Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile

Abstract

Currently used immunosuppressants exacerbate cardiovascular risk. However, attempts to limit the use of these agents increase the risk of allograft rejection. Immunosuppressants targeting signal 2 and signal 3 lymphocyte activation pathways are under clinical development. Clinical data from trials of the Janus family protein tyrosine kinase-3 inhibitor tasocitinib and the costimulation blocker belatacept are presented. Additional pipeline agents are described. Results from two phase III clinical trials of belatacept revealed efficacy that is not inferior to that provided by cyclosporine (CsA). In the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial enrolling recipients of standard criteria living or deceased donor organs, the risk of rejection was higher among patients treated with a more intensive treatment regimen. Increased risk of posttransplant lymphoproliferative disorder, particularly among Epstein-Barr virus-patients, was a notable adverse event. Data from a phase II trial of tasocitinib suggested good prophylaxis of rejection. Safety signals included increased risk of infection and potential myelosuppression, leading to anemia, neutropenia, and leukopenia. Both belatacept and tasocitinib were associated with a low cardiovascular risk profile and improved renal function compared with CsA. New immunosuppressive regimens should maintain the effectiveness provided by current agents while preserving renal function and cardiovascular health. Surveillance for new adverse events must be an integral part of the long-term management strategy.

The Future of Heart Transplantation

“…Other new drugs under evaluation include drugs for maintenance therapy (anti‐protein kinase C (65), anti‐Janus kinase‐3 (66), B‐lymphocyte stimulator (67) and novel CNIs).…”

Immunosuppressive and metabolic agents that influence allo‐ and xenograft survival by in vivo expansion of T regulatory cells

“…[1][2][3] Almost all patients with organ transplants require immunosuppressive drug therapy, but the complications and side effects of these agents remain problematic, eg, increased risks of infectious diseases, [4][5][6] lymphoproliferative disorders, 7 cardiovascular disease, renal failure, and diabetes. 8,9 The induction of self-perpetuating tolerance by a short-term intervention might be able to achieve long-term acceptance of an organ graft. 10 Some immunosuppressive and other agents may not only inhibit T cell activation, but also help maintain or promote regulatory T cell (Treg) expansion, stability, and maintenance in vitro and in vivo.…”

“…Organ transplantation remains the preferred treatment for patients with end‐stage organ failure 1‐3 . Almost all patients with organ transplants require immunosuppressive drug therapy, but the complications and side effects of these agents remain problematic, eg, increased risks of infectious diseases, 4‐6 lymphoproliferative disorders, 7 cardiovascular disease, renal failure, and diabetes 8,9 …”