Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans.
ABSTRACT Chronic GVHD (cGVHD) poses a significant risk for HSCT patients. Preclinical development of new therapeutic modalities has been hindered by models with pathologic findings that may not simulate the development of human cGVHD. Previously, we have demonstrated that cGVHD induced by allogeneic HSCT after a conditioning regimen of cyclophosphamide and total-body radiation results in pulmonary dysfunction and airway obliteration, which leads to bronchiolitis obliterans (BO), which is pathognomonic for cGVHD of the lung. We now report cGVHD manifestations in a wide spectrum of target organs, including those with mucosal surfaces. Fibrosis was demonstrated in the lung and liver and was associated with CD4(+) T cells and B220(+) B-cell infiltration and alloantibody deposition. Donor bone marrow obtained from mice incapable of secreting IgG alloantibody resulted in less BO and cGVHD. Robust germinal center reactions were present at the time of cGVHD disease initiation. Blockade of germinal center formation with a lymphotoxin-receptor-immunoglobulin fusion protein suppressed cGVHD and BO. We conclude that cGVHD is caused in part by alloantibody secretion, which is associated with fibrosis and cGVHD manifestations including BO, and that treatment with a lymphotoxin-β receptor-immunoglobulin fusion protein could be beneficial for cGVHD prevention and therapy.
SourceAvailable from: Joseph Antin[Show abstract] [Hide abstract]
ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.The Journal of clinical investigation 10/2014; DOI:10.1172/JCI75328 · 13.77 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Chronic graft-versus-host disease (cGVHD) is a serious and frequent complication of allogeneic hematopoietic stem cell transplantation (HCT). Currently, no biomarkers for prediction and diagnosis of cGVHD are available. We performed a large prospective study focusing on noninvasive biomarkers for NIH-defined cGVHD patients (n=163) in comparison to time-matched HCT recipients never experiencing cGVHD (n=64) analyzed from day 100 after HCT. In logistic regression analysis CD19(+)CD21(low) B-cells (p = 0.002, hazard ratio HR 3.31, 95% confidence interval CI 1.53 - 7.17) and CD4(+)CD45RA(+)CD31(+) T-cells (p < 0.001, HR 3.88, 95% CI 1.88 - 7.99) assessed on day 100 after HCT were significantly associated with subsequent development of cGVHD independently of clinical parameters. A significant association with diagnosis of cGVHD was only observed for CD19(+)CD21(low) B-cells (p = 0.008, HR 3.00, 95% CI, 1.33 - 6.75) and CD4(+)CD45RA(+)CD31(+) T-cells (p = 0.017, HR 2.80, 95% CI, 1.19 - 6.55). CD19(+)CD21(low) B-cells were found to have the highest discriminatory value with an area under the receiver operating curve of 0.77 (95% CI, 0.64 - 0.90). Our results demonstrate that CD19(+)CD21(low) B-cells and CD4(+)CD45RA(+)CD31(+) T-cells are significantly elevated in patients with newly diagnosed cGVHD. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2014; 21(2). DOI:10.1016/j.bbmt.2014.11.010 · 3.35 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Chronic graft-versus-host disease (cGVHD) continues to be a common complication of allogeneic hematopoietic stem cell transplantation. Unlike that of acute graft-versus-host disease, which is mediated almost entirely by donor T cells, the immune pathology of cGVHD is more complex and donor B cells have also been found to play an important role. Recent studies from several laboratories have enhanced our understanding of how donor B cells contribute to this clinical syndrome and this has led to new therapeutic opportunities. Here, Dr Sarantopoulos reviews some of the important mechanisms responsible for persistent B cell activation and loss of B cell tolerance in patients with cGVHD. Dr Blazar describes recent studies in preclinical models that have identified novel B cell–directed agents that may be effective for prevention or treatment of cGVHD. Some B cell–directed therapies have already been tested in patients with cGVHD and Dr Cutler reviews the results of these studies documenting the potential efficacy of this approach. Supported by mechanistic studies in patients and preclinical models, new B cell–directed therapies for cGVHD will now be evaluated in clinical trials.Biology of Blood and Marrow Transplantation 11/2014; 21(2S). DOI:10.1016/j.bbmt.2014.10.029 · 3.35 Impact Factor