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Proc Natl Acad Sci U S A. 2016 Dec 27;113(52):E8425-E8432. doi: 10.1073/pnas.1618548114. Epub 2016 Dec 12.

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

Author information

1
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
2
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065.
3
Department of Biochemistry, Milstein Chemistry Core Facility, Weill Cornell Medicine, New York, NY 10065.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
5
Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021.
6
NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
7
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065.
8
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.
9
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.

Abstract

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.

KEYWORDS:

T-cell exhaustion; allograft; effector T cells; immunoproteasome; memory T cells

PMID:
27956634
PMCID:
PMC5206568
DOI:
10.1073/pnas.1618548114
[Indexed for MEDLINE]
Free PMC Article

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