Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile.
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.
Djamali
Arjang
A
Department of Medicine, University of Wisconsin, Madison, Wisconsin 53793, USA. axd@medicine.wisc.edu
Pietrangeli
Carolynn E
CE
Gordon
Robert D
RD
Legendre
Christophe
C
D000069594:Abatacept; D002318:Cardiovascular Diseases / Q000209:etiology*; D002986:Clinical Trials as Topic; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D007165:Immunosuppression Therapy / Q000009:adverse effects* / Q000379:methods; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors; D016030:Kidney Transplantation / Q000009:adverse effects*; D010880:Piperidines; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use
D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D000069594:Abatacept; C479163:tofacitinib; D053616:Janus Kinase 3