Bruce R Blazar

Indiana Blood and Marrow Transplantation, Indianapolis, Indiana, United States

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Publications (662)4681.57 Total impact

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    ABSTRACT: The impact of allele level HLA mismatch is uncertain in recipients of double umbilical cord blood transplantation (dUCBT). We report a single center retrospective study of the clinical effect of using allele-level HLA mismatch HLA-A, -B, -C, -DRB1 and -DQB1 of the two UCB units. We studied 342 patients with hematological malignancy. Donor-recipient pairs were grouped according to the number of matched HLA alleles with 32 matched at 9-10/10, 202 at 6-8/10 and 108 at 2-5/10 alleles. The incidence of hematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), and non-relapse mortality (NRM) and treatment failure was similar between groups. In an exploratory analysis of 174 patients with acute leukemia, after adjusting for length of first remission and cytogenetic risk group, 2-5/10 HLA match was associated with lower risk of relapse and treatment failure. These data indicate that a high degree of allele level HLA mismatch does not adversely affect transplant outcomes and may be associated with reduced relapse risk in patients with acute leukemia.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2015; DOI:10.1016/j.bbmt.2015.09.025 · 3.40 Impact Factor
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    ABSTRACT: We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL-2) and anti-CD40 (αCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of negative regulators such as cytotoxic T lymphocyte antigen-4 (CTLA-4) could simultaneously prolong CD8(+) T cell responses and augment T cell anti-tumor effects. We devised a regimen in which anti-CTLA-4 was administered late so as to delay contraction and minimize toxicities. This late administration both enhanced and prolonged CD8 T cell activation without the need for additional IL-2. The quality of the T cell response was improved with increased frequency of effector/effector memory phenotype cells along with improved lytic ability and bystander expansion. This enhanced CD8 response translated to improved anti-tumor responses both at the primary and metastatic sites. Importantly, toxicities were not exacerbated with combination. This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities.
    Cancer Immunology and Immunotherapy 10/2015; DOI:10.1007/s00262-015-1759-4 · 3.94 Impact Factor
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    ABSTRACT: We have recently described a specialized subset of human natural killer (NK) cells with a CD56(dim)CD57(+)NKG2C(+) phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% [17-35%], p=0.05) and superior disease-free survival (DFS) (55% [45-65%] p=0.04) 1 year after reduced intensity conditioning (RIC) compared to CMV seronegative recipients who experienced higher relapse rates (35% [27-43%]) and lower DFS (46% [38-54%]). This protective effect was independent of age and graft-versus-host disease (GvHD) and was not observed in recipients who received myeloablative (MA) regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56(dim)CD57(+)NKG2C(+) NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months post-transplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on post-transplant relapse is in part driven by adaptive NK cell responses.Leukemia accepted article preview online, 29 September 2015. doi:10.1038/leu.2015.260.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2015; DOI:10.1038/leu.2015.260 · 10.43 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic cell transplantation is often complicated by graft-versus-host disease (GVHD). We analyzed the incidence and risk factors for acute and chronic graft-versus-host disease (GVHD), and their impact on disease relapse and survival, among recipients of single umbilical cord blood (sUCB, n=295), double umbilical cord blood (dUCB, n=416), and matched sibling donor (MSD, n=469) allografts. The incidence of grade II-IV aGVHD and chronic GVHD among dUCB, sUCB, and MSD was 56%, 26% and 37% and 26%, 7%, and 40%, respectively. Development of acute GVHD had no effect on relapse, non-relapse mortality, or overall survival among UCB recipients, but was associated with worse non-relapse mortality and survival in MSD recipients. Development of cGVHD was only associated with lower relapse in dUCBT. In multivariate analysis of GVHD incidence, age > 18 years was associated with higher incidence of aGVHD and cGVHD across all cohorts, while worse HLA match and prior aGVHD were associated with higher risks of aGVHD in both UCB cohorts. Non-myeloablative conditioning limited the risk of aGVHD compared to myeloablative conditioning in dUCB recipients. Cyclosporine A and mycophenolate mofetil as GVHD prophylaxis lowered the risk of cGVHD compared to steroids with cyclosporine A among sUCB recipients. This large contemporary analysis suggests similarity of risks and consequences of GVHD for UCB and MSD recipients. Limiting the severity of aGVHD remains important in all groups. Increasing the UCB inventory or developing strategies that reduce the cell-dose threshold and thereby increase the chance of identifying an adequately dosed, better HLA-matched single UCB unit may further limit risks of acute GVHD after UCB transplantation.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2015; DOI:10.1016/j.bbmt.2015.09.008 · 3.40 Impact Factor
  • Beau R. Webber · Jakub Tolar · Michael Kyba · Bruce R. Blazar
    Experimental Hematology; 09/2015
  • OncoImmunology 08/2015; DOI:10.1080/2162402X.2015.1075114 · 6.27 Impact Factor
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    ABSTRACT: Myeloid-derived suppressor cells (MDSC) are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses. In vitro generation of MDSC from bone marrow have been shown to enhance survival in an acute model of lethal graft-versus-host disease (GvHD). However, donor MDSC infusion only partially ameliorates GvHD lethality. In order to improve the potential therapeutic benefit and ultimately survival outcomes we set out to investigate the fate of MDSC after transfer in the setting of acute GvHD (aGvHD). MDSC transferred to lethally irradiated recipients of allogeneic donor hematopoietic grafts are exposed to an intense inflammatory environment associated with aGvHD, which we now show directly undermines their suppressive capacity. Under conditioning regimen and GvHD inflammatory settings, MDSC rapidly lose suppressor function and their potential to inhibit GvHD lethality, which is associated with their induced conversion towards a mature inflammasome-activated state. We find even brief in vitro exposure to inflammasome-activating mediators negates the suppressive potential of cultured murine and human-derived MDSCs. Consistent with a role for the inflammasome, donor MDSC deficient in the adaptor ASC (Apoptosis-associated speck-like protein containing a CARD), that assembles inflammasome complexes, conferred improved survival of mice developing GvHD compared to wild-type donor MDSC. These data suggest the use of MDSC as a therapeutic approach for preventing GvHD and other systemic inflammatory conditions will be more effective when combined with approaches limiting in vivo MDSC inflammasome activation empowering MDSCs to maintain their suppressive potential. Copyright © 2015 American Society of Hematology.
    Blood 08/2015; DOI:10.1182/blood-2015-03-634691 · 10.45 Impact Factor
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    ABSTRACT: T lymphocytes are critical mediators of the adaptive immune system and have the capacity to serve as therapeutic agents in the areas of transplant and cancer immunotherapy. While T-cells can be isolated and expanded from patients, T-cells derived in vitro from both hematopoietic stem/progenitor cells (HSPC) and human pluripotent stem cells (hPSC) offer great potential advantages in generating a self-renewing source of T-cells that can be readily genetically modified. T-cell differentiation in vivo is a complex process requiring tightly regulated signals; providing the correct signals in vitro to induce T-cell lineage commitment followed by their development into mature, functional, single positive T-cells, is similarly complex. In this review, we discuss current methods for the in vitro derivation of T-cells from murine and human HSPCs and hPSCs that utilize feeder-cell and feeder-cell-free systems. Further, we explore their potential for adoption for use in T-cell based therapies. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 07/2015; DOI:10.1002/stem.2115 · 6.52 Impact Factor
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    ABSTRACT: Despite major improvements in allogeneic hematopoietic cell transplantation over the last decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%,95% CI) and 97.4% (92.3-100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV-reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.Leukemia accepted article preview online, 31 July 2015. doi:10.1038/leu.2015.212.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2015; DOI:10.1038/leu.2015.212 · 10.43 Impact Factor
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    ABSTRACT: Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing "bystander" T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4(+) T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4(+) but not CD8(+) T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4(+) T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4(+) T cells during inflammatory conditions. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 07/2015; 43(2). DOI:10.1016/j.immuni.2015.06.023 · 21.56 Impact Factor
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    ABSTRACT: Cytomegalovirus (CMV) reactivates in >30% of CMV seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of NK cells expressing NKG2C, CD57 and inhibitory killer-cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation post-HCT. These NK cells persist after the resolution of infection and display 'adaptive' or memory properties. Despite these findings, the differential impact of persistent/inactive vs. reactivated CMV on NK vs. T cell maturation following HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pre-transplant CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an 'adaptive' phenotype (NKG2C(+)CD57(+)). Compared to CMV seronegative recipients, those who reactivated CMV (React(+)) had the highest adaptive cell frequencies, while intermediate frequencies were observed in CMV seropositive recipients harboring persistent/non-replicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV seropositive recipients of sibling, but not UCB grafts, and correlated with lower rates of CMV reactivation (sibling 33% vs. UCB 51%; p<0.01). These data suggest that persistent/non-replicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling, but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation. Copyright © 2015 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 06/2015; 21(9). DOI:10.1016/j.bbmt.2015.05.025 · 3.40 Impact Factor
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    ABSTRACT: Hematopoietic stem cell transplantation (HSCT) recipients lacking HLA-matched related donors have increased graft-vs.-host disease (GVHD) and non-relapse mortality (NRM). Bortezomib added to reduced-intensity conditioning can offer benefit in T-replete HLA-mismatched HSCT, and may also benefit myeloablative conditioning (MAC) transplants. We conducted a phase II trial of short-course bortezomib plus standard tacrolimus/methotrexate after busulfan/fludarabine MAC in 34 patients with predominantly myeloid malignancies. Fourteen (41%) received 8/8 HLA-matched unrelated donor (MUD) and 20 (59%) received 7/8 HLA-mismatched related/unrelated donor (MMRD/MMUD) peripheral blood stem cell grafts. Median age was 49 years (range, 21-60) and median follow-up was 25 months (range, 11-36). The regimen was well tolerated. No dose-modifications were required. Neutrophil and platelet engraftment occurred at a median of 14 (range, 10-33) and 17 (range, 10-54) days respectively. Median 30-day donor chimerism was 99% (range, 90-100). 100-day grade II-IV and III-IV acute GVHD incidence was 32% and 12% respectively. One-year chronic GVHD incidence was 50%. Two-year cumulative incidence of both NRM and relapse was 16%. Two-year progression-free and overall survival was 70% and 71% respectively. Outcomes were comparable to an 8/8 MUD MAC cohort (n=45). Immune reconstitution was robust. Bortezomib-based MAC HSCT is well tolerated, with HLA-mismatched outcomes comparable to 8/8 MUD MAC sHSCT, and is suitable for randomized evaluation. Copyright © 2015 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 06/2015; DOI:10.1016/j.bbmt.2015.05.027 · 3.40 Impact Factor
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    ABSTRACT: Hematopoietic cell transplantation (HCT) has been used as a part of cancer therapy for over half a decade. Beyond the necessity for donor-derived cells to reconstitute hematopoiesis after radiation and chemotherapy, immunologic reconstitution from allogeneic cells is important for the elimination of residual tumor cells. Natural killer (NK) cells are first among lymphocytes to reconstitute post-transplant and protect against cancer relapse. In this review, we provide a historical perspective on the role of NK cells in cancer control in the transplant setting and focus on current research aimed at improving NK cell responses for therapeutic benefit.
    Current topics in microbiology and immunology 06/2015; DOI:10.1007/82_2015_445 · 4.10 Impact Factor
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    ABSTRACT: Death receptor 3 (DR3, TNFRSF25) is expressed by activated lymphocytes and signaling by its ligand, TL1A, enhances cytokine expression and proliferation. Recent studies show that DR3 is also present on murine type 2 innate lymphoid cells (ILC2s). Here, we show that DR3 is expressed by IL-22-producing human group 3 innate lymphoid cells (ILC3s). Stimulation of ILC3s with exogenous TL1A alone had no impact on cytokine production or proliferation. Addition of TL1A to IL-1β + IL-23 significantly enhanced the amount IL-22 produced by ILC3s as well as the percentage IL-22- and IL-8-producing cells. Addition of TL1A to IL-1β + IL-23 also augmented ILC3 proliferation in short term. Mechanistically, this occurred through the upregulation of CD25 and responsiveness to IL-2 stimulation. The combination of TL1A, IL-1β+ IL-23 and IL-2 expanded ILC3s while IL-1β+ IL-23 did not increase proliferation above controls. After two weeks of expansion, ILC3s maintained their phenotype, transcription factor expression and function (IL-22 production). These findings identify DR3 as a costimulatory molecule on ILC3s that could be exploited for ex vivo expansion and clinical use. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; 45(8). DOI:10.1002/eji.201445213 · 4.03 Impact Factor
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    ABSTRACT: Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multi-organ system, non-sclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells but not T cells for disease progression. BM-specific Syk deletion in vivo was effective in treating established cGVHD as was a small molecule inhibitor of Syk, fostamatinib which normalized GC formation and decreased activated CD80/86+ dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunological effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD. Copyright © 2015 American Society of Hematology.
    Blood 04/2015; 125(26). DOI:10.1182/blood-2014-08-595470 · 10.45 Impact Factor
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    ABSTRACT: Although CMV reactivation has long been implicated in post-transplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T cell subpopulation sorting with high-throughput sequencing of the T cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T cell reconstitution after unrelated-donor HSCT. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B(high)/CD28(low)/CD57(high)/CD8+ effector-memory T cells and resulted in a linked contraction of all naïve T cells, including CD31+/CD4+ putative thymic emigrants. TCRβ deep sequencing revealed a striking contraction of CD8+ Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T cell repertoire. Registered to as #NCT01012492. Copyright © 2015 American Society of Hematology.
    Blood 04/2015; 125(25). DOI:10.1182/blood-2015-03-631853 · 10.45 Impact Factor
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    ABSTRACT: Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential changes to the HCT conditioning regimen. One-hundred-and-thirty FA patients (median age 9.0 years, range 1-48) underwent alternative donor HCT at the University of Minnesota between 1995-2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell depleted bone marrow (BM) or unmanipulated umbilical cord blood (UCB) transplantation. The addition of FLU enhanced engraftment three-fold. The incidence of grades II-IV acute and chronic graft-versus-host disease (GVHD) was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age, or with a history of opportunistic infections or transfusions prior to HCT. Mortality was lowest in patients without a prior history of opportunistic infection or transfusions, and who received conditioning with TBI 300 cGy, CY, FLU and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(24). DOI:10.1182/blood-2015-02-626002 · 10.45 Impact Factor
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    ABSTRACT: Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is up-regulated in GVHD target organs including the colon, liver, and lung. Infusion of allogeneic donor T-cells into B7-H3(-/-) vs wildtype (WT) recipients resulted in increased GVHD lethality, associated with increased T-cell proliferation, colonic inflammatory cytokines as well as epithelial barrier destruction. Allogeneic B7-H3(-/-) versus WT donor T-cells also had increased T-cell proliferation and GVHD lethality, associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7H3 mRNA. Consistent with these data, GVHD was augmented in recipients of B7-H3(-/-) Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T-cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support the developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early post-BMT to prevent GVHD and developing potent antagonistic antibodies later post-transplant to facilitate DLI-mediated GVL without GVHD complications. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(21). DOI:10.1182/blood-2014-09-603357 · 10.45 Impact Factor
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    ABSTRACT: IL-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory GVHD and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by non-hematopoietic cells in the GI tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and TNF-α production was significantly reduced in il33(-/-) recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2(-/-) versus wildtype donor T cells had a marked reduction in GvHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2(-/-) T cells, and linked to reduced IFN-γ production by st2(-/-) versus wildtype T cells during GVHD. Blockade of IL-33/ST2 interactions during allo-hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to targeting of the IL-33/ST2 axis as a novel and potent target for GVHD therapy. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(20). DOI:10.1182/blood-2014-10-606830 · 10.45 Impact Factor
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    ABSTRACT: Although major advances have been made in solid organ and hematopoietic stem cell transplantation in the last 50 years, big challenges remain. This review outlines the current immunological limitations for hematopoietic stem cell and solid organ transplantation and discusses new immune-modulating therapies in preclinical development and in clinical trials that may allow these obstacles to be overcome. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 03/2015; 7(280):280rv2. DOI:10.1126/scitranslmed.aaa6853 · 15.84 Impact Factor

Publication Stats

30k Citations
4,681.57 Total Impact Points


  • 2005–2015
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
    • Harvard University
      Cambridge, Massachusetts, United States
    • Neural Stem Cell Institute
      رنسلیر، نیویورک, New York, United States
  • 1988–2015
    • University of Minnesota Duluth
      • • Medical School
      • • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States
  • 2013
    • American Cancer Society
      Atlanta, Georgia, United States
  • 2005–2013
    • University of North Carolina at Chapel Hill
      • • Department of Medicine
      • • Lineberger Comprehensive Cancer Center
      Chapel Hill, NC, United States
  • 2012
    • ICL
      Londinium, England, United Kingdom
    • Universität Basel
      • Department of Biomedicine
      Bâle, Basel-City, Switzerland
    • University of California, Davis
      • Department of Dermatology
      Davis, CA, United States
  • 2011
    • Harvard Medical School
      • Department of Pathology
      Boston, MA, United States
    • Georgia Health Sciences University
      • Cancer Center
      Augusta, GA, United States
  • 1997–2011
    • University of Minnesota Twin Cities
      • Department of Pediatrics
      Minneapolis, MN, United States
  • 2001–2010
    • Emory University
      • • Department of Surgery
      • • Department of Biochemistry
      Atlanta, Georgia, United States
    • University of Cambridge
      • Department of Pathology
      Cambridge, England, United Kingdom
    • Baylor College of Medicine
      Houston, Texas, United States
  • 2009
    • University of South Florida
      • Department of Oncologic Sciences
      Tampa, Florida, United States
  • 1990–2009
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2008
    • Yale University
      • Department of Laboratory Medicine
      New Haven, Connecticut, United States
    • Hannover Medical School
      • Department of Paediatric Haematology and Oncology
      Hannover, Lower Saxony, Germany
    • Yale-New Haven Hospital
      • Department of Laboratory Medicine
      New Haven, Connecticut, United States
  • 1988–2007
    • Children's Hospitals and Clinics of Minnesota
      Minneapolis, Minnesota, United States
  • 2006
    • Weizmann Institute of Science
      • Department of Immunology
  • 2001–2005
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2004
    • Children's Hospital Los Angeles
      Los Ángeles, California, United States
    • University of California, San Francisco
      San Francisco, California, United States
    • University of Nevada, Reno
      • Department of Microbiology and Immunology
      Reno, Nevada, United States
  • 2002–2004
    • Mayo Clinic - Rochester
      • Department of Immunology
      Рочестер, Minnesota, United States
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
    • NCI-Frederick
      Maryland, United States
    • Medical College of Wisconsin
      • Department of Pediatrics
      Milwaukee, WI, United States
    • Università degli Studi di Perugia
      • Department of Clinical and Experimental Medicine
      Perugia, Umbria, Italy
  • 2003
    • Juntendo University
      Edo, Tōkyō, Japan
  • 1998–2002
    • Dartmouth College
      • Department of Microbiology and Immunology
      Hanover, New Hampshire, United States
  • 1999
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • Dong-A University
      Tsau-liang-hai, Busan, South Korea
  • 1995
    • Laval University
      Quebec City, Quebec, Canada
  • 1992
    • Berkeley Earth
      Washington, Washington, D.C., United States