Role of CD4+ and CD8+ T cells in the rejection of concordant pancreas xenografts
Background We studied the ability of CD4+ and CD8+ T cells to induce rejection of pancreas xenografts in a concordant combination using rat pancreas xenografts as donors and chemically induced diabetic mice as recipients.
Materials and methods Lewis rat (two to three weeks old) pancreas xenografts were transplanted into C57BL/6, C57BL/6-CD4 knockout, C57BL/6-CD8 knockout, and C57BL/6-mMT/mMT (B cell deficient) mice that were made diabetic by streptozotocin (STZ). Lymphocyte proliferation and cytokine production were also analyzed in vitro. Rejected and long-term surviving pancreas xenografts were assessed by functional (blood glucose) and histopathological examination.
Results The current results show that Lewis rat pancreas grafts were rejected within 10-13 days and islet degeneration and mononuclear cell infiltrate accompanied with tissue necrosis were observed in streptozotocin (STZ)-induced diabetic C57BL/6 mice. A predominant TCRab+/CD4+ cell (on day 4) and TCRab+/CD8+ cell (on day 8) infiltrate and IgM deposition were found in the pancreas xenografts post-transplantation. Anti-CD4 mAbs (GK1.5), but not anti-CD8 mAbs (YTS 169.4), resulted in a prolonged survival of Lewis rat pancreas xenografts (MST = 33.8d). In T cell and B cell deficient mice (Rag2−/−) and CD4 knockout mice (but not in CD8 knockout mice) Lewis pancreas xenografts were permanently accepted. The rejection was slightly delayed to a mean survival time of 15.3 days in B cell deficient mice (μMT/μMT). Transfer of CD4+ but not CD8+ spleen cells from naive C57BL/6 mice into Rag2−/− mice led to acute rejection of transplanted pancreas xenografts. However, transfer of activated CD8+ spleen cells from pancreas grafted C57BL/6 recipients into Rag2−/− mice elicited rejection of Lewis rat pancreas xenografts.
Conclusion The current results show that CD4+ T cells are necessary and sufficient for mediating the rejection of Lewis rat pancreas xenografts in STZ-induced diabetic mice. However, activated CD8+ cells, but not naïve CD8+ cells, can also induce acute rejection of concordant pancreas xenografts.