Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice.
Proc Natl Acad Sci U S A
; 113(52): E8425-E8432, 2016 12 27.
Article
em En
| MEDLINE
| ID: mdl-27956634
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 ß5i that has thousands-fold selectivity over constitutive ß5c. 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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transplante de Coração
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Complexo de Endopeptidases do Proteassoma
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Inibidores de Proteassoma
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Sobrevivência de Enxerto
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Imunossupressores
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article