Treatment of chronic graft-versus-host disease with bortezomib

Pai, Chien Chun Steven; Chen, Mingyi; Mirsoian, Annie; Grossenbacher, Steven K.; Tellez, Joseph; Ames, Erik; Sun, Kai; Jagdeo, Jared; Blazar, Bruce R.; Murphy, William J.; Abedi, Mehrdad

doi:10.1182/blood-2014-02-554279

Cited by 68 publications

(54 citation statements)

References 33 publications

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“…At the most final stage of aberrant B-cell response, depletion of alloantibodyproducing plasma cells by proteosome inhibition (eg, bortezomib) is supported by evidence of efficacy in animal systems and early clinical studies. 160 Finally, targeting macrophages by preventing differentiation and survival in tissue through the inhibition of CSF-1R has proven highly effective in animal systems, 112 as has the inhibition of TGFb. 112,161 18.…”

Section: 29mentioning

confidence: 99%

Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

MacDonald¹,

Hill

Blazar

2017

Blood

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228

212

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With the increasing use of mismatched, unrelated, and granulocyte colony-stimulating factor–mobilized peripheral blood stem cell donor grafts and successful treatment of older recipients, chronic graft-versus-host disease (cGVHD) has emerged as the major cause of nonrelapse mortality and morbidity. cGVHD is characterized by lichenoid changes and fibrosis that affects a multitude of tissues, compromising organ function. Beyond steroids, effective treatment options are limited. Thus, new strategies to both prevent and treat disease are urgently required. Over the last 5 years, our understanding of cGVHD pathogenesis and basic biology, born out of a combination of mouse models and correlative clinical studies, has radically improved. We now understand that cGVHD is initiated by naive T cells, differentiating predominantly within highly inflammatory T-helper 17/T-cytotoxic 17 and T-follicular helper paradigms with consequent thymic damage and impaired donor antigen presentation in the periphery. This leads to aberrant T- and B-cell activation and differentiation, which cooperate to generate antibody-secreting cells that cause the deposition of antibodies to polymorphic recipient antigens (ie, alloantibody) or nonpolymorphic antigens common to both recipient and donor (ie, autoantibody). It is now clear that alloantibody can, in concert with colony-stimulating factor 1 (CSF-1)-dependent donor macrophages, induce a transforming growth factor β–high environment locally within target tissue that results in scleroderma and bronchiolitis obliterans, diagnostic features of cGVHD. These findings have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition. This new understanding of cGVHD finally gives hope that effective therapies are imminent for this devastating transplant complication.

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Section: 29mentioning

confidence: 99%

Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

MacDonald¹,

Hill

Blazar

2017

Blood

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228

212

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“…21,24 GC reactions may play a major role in the pathogenesis of cGVHD in mice. [25][26][27] GC-derived "plasmablast-like" B cells are increased in human cGVHD. 11 Recent studies have shown that the latter cell subset bears regulatory properties and may be the main IL-10-producing B-cell subset in mice.…”

Section: Introductionmentioning

confidence: 99%

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Masson

Bouaziz

Buanec

et al. 2015

Blood

143

119

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Key Points• Chronic graft-versus-host disease is associated with a global Breg defect.• This defect is particularly accentuated in the CD24 hi CD27 1 Breg compartment.Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24 hi CD27 1 and CD27 hi CD38 hi plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24 hi CD27 1 B cells and IL-10-producing CD24 hi CD27 1 B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24 hi CD27 1 B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. (Blood. 2015;125(11):1830-1839 IntroductionChronic graft-versus-host disease (cGVHD) is the leading cause of morbi-mortality after allogeneic hematopoietic stem cell transplantation (AHSCT). 1 GVHD prevention by means of adoptive transfer of regulatory T cells (Tregs) 2,3 and cGVHD treatment by in vivo induction of Tregs by low-dose interleukin 2 (IL-2) 4,5 may be effective. The exact role of IL-10-producing regulatory B cells (Bregs) in cGVHD is yet to be understood. Bregs have been shown to downmodulate adaptive 6 or innate immune responses 7 in mice and humans. In cGVHD, B cells are essentially recognized as positive regulators of inflammation. 1,8,9 Increased B-cell receptor responsiveness was found in cGVHD patients. 10 B-cell homeostatic defects were described in cGVHD, including elevated B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF)/B-cell ratios, 11-15 expansion of CD21 lo B cells, 16 reduced CD5 1 B1-like cell numbers, 17 decreased CD27 1 memory B cells, and hypogammaglobulinemia. 18 BAFF concentrations correlated with increased circulating pre-germinal center (GC) B-cell and post-GC plasmablast cell counts in patients with cGVHD. 11 B-cell depletion with rituximab prevented cGVHD in humans. 19 Patients with cGVHD frequently have circulating antibodies reactive to recipient cells. 1,9,20 Besides their functions in antibody secretion, cytokine and chemokine production, and antigen presentation, B cells exhibit regulatory properties in several human autoimmune diseases including systemic lupus erythemat...

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“…A pilot study investigating the use of bortezomib as salvage therapy for steroid-refractory/dependent cGVHD was recently conducted based on favorable results from mice experiments [97]. Ten patients were enrolled in the doseescalating study, which started from 0.2 mg/m 2 subcutaneously once a week, and then increased every 2 weeks by 0.2 mg/m 2 until the patients responded or grade III to IV dose-limited toxicity occurred.…”

Section: Salvage Treatment For Steroid-refractory/dependent Cgvhdmentioning

confidence: 99%