Immunosuppressive Medications

Abstract

Immunosuppressive agents are commonly used in the nephrologist's practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist.

Keywords: GN; activation; cell; cytokines; immunology; kidney transplantation.

Figure 1.

Schematic representation and nomenclature of mAbs in clinical use. The suffix denotes of the degree of human versus nonhuman components.

Figure 2.

Immunosuppressive agents targeting T cell/antigen-presenting cell interaction and early T cell activation. This depicts agents that inhibit signal 1 and signal 2 in T cell activation. APC, antigen-presenting cell; CNI, calcineurin inhibitor; CTLA4, cytotoxic T lymphocyte–associated protein 4; ICAM, intracellular adhesion molecule 1; LFA-1, lymphocyte function–associated antigen-1; NFAT, nuclear factor of activated T cells; TCR, T cell receptor.

Figure 3.

Immunosuppressive agents targeting T cell/B cell interaction, plasma cell function, and complement-mediated injury. APRIL, proliferation-inducing ligand; BAFF, B cell–activating factor; MAC, membrane attack complex; TACI, transmembrane activator and CAML interactor; TCR, T cell receptor.

Figure 4.

Immunosuppressive agents targeting later stages of T cell differentiation and proliferation and selected cytokines. This depicts agents that inhibit signal 3, T cell proliferation. JAK, Janus kinase; mTOR, mammalian target of rapamycin; PI-3K, phosphoinositide 3-kinase; R, receptor; STAT, signal transducer and activator of transcription.