Improving the Efficacy of Costimulation Blockade by Targeting T Cell Memory

Islet transplantation has been shown to eliminate the requirement for insulin in patients with type 1 diabetes. However, successful islet transplantation requires the use of immunosuppressive drugs to prevent rejection, and this substantially limits its benefit and adds to its risk. In particular, drugs such as calcineurin inhibitors (CNIs) and corticosteroids themselves cause diabetes and substantially worsen islet function. Additionally, current therapies impair other immune responses. Ideally a regimen should avoid causing diabetes and leave protective immunity relatively intact. Costimulation blockade (CoB) remains an attractive strategy for the prevention of islet rejection without generalized immune incompetence. Agents blocking the CD28/B7 pathway are the most immediately relevant for clinical application but fail to work optimally when patients have a particular type of activated cell (the memory T cells) that reacts against the donor. This application seeks to develop a safe and effective means of optimizing CoB by combining CoB with sirolimus and a drug, alefacept that has the ability to neutralize CoB resistant memory T cells. We have shown that a drug regimen combining sirolimus, alefacept and CoB prevents kidney transplant rejection in monkeys, in some cases resulting in lasting rejection-free survival long beyond the period of drug therapy. Importantly, the regimen does so without the drugs that cause diabetes (such as CNIs). We propose to optimize this approach in islet transplantation, developing a clinically applicable therapy that avoids CNIs, steroids, or gross T cell depletion. Results in this model will be immediately applicable in human islet transplantation.