Belatacept and basiliximab diminish human antiporcine xenoreactivity and synergize to inhibit alloimmunity.
BACKGROUND
Maintenance immunosuppression with calcineurin inhibitor therapy has improved survival rates in solid organ transplantation over the past decade. However, these drugs are associated with negative side effects, including nephrotoxicity and new-onset diabetes. Selective immunomodulatory agents such as belatacept and basiliximab have shown great promise in promoting allograft survival. In the present study, in vitro experiments were conducted to determine if these agents could synergize to inhibit immune responses.


METHODS
Porcine and human lymphocytes were incubated with each drug and analyzed using flow cytometry to measure binding capability. The inhibitory effects of each drug were evaluated using mixed lymphocyte reactions with drug doses comparable to the trough levels observed in treated human patients.


RESULTS
Our data demonstrates that belatacept and basiliximab bind to porcine peripheral blood mononuclear cells. Mixed lymphocyte reactions revealed that both belatacept and basiliximab monotherapy potently inhibited allogeneic immune responses and human antipig xenoreactivity. These data also demonstrate that combination of belatacept and basiliximab produces a synergistic inhibition of allogeneic immune responses.


CONCLUSIONS
These studies suggest that the combination of belatacept and basiliximab will potently inhibit alloreactivity in vivo when used as maintenance immunosuppression. We have further shown that belatacept and basiliximab are significantly reduce xenoreactivity of human lymphocytes in vitro.
Emamaullee
Juliet A
JA
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. juliete@ualberta.ca
Merani
Shaheed
S
Larsen
Christian P
CP
Shapiro
A M James
AM
D000069594:Abatacept; D000818:Animals; D000910:Antibodies, Heterophile / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D015478:Antigens, Heterophile / Q000378:metabolism*; D000077552:Basiliximab; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D023421:Models, Animal; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D000910:Antibodies, Heterophile; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015478:Antigens, Heterophile; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D000077552:Basiliximab