CD45RB-targeting strategies for promoting long-term allograft survival and preventingchronic allograft vasculopathy.
BACKGROUND
CD45RB is a potent immunomodulatory target to achieve long-term allograft survival. We evaluated the in vivo effect of anti-CD45RB monoclonal antibody (mAb) treatment in combination with conventional immunosuppression or costimulatory blockade strategies as a therapeutic modality for future clinical application.


METHODS
A fully MHC-mismatched vascularized mouse cardiac allograft model was used to test the interactions between anti-CD45RB mAb and conventional immunosuppressive drugs or costimulatory blockade of the CD40/CD154 or B7/CD28 pathway. Chronic rejection was examined histologically for development of chronic allograft vasculopathy.


RESULTS
Cyclosporine significantly abrogated the effect of anti-CD45RB therapy. In contrast, rapamycin acted synergistically with anti-CD45RB mAb in promoting long-term allograft survival. CD154 blockade further enhanced the tolerogenic efficacy of anti-CD45RB mAb. These synergistic effects of combination treatments also prevented the development of chronic allograft vasculopathy.


CONCLUSIONS
CD45RB-targeting strategy in combination with the use of rapamycin or costimulatory blockade promotes allograft tolerance and prevents chronic rejection.
Sho
Masayuki
M
Department of Medicine, Children's Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Harada
Hiroshi
H
Rothstein
David M
DM
Sayegh
Mohamed H
MH
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018122:B7-1 Antigen / Q000276:immunology; D001787:Blood Group Incompatibility; D018106:CD28 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D002908:Chronic Disease; D003327:Coronary Disease / Q000517:prevention & control*; D016572:Cyclosporine / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D017493:Leukocyte Common Antigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000627:therapeutic use; D023001:Transplantation Tolerance / Q000187:drug effects; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D018106:CD28 Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D000069594:Abatacept; D016572:Cyclosporine; D017493:Leukocyte Common Antigens; D020123:Sirolimus