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

Overview

MeSH Major

  • Amino Acids
  • Dipeptides
  • Peptidomimetics
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors

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.

publication date

  • December 27, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5206568

Digital Object Identifier (DOI)

  • 10.1073/pnas.1618548114

PubMed ID

  • 27956634

Additional Document Info

start page

  • E8425

end page

  • E8432

volume

  • 113

number

  • 52