Inhibition of the Immunoproteasome Subunit LMP7 with ONX 0914 Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompatibility Antigen–Disparate Murine Model

Zilberberg, Jenny; Matos, Jennifer; Dziopa, Eugenia; Dziopa, Leah; Yang, Zheng; Kirk, Christopher J.; Assefnia, Shahin; Korngold, Robert

doi:10.1016/j.bbmt.2015.06.010

Cited by 15 publications

(8 citation statements)

References 24 publications

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“…Interestingly, Zilberberg et al reported LMP7 inhibition to be ef fective in ameliorating graft versus host disease (GvHD) in a miHA disparate murine blood and marrow transplant (BMT) model by de creasing endogenous miHA presentation and consequently reducing allogeneic stimulation and cytokine production (Zilberberg et al, 2015). In contrast to our study, Zilberberg et al used a daily or even 2 x daily treatment regimen, which might have a stronger effect than our treatment strategy.…”

Section: Discussioncontrasting

confidence: 61%

“…LMP7 inhibition was shown to suppress the differentiation of Th1 and Th17 cells in vitro and in vivo (Muchamuel et al, 2009;Basler et al, 2014;Kalim et al, 2012;Mundt et al, 2016b;Zilberberg et al, 2015). Consequently, the decreased allo specific Th17 differentiation of ONX 0914 treated cells in vitro prompted us to investigate the influence of LMP7 inhibition on allogeneic immune responses in vivo using a murine skin allograft transplantation model.…”

Section: Onx 0914 Treatment Does Not Prolong Graft Survival In An Mhcmentioning

confidence: 99%

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No prolongation of skin allograft survival by immunoproteasome inhibition in mice

Mundt

Basler

Sawitzki

et al. 2017

Molecular Immunology

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The immunoproteasome, a distinct class of proteasomes, which is inducible under inflammatory conditions and constitutively expressed in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Moreover, inhibition of the immunoproteasome subunit LMP7 ameliorates clinical symptoms of autoimmune diseases in vivo and was shown to suppress the development of T helper cell (Th) 1 and Th17 cells and to promote regulatory T-cell (Treg) generation independently of its function in antigen processing. Since Th1 and Th17 cells are detrimental and Treg cells are critical for transplant acceptance, we investigated the influence of the LMP7-selective inhibitor ONX 0914 in a mixed lymphocyte reaction (MLR) in vitro as well as on allograft rejection in a MHC-disparate (C57BL/6 to BALB/c) and a multiple minor histocompatibility antigen (miHA)-disparate (B10.Br to C3H) model of skin transplantation in vivo. Although we observed reduced allo-specific IL-17 production of T cells in vitro, we found that selective inhibition of LMP7 had neither an influence on allograft survival in an MHC-mismatch model nor in a multiple minor mismatch skin transplantation model. We conclude that inhibition of the immunoproteasome is not effective in prolonging skin allograft survival in skin allotransplantation.

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Section: Discussioncontrasting

confidence: 61%

Section: Onx 0914 Treatment Does Not Prolong Graft Survival In An Mhcmentioning

confidence: 99%

No prolongation of skin allograft survival by immunoproteasome inhibition in mice

Mundt

Basler

Sawitzki

et al. 2017

Molecular Immunology

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“…44 Furthermore, β5i inhibition prevented experimental colitis, 45 Hashimoto thyroiditis, 46 and graft-versus-host disease in an MHC-matched minor histocompatibility antigen-disparate murine model. 47 In addition to providing irreversible proteasome inhibition, carfilzomib displays a distinct, advantageous adverse-event profile compared to bortezomib for the treatment of patients with MM. Understanding of the mechanisms of resistance to proteasome inhibition will not only allow better use of PIs, but may also facilitate rational design of more effective synergistic drug combinations for clinical trials to reduce the BMPCs responsible for alloantibody production.…”

Section: Discussionmentioning

confidence: 99%

“…[37][38][39][40][41][42][43] It is notable that the β5i-selective inhibitor ONX0914 has shown to suppress autoreactive immune responses in mouse models of arthritis and diabetes. 47 In addition to providing irreversible proteasome inhibition, carfilzomib displays a distinct, advantageous adverse-event profile compared to bortezomib for the treatment of patients with MM. 47 In addition to providing irreversible proteasome inhibition, carfilzomib displays a distinct, advantageous adverse-event profile compared to bortezomib for the treatment of patients with MM.…”

Section: Cd138 + In Vitro + Cfzmentioning

confidence: 99%

Proteasomal adaptations underlying carfilzomib-resistance in human bone marrow plasma cells

Woodle

Tremblay

Brailey³

et al. 2020

American Journal of Transplantation

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Donor-specific antibodies (DSAs) have a deleterious effect on allografts and remain a major immunologic barrier in transplantation. Current therapies to eliminate DSAs are ineffective in highly HLA-sensitized patients. Proteasome inhibitors have been employed as a strategy to target bone marrow plasma cells (BMPCs), the source of long-term antibody production; however, their efficacy has been limited by poorly defined drug-resistance mechanisms. Here, we performed transcriptomic profiling of CD138 + BMPCs that survived in vivo desensitization therapy with the proteasome inhibitor carfilzomib to identify mechanisms of drug resistance. The results revealed a genomic signature that included increased expression of the immunoproteasome, a highly specialized proteasomal variant. Western blotting and functional studies demonstrated that catalytically active immunoproteasomes and the immunoproteasome activator PA28 were upregulated in carfilzomib-resistant BMPCs.Carfilzomib-resistant BMPCs displayed reduced sensitivity to the proteasome inhibitors carfilzomib, bortezomib, and ixazomib, but enhanced sensitivity to an immunoproteasome-specific inhibitor ONX-0914. Finally, in vitro carfilzomib treatment of BMPCs from HLA-sensitized patients increased levels of the immunoproteasome β5i (PSMB8) catalytic subunit suggesting that carfilzomib therapy directly induces an adaptive immunoproteasome response. Taken together, our results indicate that carfilzomib induces structural changes in proteasomes and immunoproteasome formation. K E Y W O R D Sbasic (laboratory)

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“…The best known function of the iP is its role in antigen processing; however, since astrocytes present little or no antigen [84][85][86], alternate functions of the iP were examined, namely clearance of ROS and oxidatively damaged and poly-ubiquitinated proteins [87]. To determine the role of the iP in astrocyte viability and ROS clearance, we treated regional human astrocytes with or without IFNγ and a specific inhibitor of the iP, ONX 0914 [88][89][90]. Following iP inhibition, an increase in caspase activity was observed only in spinal cord astrocytes compared to media treatment, which was significantly enhanced compared to those from the brainstem (Fig.…”

Section: Ros and Poly-ubiquitinated Protein Accumulation Are Abrogatementioning

confidence: 99%

The impact of regional astrocyte interferon-γ signaling during chronic autoimmunity: a novel role for the immunoproteasome

Smith

Sinyuk

Jenkins

et al. 2020

J Neuroinflammation

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Background: In early autoimmune neuroinflammation, interferon (IFN)γ and its upregulation of the immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNγ has protective properties. Although dysregulation of the iP has been implicated in neurodegeneration, its function remains to be fully elucidated. Here, we demonstrate that IFNγ signaling in regional astrocytes induces the iP and promotes protection of the CNS during chronic autoimmunity. Methods: In a multiple sclerosis (MS) brain, we evaluated mRNA expression and labeled postmortem MS brainstem and spinal cord for iP subunits and indicators of oxidative stress. Primary regional human astrocytes were analyzed for iP regulation and function by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, OxyBlot, and reactive oxygen species and caspase activity detection assays. Following immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 , the role of IFNγ signaling and the iP during chronic experimental autoimmune encephalomyelitis (EAE) were assessed using pharmacologic inhibition of the iP and genetic interruption of IFNγ signaling specifically in astrocytes. Central nervous system (CNS) tissues were analyzed by immunohistochemistry (IHC) and immunofluorescence, and cell-specific colocalization was quantified. Results: In MS tissue, iP expression was enhanced in the spinal cord compared to brainstem lesions, which correlated with a decrease in oxidative stress. In vitro, IFNγ stimulation enhanced iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal model, EAE, ONX 0914 treatment exacerbated the disease and led to increased oxidative stress and polyubiquitinated protein buildup. Finally, mice with astrocyte-specific loss of the IFNγ receptor exhibited worsened chronic EAE associated with reduced iP expression, enhanced lesion size and oxidative stress, and poly-ubiquitinated protein accumulation in astrocytes. Conclusions: Taken together, our data reveal a protective role for IFNγ in chronic neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity.

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Inhibition of the Immunoproteasome Subunit LMP7 with ONX 0914 Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompatibility Antigen–Disparate Murine Model

Cited by 15 publications

References 24 publications

No prolongation of skin allograft survival by immunoproteasome inhibition in mice

No prolongation of skin allograft survival by immunoproteasome inhibition in mice

Proteasomal adaptations underlying carfilzomib-resistance in human bone marrow plasma cells

The impact of regional astrocyte interferon-γ signaling during chronic autoimmunity: a novel role for the immunoproteasome

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