Soluble donor-like MHC class I proteins induce CD4+CD25+CD8−FoxP3+ cells with potential to ameliorate graft chronic injury

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.