138:Antibodies, Blocking; D016827:CD8 Antigens; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D007140:Immunoglobulin Fab Fragments; D007376:Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma