Immunosuppressive drug therapy

Abstract

The first successful kidney transplantation between monozygotic identical twins did not require any immunosuppressive drugs. Clinical application of azathioprine and glucocorticosteroids allowed the transfer of organs between genetically disparate donors and recipients. Transplantation is now the standard of care, a life-saving procedure for patients with failed organs. Progress in our understanding of the immunobiology of rejection has been translated to the development of immunosuppressive agents targeting T cells, B cells, plasma cells, costimulatory signals, complement products, and antidonor antibodies. Modern immunopharmacologic interventions have contributed to the clinical success observed following transplantation but challenges remain in personalizing immunosuppressive therapy.

Figure 1.

The antiallograft response and sites of action of common immunosuppressive drugs. Schematic representation of human leukocyte antigen (HLA), the primary stimulus for the initiation of the antiallograft response; cell surface proteins participating in antigenic recognition and signal transduction; contribution of the cytokines and multiple cell types to the immune response; and the potential sites for the action of commonly used immunosuppressive drugs. Figure 2 shows the cell surface proteins on antigen-presenting cells (APCs) interacting with T cells to generate costimulatory/coinhibitory signals. (Adapted from Suthanthiran and Strom 1994; reprinted, with permission, from the authors.)

Figure 2.

T-cell/APC contact sites and potential targets of immunosuppressive drugs. Schematic representation of T-lymphocyte and antigen-presenting cell contact sites. Signal transduction in T cells on recognition of antigen is not by the TCR itself, but proteins CD3 and ζ noncovalently linked to the TCR. Signaling of T cells via the TCR/CD3 complex (antigenic signal) is necessary, but insufficient in itself to induce maximal T-cell proliferation; plenary activation is dependent on both the antigenic signals and the costimulatory signals engendered by the physical interactions among the cell-surface proteins expressed on antigen-specific T cells and those displayed on APCs. Of all the APCs, mature dendritic cells express the highest level of costimulatory proteins. The best-characterized T-cell costimulation pathway is the interaction of CD28 protein on the T-cell surface with the B7-1 and B7-2 (CD80 and CD86) proteins expressed on activated APCs. In the absence of this second signal, T cells either remain unresponsive or become actively tolerant to antigens. CD28-mediated signals increase the production of cytokines as well as promote the survival of T cells by increasing the expression of antiapoptotic proteins. Although costimulatory pathways were discovered as mediators of T-cell activation, homologous molecules are involved in inhibiting T-cell activation. The key inhibitory receptor is the CTLA-4, a member of CD28 family. The higher the affinity of CTLA-4, as compared to CD28, to B7 may determine the differential binding of stimulatory CD28 and inhibitory CTLA-4 to the same B7 on APCs. Several molecules on the T cells or APCs are potential targets for immunosuppressive drug development. Monoclonal antibodies (anti-CD25, anti-CD2) and recombinant fusion proteins (belatacept) targeting specific cell-surface contact sites are available or undergoing clinical trials as immunosuppressive or tolerance-inducing drugs. (Adapted from Suthanthiran 1996; reprinted, with permission, from the author.)