A hierarchy in the requirement for host MHC class II molecules in the rejection of pancreatic islet allo- and xenografts
Background Host MHC class II-restricted "indirect" graft recognition by CD4 T cells is an important component of both allograft and xenograft immunity. The purpose of this study was to systematically compare the relative contribution of this cellular pathway to the rejection of pancreatic islet allografts vs. concordant (rat) or discordant (porcine) islet xenograft.
Materials and methods Streptozotocin-induced diabetic C57B1/6 (B6; H-2b) or B6 MHC class II-deficient (C2D) mice were grafted with islet allografts (BALB/c; H-2d), WF rat (RT1u) xenografts, or neonatal porcine islet (NPI) xenografts. Parallel studies determined the degree of in vitro reactivity of B6 responding T cells to stimulator cells derived from each type of islet donor.
Results B6 lymph node cells or purified CD4+ or CD8+ T cells responded robustly to either allogeneic BALB/c or xenogeneic WF rat splenocytes but not after stimulation with porcine APCs from varied sources. In vivo, both allogeneic (n = 8) and xenogeneic (WF n = 7 and porcine n = 5) islet grafts were acutely rejected in B6 mice within 13 days post-transplantation. BALB/c islet allografts but not WF rat (n = 5) islet xenografts rejected acutely in C2D recipients (rejection in 12.8 ± 1.1 days vs. >56.8 ± 10.5, respectively). However, 5/7 WF rat xenografts eventually rejected in C2D hosts within 100 days. Interestingly, 6/6 NPI xenografts spontaneously functioned for >100 days post-transplantation in C2D recipients. Since C2D mice are also CD4 T cell deficient, wild-type CD4+ T cells were adoptively transferred into C2D recipients of porcine xenografts. Long-term NPI xenograft survival occurred in C2D hosts despite reconstitution of CD4+ T cells either at the time of grafting or at 100 days post-transplantation.
Conclusions These results indicate that the relative requirement for host MHC class II-restricted antigen presentation varies greatly according to the donor species. Although B6 T cells respond "directly" to rat stimulator cells in vitro, rat islet xenograft rejection in vivo remains largely dependent on host MHC class II/CD4 T cells relative to allograft rejection. In the case of mouse-anti-porcine responses that lack detectable "direct" reactivity in vitro, rejection appears to be almost entirely dependent on host MHC class II, even in the presence of engrafted CD4 T cells.