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New biologic immunosuppressive agents in transplantation
1Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0676.
Antigen-specific immunologic nonresponsiveness (tolerance) to alloantigens is a goal in transplantation. Most successful strategies of tolerance induction target the T cell. Activation of a quiescent T cell requires two different signals. Signal 1 is delivered when the T-cell receptor is engaged by foreign antigen presented by major histocompatibility complex molecules. Several potential pathways exist to deliver signal 2, which is also termed a costimulatory signal, although by far the best characterized pathway is through the T-cell co-receptor CD28. Blockade of either signal 1 or signal 2 may be sufficient to induce tolerance to alloantigens. Recent advances in knowledge of T-cell receptor-major histocompatibility complex interactions, in mechanisms of self-tolerance and in the identity and importance of costimulatory receptors and their ligands, have led to the development of various new strategies to block signals 1 and 2 using biologic agents. This review focuses on the most promising new modalities.
Antigen-specific immunologic nonresponsiveness (tolerance) to alloantigens is a goal in transplantation. Most successful strategies of tolerance induction target the T cell. Activation of a quiescent T cell requires two different signals. Signal 1 is delivered when the T-cell receptor is engaged by foreign antigen presented by major histocompatibility complex molecules. Several potential pathways exist to deliver signal 2, which is also termed a costimulatory signal, although by far the best characterized pathway is through the T-cell co-receptor CD28. Blockade of either signal 1 or signal 2 may be sufficient to induce tolerance to alloantigens. Recent advances in knowledge of T-cell receptor-major histocompatibility complex interactions, in mechanisms of self-tolerance and in the identity and importance of costimulatory receptors and their ligands, have led to the development of various new strategies to block signals 1 and 2 using biologic agents. This review focuses on the most promising new modalities.