Prolonged survival of fetal pig islet xenografts in mice lacking the capacity for an indirect response

Background: Xenografts of islets from organ-cultured fetal pig pancreases transplanted into non-immunosuppressed mice are rejected within 10 days. Immunosuppression with anti-T cell (anti-CD4) monoclonal antibody alone delays rejection of these xenografts for about 28 days, but rejection eventually occurs despite marked depletion of T cells. To determine if the critical CD4+ T cells responsible for xenograft islet rejection function through the direct or indirect pathway, selective class II-deficient mice that express class II antigens only on their thymic epithelium (not on peripheral cells) with normal numbers of CD4+ T cells, (class II-, CD4+), were used as recipients of xenograft islets to test if rejection occurs in the absence of an indirect response. Methods: Control (C57BL/6) or class II-, CD4+ mice were transplanted under the kidney capsule with cultured fetal pig islets. Class II-, CD4+ mice have normal numbers of B cells, CD4+, gammadelta T cells, and slightly increased numbers of CD8+ T cells. Additional mice were thymectomized before receiving anti-CD4 or anti-CD8 monoclonal antibodies. Islet graft survival was determined histologically as fetal pig islets were too immature to secrete insulin. Results: Xenograft survival in control animals was 7 to 14 days. In contrast, graft survival in class II-, CD4+ mice was significantly prolonged to greater than 35 days. Depletion of CD8+ T cells in class II-, CD4+ mice prolonged graft survival to about 70 days. Depletion of CD4+ T cells from these mice further prolonged xenograft survival to about 100 days. Conclusions: These results suggest that the rejection of pig islets by mice initially depends on a CD4 dependent indirect response. The CD4 direct response also contributes to graft destruction. CD8+ T cells also participate in graft destruction, albeit weakly.