Soluble donor-like MHC class I proteins induce CD4(+)CD25(+)CD8(-)FoxP3(+) cells with potential to ameliorate graft...

Conventional immunosuppressive therapies failed to prevent allograft chronic rejection. New approaches to modulate recipient immune response are needed. Donor-like MHC class I soluble proteins demonstrated therapeutic potential to suppress chronic rejection. The present study was designed to clarify the ability of MHC class I soluble proteins to induce T regulatory cells with true regulatory potential in a fully allogeneic rat cardiac transplant model. Donor-like MHC class I proteins upregulate small population of splenic CD8(-) negative CD4(+)CD25(+)FoxP3(+) positive cells. CD4(+) splenocytes after MHC therapy suppress lymphocyte proliferation against donor antigens in vitro. ACI recipients of WF hearts treated with CD4(+) cells, induced with donor-like MHC class I proteins (CD4-MHC), demonstrated stable survival of the transplanted organ (MST >120 days; n=17). Histology revealed that grafts of recipients treated with CD4-MHC had 23.6% vessels affected 100 days postgrafting. On the contrary, hearts obtained from long-term surviving hosts treated with CD4(+) cells induced with high-dose CsA (CD4-CsA) had 50-70% of affected vessels. CD4-MHC class I treated transplants were mostly CD3(-) negative, had low level of mast and FoxP3(+) cell infiltration compared to CD4-CsA treated hearts. Intragraft CD4(+) cells were close to mast cells in morphology. The same graft tissues had similar number of CD4(+) positive cells and mast cells suggesting existence of CD4(+) positive mast cells. On the other hand, a negligible number of FoxP3(+) positive cells in the grafts after CD4-MHC treatment supports the idea of CD4(+) positive FoxP3(+) negative mast cells population. We demonstrate that donor-like MHC class I protein therapy induces population of CD4(+)CD25(+)CD8(-)FoxP3(+) cells with potential to ameliorate development of transplant vascular disease and evoke CD4(+) positive FoxP3 negative mast cells in the secondary hosts.