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(American Journal of Pathology. 2001;158:977-986.)
© 2001 American Society for Investigative Pathology

Regular Articles

CD28-B7-Mediated T Cell Costimulation in Chronic Cardiac Allograft Rejection

Differential Role of B7–1 in Initiation versus Progression of Graft Arteriosclerosis

Kyung Soo Kim{ddagger}, Mark D. Denton*, Anil Chandraker*, Andreas Knoflach*, Rolando Milord*, Anna Maria Waaga*, Laurence A. Turka{dagger}, Mary E. Russell§, Robert Peach and Mohamed H. Sayegh*

From the Laboratory of Immunogenetics,*
Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; the Department of Medicine and Institute of Human Gene Therapy,{dagger}
University of Pennsylvania, Philadelphia, Pennsylvania; the Department of Internal Medicine,{ddagger}
Pundang CHA General Hospital, Pochon CHA University, Pochon, Korea; Parexel International,§
Waltham, Massachusetts; and Bristol-Myers Squibb Pharmaceutical Research Institute,
Princeton, New Jersey

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.




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