Browsing by Author "Blazar, Bruce R"

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    B-cell targeting in chronic Graft-versus-Host disease.
    (Blood, 2018-02-01) Zeiser, Robert; Sarantopoulos, Stefanie; Blazar, Bruce R
    Over the last decade our understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) has improved considerably. In this spotlight, we discuss emerging insights into the pathophysiology of cGVHD with a focus on B-cells. First, we summarize supporting evidence derived from mouse and human studies. Next, novel cGVHD therapy approaches that target B-cells will be covered to provide treating physicians with an overview of the rationale behind the emerging armamentarium against cGVHD.
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    Consensus opinion on immune-mediated cytopenias after hematopoietic cell transplant for inherited metabolic disorders.
    (Bone marrow transplantation, 2021-06) Gupta, Ashish O; Jan Boelens, Jaap; Ebens, Christen L; Kurtzberg, Joanne; Lund, Troy C; Smith, Angela R; Wagner, John E; Wynn, Robert; Blazar, Bruce R; Orchard, Paul J
    Hematopoietic stem cell transplantation (HCT) has been increasingly used for patients with inherited metabolic disorders (IMD). Immune mediated cytopenias (IMCs) after HCT, manifesting as hemolytic anemia, thrombocytopenia, and/or neutropenia, are recognized as a significant complication in this patient population, yet our understanding of the incidence, risk factors, and pathophysiology is currently limited. Review of the published literature demonstrates a higher incidence in younger patients who undergo HCT for a nonmalignant disease indication. However, a few reports suggest that the incidence is even higher among those with IMD (incidence ranging from 10 to 56%). This review summarizes the literature, provides an approach to better understanding of the possible etiology of IMCs, and proposes a diagnostic and management plan for patients with IMD who develop single or multi-lineage cytopenias after HCT.
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    Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD.
    (Blood advances, 2018-09-18) Kolupaev, Oleg V; Dant, Trisha A; Bommiasamy, Hemamalini; Bruce, Danny W; Fowler, Kenneth A; Tilley, Stephen L; McKinnon, Karen P; Sarantopoulos, Stefanie; Blazar, Bruce R; Coghill, James M; Serody, Jonathan S
    Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients after allogeneic bone marrow (BM) or stem cell transplantation (allo-SCT). Recent work has indicated that both T and B lymphocytes play an important role in the pathophysiology of cGVHD. Previously, our group showed a critical role for the germinal center response in the function of B cells using a bronchiolitis obliterans (BO) model of cGVHD. Here, we demonstrated for the first time that cGVHD is associated with severe defects in the generation of BM B lymphoid and uncommitted common lymphoid progenitor cells. We found an increase in the number of donor CD4+ T cells in the BM of mice with cGVHD that was negatively correlated with B-cell development and the frequency of osteoblasts and Prrx-1-expressing perivascular stromal cells, which are present in the B-cell niche. Use of anti-DR3 monoclonal antibodies to enhance the number of donor regulatory T cells (Tregs) in the donor T-cell inoculum ameliorated the pathology associated with BO in this model. This correlated with an increased number of endosteal osteoblastic cells and significantly improved the generation of B-cell precursors in the BM after allo-SCT. Our work indicates that donor Tregs play a critical role in preserving the generation of B-cell precursors in the BM after allo-SCT. Approaches to enhance the number and/or function of donor Tregs that do not enhance conventional T-cell activity may be important to decrease the incidence and severity of cGVHD in part through normal B-cell lymphopoiesis.
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    Notch signaling mediated by Delta-like1/4 ligands controls the pathogenesis of chronic graft-versus-host disease in mice.
    (Blood, 2018-09-04) Radojcic, Vedran; Paz, Katelyn; Chung, Jooho; Du, Jing; Perkey, Eric T; Flynn, Ryan; Ivcevic, Sanja; Zaiken, Michael; Friedman, Ann; Yan, Minhong; Pletneva, Maria A; Sarantopoulos, Stefanie; Siebel, Christian W; Blazar, Bruce R; Maillard, Ivan
    Chronic GVHD (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) and remains an area of unmet clinical need with few treatment options available. Notch blockade prevents acute GVHD in multiple mouse models, but the impact of Notch signaling on cGVHD remains unknown. Using genetic and antibody-mediated strategies of Notch inhibition, we investigated the role of Notch signaling in complementary mouse cGVHD models that mimic several aspects of human cGVHD in search of candidate therapeutics. In the B10.D2→BALB/c model of sclerodermatous cGVHD, Delta-like4 (Dll4)-driven Notch signaling was essential for disease development. Antibody-mediated Dll4 inhibition conferred maximum benefits when pursued early in a preventative fashion, with anti-Delta-like1 (Dll1) enhancing early protection. Notch-deficient alloantigen-specific T cells showed no early defects in proliferation or helper polarization in vivo, but subsequently exhibited markedly decreased cytokine secretion and enhanced accumulation of FoxP3+ regulatory T cells. In the B6→B10.BR MHC-mismatched model with multi-organ system cGVHD and prominent bronchiolitis obliterans (BO) but not skin manifestations, absence of Notch signaling in T cells provided long-lasting disease protection that was replicated by systemic targeting of Dll1, Dll4, or both Notch ligands even during established disease. Notch inhibition decreased target organ damage and germinal center formation. Moreover, decreased BO-cGVHD was observed upon inactivation of Notch1 and/or Notch2 in T cells. Systemic targeting of Notch2 alone was safe and conferred therapeutic benefits. Altogether, Notch ligands and receptors regulate key pathogenic steps in cGVHD and emerge as novel druggable targets to prevent or treat different forms of cGVHD.