Costimulatory Blockade

Drugs that block T cell costimulatory pathways reduce acute allograft rejection. The rationale for the use of these types of drugs is to prevent the delivery of costimulatory signals required for activation of T cells (see Chapter 9). A soluble high-affinity form of CTLA-4 fused to an IgG Fc domain binds to B7 molecules on APCs and prevents them from interacting with T cell CD28 (see Chapter 9, Fig. 9-7) and is near approval for use in allograft recipients. Clinical studies have shown that CTLA-4-Ig can be as effective as cyclosporine in preventing acute rejection. An antibody that binds to T cell CD40 ligand and prevents its interactions with CD40 on APCs (see Chapter 9) has also proved beneficial for preventing graft rejection in experimental animals. In some experimental protocols, simultaneous blockade of both B7 and CD40 appears to be more effective than either alone in promoting graft survival. However, the anti-CD40L antibody has a serious side effect of thrombotic complications, apparently related to the expression of CD40L on platelets.

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