An essential role for programmed death-1 in the control of autoimmunity: implications for the future of hematopoietic stem cell transplantation.

Future Oncol. (2011) 7(8), 929–932 Co-inhibitory receptors are expressed by lymphocytes and other immune system cells. Their central function is to control the activation of the lymphocyte responses by providing negative signals in conjunction with signals from lymphocyte antigen receptors (‘cosignaling’). Recently, co-inhibitory molecules have been extensively studied due to the broad spectrum of their potential application in various novel immunotherapeutic approaches. The cosignaling aspect of these receptors is particularly appealing for clinical development, as non depleting antibodies targeting these co-inhibitory receptors will only affect lymphocytes that are encountering (or have recently encountered) their cognate antigen; ligation of co-inhibitors alone, without antigen receptor signals, has no effect. Even though it is now 40 years since the initial concept of co-inhibitory signaling was pioneered [1] (and reviewed in [2]), only recently have these signaling pathways been specifically targeted for therapy. Agonistic monoclonal antibodies to co-inhibitors are a promising new approach in the prevention of transplant rejection and graftversus-host disease, and may also find application in treating autoimmune disease. Monoclonals that instead block these co-inhibitors are currently undergoing clinical trials in cancer treatment, and one such co-inhibitory blocker, specific to cytotoxic T-lymphocyte antigen 4, has recently achieved US FDA approval. Programmed death-1 (PD-1; CD279), is another important co-inhibitor. It is involved in the regulation of immune responses and self-tolerance [3]. PD-1 has two known ligands: PD-L1 (B7H1; CD274) and PD-L2 (B7DC; CD273). A recent study suggested that PD-1 may have a specific role in controlling T cells during lymphopenia, although a requirement for PD-1 in the control of lymphopenia-driven autoimmunity was not examined [4]. Autoimmunity can only rarely be attributed to variants of a single gene alone. Instead, discovery of the causes of most autoimmunity will be found in synergisms between alleles of many different genes and their interactions with the environment.