CD154 is the ligand for the receptor CD40. This ligand-receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.

We describe an altruistic nondirected (ND) and live donor/deceased donor list exchange (LE) donor program administered by an organ procurement organization (OPO) in the Washington, DC area. Screening eliminated 25 donors (17 NE; 8 LE) from the 97 donor applications (62 ND; 35 LE) completed. Twentyone donors (16 ND; 5 LE) failed to follow through with the psychiatric evaluation, which eliminated 13 donors (9 ND; 4 LE). Two donors dropped out and 12 (9 ND; 3 LE) were medically unsuitable after final clinical evaluation. Twenty donor procedures were performed (10 ND; 10 LE) with four pending (2 ND; 2 LE). This resulted in a modest 3-5% increase in the OPO-procured kidney organ pool. The average cold ischemia time of the grafts not transported between transplant centers was 205 ± 66 min compared with 243 ± 48 min for transported grafts. With no documented adverse outcomes, donors had a hospital stay of length 2.9 days and at home recuperation of 12.3 days. Three-and 6-month creatinines were 1.44 ± 1.36 and 1.68 ± 0.61 for grafts not transported between transplant centers, and 1.6 ± 0.27 and 1.6 ± 0.44 for transported grafts. An OPO-administered altruistic donor program can serve as a model for cooperative donation, recovery and allocation of living donor kidneys.

CD80 and CD86 (also known as B7-1 and B7-2, respectively) are both ligands for the T cell costimulatory receptors CD28 and CD152. Both CD80 and CD86 mediate T cell costimulation, and as such, have been studied for their role in promoting allograft rejection. In this study we demonstrate that administering monoclonal antibodies specific for these B7 ligands can delay the onset of acute renal allograft rejection in rhesus monkeys. The most durable effect results from simultaneous administration of both anti-B7 antibodies. The mechanism of action does not involve global depletion of T or B cells. Despite in vitro and in vivo evidence demonstrating the effectiveness of the anti-B7 antibodies in suppressing T cell responsiveness to alloantigen, their use does not result in durable tolerance. Prolonged therapy with murine anti-B7 antibodies is limited by the development of neutralizing antibodies, but that problem was avoided when humanized anti-B7 reagents are used. Most animals develop rejection and an alloantibody response although still on antibody therapy and before the development of a neutralizing antibody response. Anti-B7 antibody therapy may have use as an adjunctive agent for clinical allotransplantation, but using the dosing regimens we used, is not a tolerizing therapy in this non-human primate model.

Previous studies of the effect of donor factors on renal transplant outcomes have not tested the role of recipient body mass index, donor/recipient weight ratios and age matching, and other factors. We analyzed 20 309 adult (age 16 or older) recipients having solitary cadaveric renal transplants from adult donors from 1 July 1994 to 30 June 1998 in an historical cohort study (the 2000 United States Renal Data System) of death censored graft loss by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. The only independently significant findings in Cox Regression analysis were a high donor/ recipient age ratio (Ն 1.10, e.g. a 55-year-old donor given to a recipient age 50 years or younger, adjusted hazard ratio (AHR) 3.22, 95% confidence interval (CI) 2.36-4.39) and African American donor kidneys (AHR 1.64, 95% CI, 1.24-2.17). African American recipients and older donors were not at independently increased risk of graft failure in this model. Among donor factors, older donor kidneys given to younger recipients and donor African American kidneys were independently associated with graft loss in recipients of cadaver kidneys. The task for the transplant community should be to find the best means for managing all donor organs without discouraging organ donation. **The opinions are solely those of the authors and do not represent an endorsement by the Department of Defense or the National Institutes of Health. This is a government work. There are no restrictions on its use. 68