CD28-B7-mediated T cell costimulation in chronic cardiac allograft rejection: differential role of B7-1 in initiation versus progression of graft arteriosclerosis.
Provision of adequate T cell costimulation is critical for the development of acute and chronic allograft rejection. We have previously reported that early blockade of CD28-B7 T cell costimulation prevents the development of graft arteriosclerosis, in the LEW into F344 rat cardiac transplant model. In this study, we used the same model to examine the requirement for CD28-B7-mediated T cell costimulation in the progression of established chronic rejection and examined the individual roles of B7-1 (CD80) and B7-2 (CD86) costimulatory molecules. Late blockade of CD28-B7 T cell costimulation by the fusion protein CTLA4Ig, which binds both CD80 and CD86, attenuated the development of transplant arteriosclerosis, mononuclear cell infiltration, and parenchymal fibrosis in this model. Selective blockade of CD80 using the mutant fusion protein Y100F was as effective as CTLA4Ig in this regard. In contrast to CTLA4Ig, blockade of CD80 alone by Y100F was ineffective at preventing early graft loss and prolonging graft survival when given early after transplantation. This study is the first to demonstrate that late blockade of CD28-B7 T cell costimulation interrupts chronic cardiac allograft rejection, and it indicates the importance of continued T cell activation in this process. This study further defines functional differences between CD80 and CD86 costimulatory molecules in vivo.
Laboratory of Immunogenetics, Renal Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.
K S
KS
Kim
M D
MD
Denton
A
A
Chandraker
A
A
Knoflach
R
R
Milord
A M
AM
Waaga
L A
LA
Turka
M E
ME
Russell
R
R
Peach
M H
MH
Sayegh
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D020212:Carotid Artery Injuries / Q000209:etiology / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division; D003324:Coronary Artery Disease / Q000209:etiology / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D004334:Drug Administration Schedule; D005355:Fibrosis / Q000473:pathology; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects*; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000473:pathology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept