Cardiac and skin xenograft survival in different recipient mouse strains

There are conflicting reports on the importance of antibody and cell-mediated mechanisms and the influence of TH1 or TH2 cytokines on acute vascular xenograft rejection. We sought to resolve some of the recent discrepancies in the rat-to-mouse xenograft model where different recipient strains are used and investigated the TH1/TH2 influence on rejection.

Lewis rat heart xenograft survival was compared between BALB/c and C57BL/6 recipients. Antigraft antibody deposition, serum anti-rat antibody levels and B-cell deficient recipients were used to examine the contribution of antibody to rejection. To further investigate a TH1 or TH2 bias effect in vivo, we used BALB/c STAT4 knockout (KO) and STAT6 KO recipient mice. Experiments were repeated with rat skin xenografts to examine TH1/TH2 influences on cell-mediated rejection.

The median survival (MS) of rat heart xenografts in BALB/c and C57BL/6 mice was five and eight days, respectively (P = 0.002). The MS in B-cell deficient mice was 16 days (P < 0.001). The MS in STAT4 KO and STAT6 KO mice was six and seven days respectively (P = 0.009). All non-B-cell deficient recipients showed strong IgM deposition and histological features of both cellular and antibody-mediated rejection. There was no correlation between serum anti-rat antibody levels and graft outcome or graft deposition. There was no survival difference of skin xenografts in BALB/c, C57BL/6, B-cell deficient, STAT6 KO, or STAT4 KO mice (8-9 days).

Both humoral and cell-mediated immunity have significant roles in vascularized heart xenograft rejection. TH1/TH2 biases minimally affect rejection through humoral but not cellular immunity.