Th1 to Th2 immune deviation facilitates, but does not cause, islet allograft tolerance in mice.
It has been reported that Th1 to Th2 immune deviation effectively promotes peripheral tolerance in situations involving a limited T cell clone size, such as T cell-dependent autoimmunity and transplantation across minor, but not major, histocompatibility barriers. In this study, we tested the hypothesis that while Th1 to Th2 immune deviation fails to induce tolerance in the MHC-mismatched islet allograft model, it may promote a state that is permissive for tolerance induction. Here, we report that anti-IL-12 did not prevent acute rejection of islet allografts when administered alone. In conjunction with CTLA4/Fc, however, anti-IL-12 greatly facilitated long-term engraftment in three MHC-mismatched strain combinations. Similarly, while non-cytolytic IL-4/Fc, a long-lasting form of IL-4, did not prevent acute graft rejection when administered alone, a low, but not a high, dose of IL-4/Fc synergized with CTLA4/Fc in inducing significant levels of islet allograft tolerance. Moreover, by using a skin allograft adoptive transfer model, we show that these effects induced by anti-IL-12 and IL-4/Fc treatment were associated with an enhancement of the suppressive properties of CD4(+)CD25(+) regulatory T cells. Thus, anti-IL-12 and low-dose IL-4/Fc facilitate, but do not cause, islet allograft tolerance in mice by increasing the immunosuppressive potency of CD4(+)CD25(+) regulatory T cells.
Zhang
Dong
D
Division of Plastic Surgery, The Thomas E. Starzl Transplantation Institute, University of Pittsburgh WBST1557, 200 Lothrop Street, Pittsburgh, PA 15213, United States.
Sanchez-Fueyo
Alberto
A
Kawamoto
Kensaku
K
Alexopoulos
Sophoclis P
SP
Zhang
Wensheng
W
Zheng
Xin Xiao
XX
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D007165:Immunosuppression Therapy; D018664:Interleukin-12 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015847:Interleukin-4 / Q000008:administration & dosage / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D011961:Receptors, Fc / Q000008:administration & dosage / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D015847:Interleukin-4