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

• Published in: Transplant immunology Vol. 24; no. 4; pp. 203 - 209
• Main Authors: Andakyan, Arthur, Burruss, Sigrid, Hong, Long-Sheng, Shen, Xiu-Da, Romanov, Sergei, Gao, Feng, Feldman, Daniel M, Fishbein, Michael C, Semiletova, Natalya V
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-05-2011
• Subjects: Allergy and Immunology; Animals; Antigens, CD - biosynthesis; Cells, Cultured; Chronic Disease; Forkhead Transcription Factors; Graft Rejection - prevention & control; Heart Transplantation; Histocompatibility Antigens Class I - administration & dosage; Immunotherapy; Lymphocyte Activation - drug effects; Male; Mast cell; Mast Cells - drug effects; Mast Cells - immunology; Mast Cells - metabolism; Mast Cells - pathology; MHC class I protein; Rats; Rats, Inbred WF; T regulatory cell; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Transplant chronic rejection; cyclosporine; T regulatory cell; MHC class I; CD4-CsA; neointimal index; TVS; CsA; CD4 + positive cells induced with donor-like MHC class I proteins; major histocampatibility complex class I; transpalnt vascular sclerosis; MHC class I protein; CD4-MHC; T regulatory cells; CD4 + cells induced with high-dose CsA; Mast cell; NL; T-regs; Transplant chronic rejection
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/j.trim.2011.01.002

Abstract 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.