Expression of B7 molecules in recipient, not donor, mice determines the survival of cardiac allografts.
Blockade of the CD28/CTLA4/B7 costimulatory pathway using CTLA4-Ig has great therapeutic potential, and has been shown to prolong allograft survival in a variety of animal models. To gain further insight into the mechanism by which costimulatory blockade prevents allograft rejection, we studied cardiac allograft survival in the complete absence of B7 costimulation using mice lacking B7-1 and B7-2 (B7-1/B7-2-/- mice). To determine the role of B7 on donor vs recipient cells, we used B7-1/B7-2-/- mice as either donors or recipients of allografts. Wild-type (WT) recipients acutely reject fully allogeneic hearts from both WT and B7-1/B7-2-/- mice. In contrast, B7-1/B7-2-/- recipients allow long-term survival of grafts from both WT and B7-1/B7-2-/- mice, with minimal histologic evidence of either acute or chronic rejection in grafts harvested after 90 days. The B7-1/B7-2-/- mice acutely reject B7-1/B7-2-/- allografts if CD28 stimulation is restored by the administration of Ab to CD28 and can mount an alloresponse in mixed lymphocyte reactions. Therefore, B7-1/B7-2-/- mice are capable of generating alloresponses both in vivo and in vitro. Our results demonstrate that in the alloresponse to mouse heterotopic cardiac transplantation, B7 molecules on recipient cells rather than donor cells provide the critical costimulatory signals. The indefinite survival of allografts into B7-1/B7-2-/- recipients further shows that the absence of B7 costimulation alone is sufficient to prevent rejection.
Mandelbrot
D A
DA
Immunology Research Division, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. dmanandelbr@bics.bwh.harvard.edu
Furukawa
Y
Y
McAdam
A J
AJ
Alexander
S I
SI
Libby
P
P
Mitchell
R N
RN
Sharpe
A H
AH
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000096:biosynthesis; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014184:Transplantation, Homologous
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D000069594:Abatacept