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Jennifer J Tsai,
Jarrod A Dudakov,
Koichi Takahashi,
Jae-Hung Shieh,
Enrico Velardi,
Amanda M Holland,
Natalie V Singer,
Mallory L West,
Odette M Smith,
Lauren F Young,
Yusuke Shono, Arnab Ghosh,
Alan M Hanash,
Hien T Tran,
Malcolm A S Moore,
Marcel R M van den Brink
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ABSTRACT: Coordinating the balance between haematopoietic stem cell (HSC) quiescence and self-renewal is crucial for maintaining haematopoiesis lifelong. Equally important for haematopoietic function is modulating HSC localization within the bone marrow niches, as maintenance of HSC function is tightly controlled by a complex network of intrinsic molecular mechanisms and extrinsic signalling interactions with their surrounding microenvironment. In this study we demonstrate that nuclear factor erythroid 2-related factor 2 (Nfe2l2, or Nrf2), well established as a global regulator of the oxidative stress response, plays a regulatory role in several aspects of HSC homeostasis. Nrf2 deficiency results in an expansion of the haematopoietic stem and progenitor cell compartment due to cell-intrinsic hyperproliferation, which was accomplished at the expense of HSC quiescence and self-renewal. We further show that Nrf2 modulates both migration and retention of HSCs in their niche. Moreover, we identify a previously unrecognized link between Nrf2 and CXCR4, contributing, at least partially, to the maintenance of HSC function.
Nature Cell Biology 02/2013; 15(3):309-16. · 19.49 Impact Factor
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Alan M Hanash,
Jarrod A Dudakov,
Guoqiang Hua,
Margaret H O'Connor,
Lauren F Young,
Natalie V Singer,
Mallory L West,
Robert R Jenq,
Amanda M Holland,
Lucy W Kappel, [......],
Nury L Yim,
Odette M Smith,
Enrico Velardi,
Elena B Hawryluk,
George F Murphy,
Chen Liu,
Lynette A Fouser,
Richard Kolesnick,
Bruce R Blazar,
Marcel R M van den Brink
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ABSTRACT: Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.
Immunity 08/2012; 37(2):339-50. · 21.64 Impact Factor
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Robert R Jenq,
Carles Ubeda,
Ying Taur,
Clarissa C Menezes,
Raya Khanin,
Jarrod A Dudakov,
Chen Liu,
Mallory L West,
Natalie V Singer,
Michele J Equinda, [......],
Lauren Lipuma,
Lauren F Young,
Odette M Smith, Arnab Ghosh,
Alan M Hanash,
Jenna D Goldberg,
Kazutoshi Aoyama,
Bruce R Blazar,
Eric G Pamer,
Marcel R M van den Brink
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ABSTRACT: Despite a growing understanding of the link between intestinal inflammation and resident gut microbes, longitudinal studies of human flora before initial onset of intestinal inflammation have not been reported. Here, we demonstrate in murine and human recipients of allogeneic bone marrow transplantation (BMT) that intestinal inflammation secondary to graft-versus-host disease (GVHD) is associated with major shifts in the composition of the intestinal microbiota. The microbiota, in turn, can modulate the severity of intestinal inflammation. In mouse models of GVHD, we observed loss of overall diversity and expansion of Lactobacillales and loss of Clostridiales. Eliminating Lactobacillales from the flora of mice before BMT aggravated GVHD, whereas reintroducing the predominant species of Lactobacillus mediated significant protection against GVHD. We then characterized gut flora of patients during onset of intestinal inflammation caused by GVHD and found patterns mirroring those in mice. We also identified increased microbial chaos early after allogeneic BMT as a potential risk factor for subsequent GVHD. Together, these data demonstrate regulation of flora by intestinal inflammation and suggest that flora manipulation may reduce intestinal inflammation and improve outcomes for allogeneic BMT recipients.
Journal of Experimental Medicine 04/2012; 209(5):903-11. · 13.85 Impact Factor
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Jarrod A Dudakov,
Alan M Hanash,
Robert R Jenq,
Lauren F Young, Arnab Ghosh,
Natalie V Singer,
Mallory L West,
Odette M Smith,
Amanda M Holland,
Jennifer J Tsai,
Richard L Boyd,
Marcel R M van den Brink
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ABSTRACT: Endogenous thymic regeneration is a crucial function that allows for renewal of immune competence after stress, infection, or immunodepletion. However, the mechanisms governing this regeneration remain poorly understood. We detail such a mechanism, centered on interleukin-22 (IL-22) and triggered by the depletion of CD4(+)CD8(+) double-positive thymocytes. Intrathymic levels of IL-22 were increased after thymic insult, and thymic recovery was impaired in IL-22-deficient mice. IL-22, which signaled through thymic epithelial cells and promoted their proliferation and survival, was up-regulated by radio-resistant RORγ(t)(+)CCR6(+)NKp46(-) lymphoid tissue inducer cells after thymic injury in an IL-23-dependent manner. Administration of IL-22 enhanced thymic recovery after total body irradiation. These studies reveal mechanisms of endogenous thymic repair and offer innovative regenerative strategies for improving immune competence.
Science 03/2012; 336(6077):91-5. · 31.20 Impact Factor
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Il-Kang Na,
John C Markley,
Jennifer J Tsai,
Nury L Yim,
Bradley J Beattie,
Alexander D Klose,
Amanda M Holland, Arnab Ghosh,
Uttam K Rao,
Matthias T Stephan,
Inna Serganova,
Elmer B Santos,
Renier J Brentjens,
Ronald G Blasberg,
Michel Sadelain,
Marcel R M van den Brink
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ABSTRACT: We have developed a dual bioluminescent reporter system allowing noninvasive, concomitant imaging of T-cell trafficking, expansion, and activation of nuclear factor of activated T cells (NFAT) in vivo. NFAT activation plays an important role in T-cell activation and T-cell development. Therefore we used this system to determine spatial-temporal activation patterns of (1) proliferating T lymphocytes during graft-versus-host disease (GVHD) and (2) T-cell precursors during T-cell development after allogeneic hematopoietic stem cell transplantation (HSCT). In the first days after HSCT, donor T cells migrated to the peripheral lymph nodes and the intestines, whereas the NFAT activation was dominant in the intestines, suggesting an important role for the intestines in the early stages of alloactivation during development of GVHD. After adoptive transfer of in vitro-derived T-cell receptor (TCR) H-Y transgenic T-cell precursors into B6 (H-2(b)) hosts of both sexes, NFAT signaling and development into CD4(+) or CD8(+) single-positive cells could only be detected in the thymus of female recipients indicating either absence of positive selection or prompt depletion of double-positive thymocytes in the male recipients. Because NFAT plays an important role in a wide range of cell types, our system could provide new insights into a variety of biologic processes.
Blood 09/2010; 116(11):e18-25. · 9.90 Impact Factor
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Olaf Penack,
Erik Henke,
David Suh,
Chris G King,
Odette M Smith,
Il-Kang Na,
Amanda M Holland, Arnab Ghosh,
Sydney X Lu,
Robert R Jenq,
Chen Liu,
George F Murphy,
Theresa T Lu,
Chad May,
David A Scheinberg,
Ding Cheng Gao,
Vivek Mittal,
Glenn Heller,
Robert Benezra,
Marcel R M van den Brink
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ABSTRACT: BACKGROUND Blood vessels are formed either by sprouting of resident tissue endothelial cells (angiogenesis) or by recruitment of bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs, vasculogenesis). Neovascularization has been implicated in tumor growth and inflammation, but its roles in graft-vs-host disease (GVHD) and in tumors after allogeneic BM transplantation (allo-BMT) were not known. METHODS We analyzed neovascularization, the contribution of endothelial cells and EPCs, and the ability of anti-vascular endothelial-cadherin antibody, E4G10, to inhibit neovascularization in mice with GVHD after allo-BMT using immunofluorescence microscopy and flow cytometry. We examined survival and clinical and histopathologic GVHD in mice (n = 10-25 per group) in which GVHD was treated with the E4G10 antibody using immunohistochemistry, flow cytometry, and cytokine immunoassay. We also assessed survival, the contribution of green fluorescent protein-marked EPCs to the tumor vasculature, and the ability of E4G10 to inhibit tumor growth in tumor-bearing mice (n = 20-33 per group) after allo-BMT using histopathology and bioluminescence imaging. All statistical tests were two-sided. RESULTS We found increased neovascularization mediated by vasculogenesis, as opposed to angiogenesis, in GVHD target tissues, such as liver and intestines. Administration of E4G10 inhibited neovascularization by donor BM-derived cells without affecting host vascularization, inhibited both GVHD and tumor growth, and increased survival (at 60 days post-BMT and tumor challenge with A20 lymphoma, the probability of survival was 0.29 for control antibody-treated allo-BMT recipients vs 0.7 for E4G10-treated allo-BMT recipients, 95% confidence interval = 0.180 to 0.640, P < .001). CONCLUSIONS Therapeutic targeting of neovascularization in allo-BMT recipients is a novel strategy to simultaneously ameliorate GVHD and inhibit posttransplant tumor growth, providing a new approach to improve the overall outcome of allogeneic hematopoietic stem cell transplantation.
CancerSpectrum Knowledge Environment 06/2010; 102(12):894-908. · 14.07 Impact Factor
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Il-Kang Na,
Sydney X Lu,
Nury L Yim,
Gabrielle L Goldberg,
Jennifer Tsai,
Uttam Rao,
Odette M Smith,
Christopher G King,
David Suh,
Daniel Hirschhorn-Cymerman, [......],
Amanda M Holland,
Robert R Jenq, Arnab Ghosh,
Hien Tran,
Taha Merghoub,
Chen Liu,
Gregory D Sempowski,
Melissa Ventevogel,
Nicole Beauchemin,
Marcel R M van den Brink
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ABSTRACT: Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits alphaE and beta7, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8-like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.
The Journal of clinical investigation 12/2009; 120(1):343-56. · 15.39 Impact Factor
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Olaf Penack,
Odette M Smith,
Amy Cunningham-Bussel,
Xin Liu,
Uttam Rao,
Nury Yim,
Il-Kang Na,
Amanda M Holland, Arnab Ghosh,
Sydney X Lu,
Robert R Jenq,
Chen Liu,
George F Murphy,
Katharina Brandl,
Marcel R M van den Brink
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ABSTRACT: Nucleotide-binding oligomerization domain 2 (NOD2) polymorphisms are independent risk factors for Crohn's disease and graft-versus-host disease (GVHD). In Crohn's disease, the proinflammatory state resulting from NOD2 mutations have been associated with a loss of antibacterial function of enterocytes such as paneth cells. NOD2 has not been studied in experimental allogeneic bone marrow transplantation (allo-BMT). Using chimeric recipients with NOD2(-/-) hematopoietic cells, we demonstrate that NOD2 deficiency in host hematopoietic cells exacerbates GVHD. We found that proliferation and activation of donor T cells was enhanced in NOD-deficient allo-BMT recipients, suggesting that NOD2 plays a role in the regulation of host antigen-presenting cells (APCs). Next, we used bone marrow chimeras in an experimental colitis model and observed again that NOD2 deficiency in the hematopoietic cells results in increased intestinal inflammation. We conclude that NOD2 regulates the development of GVHD through its inhibitory effect on host APC function.
Journal of Experimental Medicine 10/2009; 206(10):2101-10. · 13.85 Impact Factor
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ABSTRACT: Hematopoietic stem cell transplantation is a curative therapy for hematological malignancies. T cell deficiency following transplantation is a major cause of morbidity and mortality. In this review, we discuss adoptive transfer of committed precursor cells to enhance T cell reconstitution and improve overall prognosis after transplantation.
Seminars in Immunopathology 12/2008; 30(4):479-87. · 6.27 Impact Factor
