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Designing a Novel Highly Selective Immunoproteasome Inhibitor That Promotes Longterm Heart Allograft Acceptance While Inducing Immune Cell Exhaustion, Treg Induction and Memory Cell Suppression.

E. Sula Karreci,1 A. Mihali,1 M. Uehara,1 A. Kurdi,1 L. Riella,1 R. Abdi,1 H. Fan,2 P. Singh,2 C. Nathan,2 G. Lin,2 J. Azzi.1

1Transplantation Research Center, Harvard Medical School, Boston, MA
2Department of Microbiology and Immunology, Weill Cornell Medicine, New York City, NY.

Meeting: 2016 American Transplant Congress

Abstract number: 84

Keywords: Immunosuppression, Rejection, T cell activation, Tolerance

Session Information

Date: Sunday, June 12, 2016

Session Name: Concurrent Session: Allograft Tolerance 1: Animal Models

Session Time: 4:30pm-6:00pm

 Presentation Time: 4:42pm-4:54pm

Location: Room 306

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The constitutive Proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. However, immunoproteasomes (IP or i-20S) are primarily expressed in immune cells. C-20S and i-20S differ only in the 3 proteolytic β subunits. We show here that in a murine heart transplant model, effector and memory T and B cells upregulate their expression of i-20S. We hypothesized that i-20S inhibition would target memory T and B cells and suppress alloimmunity without the toxicity of inhibiting c-20S.

We designed and synthesized a specific, non-covalent, small molecule inhibitor (DPLG3) of the i-20S β5i subunits. DPLG3 inhibited mouse i-20S with IC50 of 9.4 nM and 1500-fold selectivity over mouse c-20S, and inhibited human i-20S with an IC50 of 4.5 nM and 7000-fold selectivity over human c-20S. C57BL/6 recipients of BALB/c hearts treated with low dose CTLA4Ig (250 [micro]g on day 2) and 14 days injection of DPLG3 (25 mg/kg/day) exhibited indefinite heart survival compared to control (CTLA4Ig + vehicle) (MST >100 and 30 days respectively, n=6/group, p<0.05). DPLG3 significantly reduced effector CD4+ and CD8+ T cells (Teff) coupled with a marked increase in regulatory T cells (Tregs) in spleen and draining LN. Furthermore, Teff in DPLG3-treated mice acquired an exhaustion phenotype with an increased expression of PD1, TIM3 and LAG3, lower Th1, Th17 cytokines and lower GrB expression in CD8+ Teff (P<0.05, n=8 mice/group). Furthermore, RAG-/- mice recipients of BALB/c skin received 10 x 106 CD3 Foxp3-GFP negative cells. DPLG3 treated mice (25 mg/kg/d for 7 d) showed 5-fold increase in induced Tregs in vivo. Furthermore, CD4 and CD8 Teff exhibited more exhaustion phenotype and more apoptosis in DPLG3-treated mice (p<0.05, n= 8 mice/group). Similar results were shown in vitro. Furthermore, CD4+, CD8+ Teff and Treg cells were sorted from DPLG3-treated and vehicle-treated mice and whole RNA seq analysis is underway.

A novel, potent, non-covalent, highly selective IP inhibitor revealed a critical role for the IP in protecting T cells against exhaustion and inhibiting induction of Tregs cells in response to alloimmune activation.

CITATION INFORMATION: Sula Karreci E, Mihali A, Uehara M, Kurdi A, Riella L, Abdi R, Fan H, Singh P, Nathan C, Lin G, Azzi J. Designing a Novel Highly Selective Immunoproteasome Inhibitor That Promotes Longterm Heart Allograft Acceptance While Inducing Immune Cell Exhaustion, Treg Induction and Memory Cell Suppression. Am J Transplant. 2016;16 (suppl 3).

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To cite this abstract in AMA style:

Karreci ESula, Mihali A, Uehara M, Kurdi A, Riella L, Abdi R, Fan H, Singh P, Nathan C, Lin G, Azzi J. Designing a Novel Highly Selective Immunoproteasome Inhibitor That Promotes Longterm Heart Allograft Acceptance While Inducing Immune Cell Exhaustion, Treg Induction and Memory Cell Suppression. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/designing-a-novel-highly-selective-immunoproteasome-inhibitor-that-promotes-longterm-heart-allograft-acceptance-while-inducing-immune-cell-exhaustion-treg-induction-and-memory-cell-suppression/. Accessed January 25, 2021.

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