Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashion

Al-Homsi, Ahmad Samer; Goodyke, Austin; Cole, Kelli; Muilenburg, Marlee; McLane, Michael; Abdel-Mageed, Sarah; Feng, Yi

doi:10.1016/j.exphem.2016.12.002

Cited by 10 publications

(8 citation statements)

References 25 publications

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“…Enhanced release of IL-1β by prestimulated DCs represents a plausible explanation [17,18]. Additionally, we have demonstrated that this phenomenon is associated with an accumulation of donor T cells [19].…”

Section: Introductionmentioning

confidence: 57%

“…Although early administration of proteasome inhibitors after allogeneic HSCT ameliorates GVHD in an experimental murine model, prolonged administration has been associated with worsening gastrointestinal alloreactivity-dependent toxicity and abrupt death [17,18]. We have shown that ixazomib rescues a proportion of mice subjected to lethal experimental GVHD when administered on days +1 and +4 or on days −1, +2, and +5 [19]. However, GVHD aggravation and sudden death occurred in a proportion of mice receiving the prolonged schedule, albeit less frequently than what is reported with bortezomib [19].…”

Section: Discussionmentioning

confidence: 89%

“…Therefore, cells treated with ixazomib are more capable of recovering their proteasome activity than cells treated with bortezomib [20]. We have demonstrated that ixazomib suppresses naïve human DC maturation and cytokine production with a limited impact on cell viability [19]. Several studies indicate that host DCs, necessary for the initiation of GVHD, wane off rapidly after transplantation [25][26][27].…”

Section: Discussionmentioning

confidence: 92%

“…We have shown that ixazomib rescues a proportion of mice subjected to lethal experimental GVHD when administered on days +1 and +4 or on days −1, +2, and +5 [19]. However, GVHD aggravation and sudden death occurred in a proportion of mice receiving the prolonged schedule, albeit less frequently than what is reported with bortezomib [19]. In the current study, the addition of cyclophosphamide completely abrogated the small intestine's GVHD acceleration and sudden death, possibly because of the concomitant deple- tion of alloreactive donor T cells.…”

Section: Discussionmentioning

confidence: 97%

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Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone

Al-Homsi

Goodyke

McLane

et al. 2017

Biology of Blood and Marrow Transplantation

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Lapses in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) warrant novel approaches. Such approaches include, among others, the use of post-transplantation cyclophosphamide (PTC) and proteasome inhibitors. Although PTC alone consistently produces low rates of chronic GVHD, the incidence of acute GVHD remains significant. Inversely, prolonged post-transplantation administration of proteasome inhibitors carries a risk of paradoxical aggravation of GVHD. We examined whether the combination of cyclophosphamide and ixazomib addresses the limitations of each of these agents when used alone to prevent GVHD in mice subjected to allogeneic HSCT across MHC barriers. We chose ixazomib, an orally bioavailable proteasome inhibitor, because of its favorable physiochemical characteristics. The combination of cyclophosphamide and ixazomib improved overall survival of mice in comparison to an untreated control group and to groups receiving either cyclophosphamide alone or ixazomib alone. Furthermore, cyclophosphamide prevented the surge of IL-1β, GVHD aggravation, and sudden death associated with prolonged administration of ixazomib after HSCT. Finally, we demonstrated that although ixazomib was administered before cyclophosphamide, it did not impair the preferential depletion of proliferating as opposed to resting donor T cells. Our data suggest that the combination of cyclophosphamide and ixazomib for the prevention of GVHD after allogeneic HSCT is promising and merits further investigation in clinical trials.

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Section: Introductionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 97%

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Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone

Al-Homsi

Goodyke

McLane

et al. 2017

Biology of Blood and Marrow Transplantation

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“…Ixazomib . Interesting data are coming from the murine model where ixazomib, a second-generation proteasome inhibitor, has been used: it suppressed naïve human dendritic cells (DC) maturation, reducing their pro-inflammatory cytokine production, with a final improved survival of mice ( 85 ). Ixazomib was also able to induce apoptosis of activated T lymphocytes, reduce effector CD4+ T cells in bone marrow and spleen, increase Tregs in lymph nodes, Peyer patches and thymus, so suggesting the possibility of using this drug, usually employed in relapsed multiple myeloma ( 120 ), for treating cGvHD ( 50 ).…”

Section: Emerging Therapies For Chronic Graft-versus-host Diseasementioning

confidence: 99%

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

et al. 2020

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Chronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. The condition often requires enduring immunosuppressive therapy, which can also lead to the development of severe side effects. Several approaches including small molecule inhibitors, antibodies, cytokines, and cellular therapies are now being developed for the treatment of cGvHD, and some of these therapies have been or are currently tested in clinical trials. In this review, we discuss these emerging therapies with particular emphasis on tyrosine kinase inhibitors (TKIs). TKIs are a class of compounds that inhibits tyrosine kinases, thereby preventing the dissemination of growth signals and activation of key cellular proteins that are involved in cell growth and division. Because they have been shown to inhibit key kinases in both B cells and T cells that are involved in the pathophysiology of cGvHD, TKIs present new promising therapeutic approaches. Ibrutinib, a Bruton tyrosine kinase (Btk) inhibitor, has recently been approved by the Food and Drug Administration (FDA) in the United States for the treatment of adult patients with cGvHD after failure of first-line of systemic therapy. Also, Janus Associated Kinases (JAK1 and JAK2) inhibitors, such as itacitinib (JAK1) and ruxolitinib (JAK1 and 2), are promising in the treatment of cGvHD. Herein, we present the current status and future directions of the use of these new drugs with particular spotlight on their targeting of specific intracellular signal transduction cascades important for cGvHD, in order to shed some light on their possible mode of actions.

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Enrichment of boron element in follicular fluid and its potential effect on the immune function

Zhang

Wang

Zhuang

et al. 2022

Environmental Pollution

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Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashion

Cited by 10 publications

References 25 publications

Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone

Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

Enrichment of boron element in follicular fluid and its potential effect on the immune function

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