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Human Anti-Porcine T Cell Response: Blocking with Anti-Class I Antibody Leads to Hyporesponsiveness and a Switch in Cytokine Production

Department of Molecular and Cellular Biology, Diacrin, Inc., Charlestown, MA 02129

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- 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.

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