Current landscape for T-cell targeting in autoimmunity and transplantation

Abstract

In recent years, substantial advances in T-cell immunosuppressive strategies and their translation to routine clinical practice have revolutionized management and outcomes in autoimmune disease and solid organ transplantation. More than 80 diseases have been considered to have an autoimmune etiology, such that autoimmune-associated morbidity and mortality rank as third highest in developed countries, after cardiovascular diseases and cancer. Solid organ transplantation has become the therapy of choice for many end-stage organ diseases. Short-term outcomes such as patient and allograft survival at 1 year, acute rejection rates, as well as time course of disease progression and symptom control have steadily improved. However, despite the use of newer immunosuppressive drug combinations, improvements in long-term allograft survival and complete resolution of autoimmunity remain elusive. In addition, the chronic use of nonspecifically targeted immunosuppressive drugs is associated with significant adverse effects and increased morbidity and mortality. In this article, we discuss the current clinical tools for immune suppression and attempts to induce long-term T-cell tolerance induction as well as much-needed future approaches to produce more short-acting, antigen-specific agents, which may optimize outcomes in the clinic.

Figure 1. Current immunosuppressive drugs and their targets

Signal 1 results from MHC–antigen recognition through the T-cell receptor–CD3 complex, a process blocked by anti-CD3 mAbs and indirectly by rituximab. Signal 2 results in costimulation, a process that can be blocked by belatacept. Costimulation activates downstream signaling pathways, resulting in calcineurin activation, a stage that can be inhibited by tacrolimus and cyclosporine A. Activated calcineurin dephosphorylates NF-AT, allowing IL-2 transcription to initiate signal 3. IL-2 receptor stimulation, a step that can be blocked by basiliximab, activates the mTOR signaling cascade, which can be inhibited by sirolimus. This pathway induces the T cell to enter the cell cycle and proliferate, which in turn can be blocked by methotrexate, mycophenolate and azathioprine. rATG exerts polyclonal effects while alemtuzumab binds to CD52, both resulting in immunodepletion. mAb: Monoclonal antibody; NF-AT: Nuclear factor of activated T cell; rATG: Rabbit antithymocyte globulin.

Figure 2. In vitro proliferation assays using freshly isolated human peripheral blood monocyte incubated with OKT3, TOL101, media alone (negative control) or phorbol 12-myristate 13-acetate and ionomycin (positive control)

After (A) 36 h or (B) 72 h, tritiated thymidine was added to the cultures for 12 h, after which the plates were harvested and the incorporation of thymidine measured as a reflection of the mitogenic capacity of each treatment. While OKT3 and PMA and ionomysin induced significant T-cell proliferation, TOL101 did not. The inability to induce T-cell proliferation was also reflected in a lack of proinflammatory cytokine: (C) IFN-γ, (D) TNF and (E) IL-6. Data presented are the mean and standard deviations from three individual patients’ PBMCs. These experiments have been repeated over three times with over nine independent donors. mAb: Monoclonal antibody; PBMC: Peripheral blood monocyte; PMA: Phorbol 12-myristate 13-acetate.