Journal
CURRENT OPINION IN ORGAN TRANSPLANTATION
Volume 10, Issue 4, Pages 265-269Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.mot.0000186082.47623.76
Keywords
CD28; CD40; CD 154; rejection; T cell costimulation; transplantation
Categories
Ask authors/readers for more resources
Purpose of review Blockade of T cell costimulatory pathways has enormous potential as an immunosuppressive strategy to prolong the survival of solid organ transplants. Discovery of the CD28 costimulatory pathway led to the development of both monoclonal antibodies and fusion proteins that interrupt CD28 signaling. Subsequent studies in both animal models and humans demonstrated that although these molecules had promise as immunosuppressive agents for solid organ transplantation, they lacked the desired clinical efficacy. Recent advances in the field of immunobiologics allowed for the development of rationally modified agents, such as LEA29Y (belatacept), that more effectively target costimulatory molecules. This review summarizes the current understanding of the role of CD28 costimulatory blockade as an immunosuppressive strategy in organ transplantation. Recent findings This review highlights the strategy used to engineer a fusion protein (LEA29Y, belatacept) from its parent compound (cytotoxic T lymphocyte 4-immunoglobulin) that has higher avidity for CD28 ligands and more potent immunosuppressive effects. Summary Before the development of cyclosporine in the early 1980s, the success of transplantation was limited by high rates of rejection and consequent organ loss. Unfortunately, cyclosporine and most subsequently developed immunosuppressive drugs target ubiquitously expressed molecules, causing a myriad of significant side effects unrelated to their primary immunosuppressive effect. Early studies demonstrated complete T cell activation to be critically dependent on signals provided by costimulatory molecules such as CD28 and its ligands B7-1 and B7-2. This provided the impetus for the investigation of agents that block or inhibit these signals with the goal of developing compounds that have less deleterious side effects.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available