Portal de Periódicos da CAPES

Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice

2016; National Academy of Sciences; Volume: 113; Issue: 52 Linguagem: Inglês

10.1073/pnas.1618548114

1091-6490

Esilida Sula Karreci, Hao Fan, Mayuko Uehara, Albana B. Mihali, Pradeep K. Singh, Ahmed T. Kurdi, Zhabiz Solhjou, Leonardo V. Riella, Irene M. Ghobrial, Teresina Laragione, Sujit Routray, Jean Pierre Assaker, Rong Wang, George Sukenick, Lei Shi, Franck J. Barrat, Carl Nathan, Gang Lin, Jamil Azzi,

Immunotherapy and Immune Responses

Significance The potential of proteasome inhibitors to prevent transplant rejection and to treat other immune disorders is hindered by mechanism-based toxicity from inhibition of constitutive proteasomes. Here, we demonstrate that briefly, reversibly, and selectively inhibiting the immunoproteasome prolonged the survival of transplanted hearts in mice and allowed long-term survival when combined with single-dose CTLA4-Ig. Immunoproteasome inhibition noncytotoxically reduced T-cell proliferation and the numbers of effector T cells in the allograft and draining nodes while increasing T-cell expression of exhaustion markers. The immunoproteasome thus appears to play a role in suppressing induction of T-cell exhaustion. Selective inhibition of the immunoproteasome may be a potential treatment option for the management of transplant rejection.