Transplantation is the treatment of choice for most end-stage diseases of the kidney, liver, and heart. Although patients benefit in terms of improved quality of life and longevity, they must take immunosuppressive drugs to prevent organ rejection. Side effects lead to significant problems including an increased incidence of cancer, infection, diabetes, osteoporosis, and renal failure. Thus, transplantation remains a trade of a fatal disease for a chronic condition, and minimization of immunosuppression has become an increasingly investigated clinical strategy. Sadly, there are no tests that adequately determine one's need for immunosuppression, nor are there tests that determine excessive immunosuppression. This group designs and implements therapy allowing for organ transplantation without long-term drug requirements or consequences of acquired immunodeficiency - a state defined as tolerance. We test tolerance regimens and immunosuppressive minimization strategies in human kidney recipients. Assays are also developed to more precisely assess immune interventions. Experimental evidence suggests that aggressive perioperative T-cell depletion can reduce the risk of allograft rejection. Our prior clinical trials with the humanized CD52-specific monoclonal antibody (Mab) alemtuzumab, a depleting agent approved for use against leukemia have shown that depletion alone does not induce tolerance as it does in some animal models. Rather, we have characterized this previously un-described form of rejection as being rich in macrophages and associated with a specific T-cell type, the effector memory T cell. In vitro studies have shown that calcineurin inhibitors uniquely prevent the activity of this cell type and we have now shown in a pilot clinical trial that the combination of depletion with a single low dose of the calcineurin inhibitor tacrolimus prevents rejection in humans without the need for steroids or multi drug immunosuppression. In addition to attenuating the activity of effector memory T cells, calcineurin inhibiton also appears to limit the liberation of critical chemokines from the allograft, and thus tacrolimus may have unrecognized effects of immune chemotaxis as well as T cell activation. One problem with the use of tacrolimus is its tendency to limit adaptive immune processes like activation induced cell death that may be required for the development of allograft tolerance. It is also nephrotoxic, a clear drawback when considering renal transplantation. The mTOR inhibitor sirolimus has been suggested to be a better long term agent as it is less nephrotoxic, and may foster specific elimination of graft specific T cells. However, we have shown that sirolimus as a stand alone agent is a sub-optimal drug for preventing post-depletional rejection. We have therefore initiated a clinical trial that combines tacrolimus and sirolimus until the risk of early rejection has decreased (approximately 6 months). Patients are then randomized to wean to either tacrolimus or sirolimus. We are now accruing patients to this trial to determine if the early use of dual therapy followed by a wean to monotherapy will favor adaptive tolerance without risking early rejection. We are specifically comparing patients that have been successfully weaned to monotherapy tacrolimus or sirolimus to determine if the predicted benifits and drawbacks of each agent are seen in humans as predicted by prior animal study. In other studies, we have investigated the use of quantitative PCR-based technologies to more precisely delineate immune activity in renal allografts compared to histology and serve as a tool to improve the diagnostic evaluation of allograft recipients. The diagnosis of acute cellular rejection (ACR) is typically made histologically. However, many patients with histological rejection have normal renal function. The significance of this so-called sub-clinical rejection (SCR) has not been deefined. The treatment of SCR is particularly controversial in tolerance trials, as treatment might disrupt potentially salutary regulation. We have developed a PCR-based platform that allows for quantitative quadruplicate analysis of 96 transcripts in quadruplicate (384 wells) from 100ng of total RNA template in approximately 3 hours. To evaluate the utility of this method, and establish a baseline for standard transplant pathology to which tolerance trials can be compared, we have characterized most states relevant to renal transplantation in patients undergoing standard immunosuppression, and correlated findings to histology. We have now identified 3 genes that have strong correlation with the functional significance of a rejection episode. These are Fas ligand, the TH1 transcription factor Tbet and CD152. We are now establishing a prospective trial to investigate the use of molecular monitoring to improve post transplant immune management and are extending the use of this transcriptional technique to other graft pathologies such as drug toxicity, BK virus infection and chronic allograft nephropathy. In an extention of our more basic work, we are now developing a clinical trial evaluating the use of a novel B7 molecule agonist in combination with depletional induction and mTOR inhibition. Pre-clinical studies suggest that this approach may foster tolerance better than depletion alone, or chronic mTOR inhibition alone.
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