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

Autor:	Sula Karreci E; Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115., Fan H; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065., Uehara M; Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115., Mihali AB; Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115., Singh PK; Department of Biochemistry, Milstein Chemistry Core Facility, Weill Cornell Medicine, New York, NY 10065., Kurdi AT; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115., Solhjou Z; Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115., Riella LV; Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115., Ghobrial I; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115., Laragione T; Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021., Routray S; Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115., Assaker JP; Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115., Wang R; NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Sukenick G; NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Shi L; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065., Barrat FJ; Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021., Nathan CF; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065; cnathan@med.cornell.edu gal2005@med.cornell.edu jazzi@rics.bwh.harvard.edu., Lin G; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065; cnathan@med.cornell.edu gal2005@med.cornell.edu jazzi@rics.bwh.harvard.edu., Azzi J; Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; cnathan@med.cornell.edu gal2005@med.cornell.edu jazzi@rics.bwh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Dec 27; Vol. 113 (52), pp. E8425-E8432. Date of Electronic Publication: 2016 Dec 12.
DOI:	10.1073/pnas.1618548114
Abstrakt:	Constitutive proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. An isoform of proteasome, the immunoproteasome (i-20S), is highly expressed in human T cells, dendritic cells (DCs), and B cells, suggesting that it could be a potential target for inflammatory diseases, including those involving autoimmunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit β5i that has thousands-fold selectivity over constitutive β5c. DPLG3 suppressed cytokine release from blood mononuclear cells and the activation of DCs and T cells, diminished accumulation of effector T cells, promoted expression of exhaustion and coinhibitory markers on T cells, and synergized with CTLA4-Ig to promote long-term acceptance of cardiac allografts across a major histocompatibility barrier. These findings demonstrate the potential value of using brief posttransplant immunoproteasome inhibition to entrain a long-term response favorable to allograft survival as part of an immunomodulatory regimen that is neither broadly immunosuppressive nor toxic. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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