Geoffrey R Hill

Queensland Institute of Medical Research, Brisbane, Queensland, Australia

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Publications (86)737.67 Total impact

  • Andrea S Henden, Geoffrey R Hill
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    ABSTRACT: Graft-versus-host disease (GVHD) is a complication of allogeneic bone marrow transplantation whereby transplanted naive and marrow-derived T cells damage recipient tissue through similar mechanisms to those that allow destruction of malignant cells, the therapeutic intent of bone marrow transplantation. The manifestations and severity of GVHD are highly variable and are influenced by the proportions of naive cells maturing along regulatory T cell, Th1, Th2, or Th17 phenotypes. This maturation is largely influenced by local cytokines, which, in turn, activate transcription factors and drive development toward a dominant phenotype. In addition, proinflammatory cytokines exert direct effects on GVHD target tissues. Our knowledge of the role that cytokines play in orchestrating GVHD is expanding rapidly and parallels other infective and inflammatory conditions in which a predominant T cell signature is causative of pathology. Because a broad spectrum of cytokine therapies is now routinely used in clinical practice, they are increasingly relevant to transplant medicine. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 05/2015; 194(10):4604-4612. DOI:10.4049/jimmunol.1500117 · 5.36 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are naturally circulating innate lymphoid cells that protect against tumor initiation and metastasis and contribute to immunopathology during inflammation. The signals that prime NK cells are not completely understood, and, although the importance of IFN type I is well recognized, the role of type III IFN is comparatively very poorly studied. IL-28R-deficient mice were resistant to LPS and cecal ligation puncture-induced septic shock, and hallmark cytokines in these disease models were dysregulated in the absence of IL-28R. IL-28R-deficient mice were more sensitive to experimental tumor metastasis and carcinogen-induced tumor formation than WT mice, and additional blockade of interferon alpha/beta receptor 1 (IFNAR1), but not IFN-γ, further enhanced metastasis and tumor development. IL-28R-deficient mice were also more susceptible to growth of the NK cell-sensitive lymphoma, RMAs. Specific loss of IL-28R in NK cells transferred into lymphocyte-deficient mice resulted in reduced LPS-induced IFN-γ levels and enhanced tumor metastasis. Therefore, by using IL-28R-deficient mice, which are unable to signal type III IFN-λ, we demonstrate for the first time, to our knowledge, the ability of IFN-λ to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-αβ.
    Proceedings of the National Academy of Sciences 04/2015; DOI:10.1073/pnas.1424241112 · 9.81 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) is an age-dependent hematological malignancy. Evaluation of immune interactions that drive MM relies on in vitro experiments that do not reflect the complex cellular stroma involved in MM pathogenesis. Here we used Vk*MYC transgenic mice, which spontaneously develop MM, and demonstrated that the immune system plays a critical role in the control of MM progression and the response to treatment. We monitored Vk*MYC mice that had been crossed with Cd226 mutant mice over a period of 3 years and found that CD226 limits spontaneous MM development. The CD226-dependent anti-myeloma immune response against transplanted Vk*MYC MM cells was mediated both by NK and CD8+ T cells through perforin and IFN-γ pathways. Moreover, CD226 expression was required for optimal antimyeloma efficacy of cyclophosphamide (CTX) and bortezomib (Btz), which are both standardly used to manage MM in patients. Activation of costimulatory receptor CD137 with mAb (4-1BB) exerted strong antimyeloma activity, while inhibition of coinhibitory receptors PD-1 and CTLA-4 had no effect. Taken together, the results of this study provide in vivo evidence that CD226 is important for MM immunosurveillance and indicate that specific immune components should be targeted for optimal MM treatment efficacy. As progressive immunosuppression associates with MM development, strategies aimed to increase immune functions may have important therapeutic implications in MM.
    The Journal of clinical investigation 04/2015; DOI:10.1172/JCI77181 · 13.77 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; DOI:10.1182/blood-2014-08-595470 · 9.78 Impact Factor
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    ABSTRACT: Granulocyte-colony stimulating factor (G-CSF) is widely used clinically to prevent neutropenia after cytotoxic chemotherapy and mobilize hematopoietic stem cell (HSC) for transplantation. Autophagy, a process of cytoplasmic component recycling, maintains cellular homeostasis and protects the cell during periods of metabolic stress or nutrient deprivation. We have observed that G-CSF activates autophagy in neutrophils and HSC from both mouse and human donors. Furthermore, G-CSF induced neutrophil and HSC mobilization is impaired in the absence of autophagy. In contrast, autophagy is dispensable for direct HSC mobilization in response to the CXCR4 antagonist AMD3100. Altogether, these data demonstrate an important role for G-CSF in invoking autophagy within hematopoietic and myeloid cells and suggest that this pathway is critical for ensuring cell survival in response to clinically relevant cytokine-induced stress. These findings have direct relevance to HSC transplantation and the increasing clinical use of agents that modulate autophagy. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; DOI:10.1182/blood-2014-03-562660 · 9.78 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of α-Mannan, a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. α-Mannan induced donor T cell polarization towards Th17 and lung specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of α-Mannan on GVHD depended on donor IL-17A production and host c-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection following allogeneic HSCT. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; DOI:10.1182/blood-2014-12-615781 · 9.78 Impact Factor
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    ABSTRACT: Idiopathic Pneumonia Syndrome (IPS) is a relatively common, frequently fatal clinical entity characterized by non-infectious acute lung inflammation following allogeneic stem cell transplantation (SCT), the mechanisms of which are unclear. Here we demonstrate that immune suppression with cyclosporin after SCT limits Th1 differentiation and IFNγ secretion by donor T cells which is critical for inhibiting IL-6 generation from lung parenchyma during an alloimmune response. Thereafter, local IL-6 secretion induces donor alloantigen-specific Th17 cells to preferentially expand within the lung and blockade of IL-17A or transplantation of grafts lacking the IL-17 receptor prevents disease. Studies using IL-6(-/-) recipients or IL-6 blockade demonstrate that IL-6 is the critical driver of donor Th17 differentiation within the lung. Importantly, IL-6 is also dysregulated in patients undergoing clinical SCT and was present at very high levels in the plasma of patients with IPS compared to SCT recipients without complications. Furthermore, at the time of diagnosis, plasma IL-6 levels were higher in a subset of IPS patients who were non-responsive to steroids and anti-TNF therapy. In sum, pulmonary-derived IL-6 promotes IPS via the induction of Th17 differentiation and strategies that target these cytokines represent logical therapeutic approaches for IPS. Copyright © 2015 American Society of Hematology.
    Blood 02/2015; DOI:10.1182/blood-2014-07-590232 · 9.78 Impact Factor
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    ABSTRACT: Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell-cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc(-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cell Stem Cell 12/2014; 15(6):775-90. DOI:10.1016/j.stem.2014.11.010 · 22.15 Impact Factor
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    ABSTRACT: Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD. We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18-65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin [5 mg/kg per day on days -1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140-300 ng/mL) for 100 days plus methotrexate [15 mg/m(2) on day 1, then 10 mg/m(2) on days 3, 6, and 11]). The primary endpoint was incidence of grade 2-4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853. Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2-4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5-24), and the incidence of grade 3-4 acute GVHD was 4% (1-13). Grade 2-4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2-4 acute GVHD were noted in patients receiving both myeloablative total body irradiation-based conditioning (12% [95% CI 2-34) and fludarabine and melphalan reduced-intensity conditioning (12% [4-27]). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted. National Health and Medical Research Council and Queensland Health. Copyright © 2014 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 12/2014; 15(13):1451-9. DOI:10.1016/S1470-2045(14)71017-4 · 24.73 Impact Factor
  • Bone Marrow Transplantation 11/2014; 50(2). DOI:10.1038/bmt.2014.265 · 3.47 Impact Factor
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    ABSTRACT: Allogeneic haematopoietic stem cell transplantation (HSCT) represents the only curative therapy for the majority of bone marrow-derived cancers. Unfortunately, HSCT can result in serious complications such as graft-versus-host disease, graft failure and infection. In the last decade, there have been major advances in the understanding of the role of autophagy in many diseases and cellular processes. Recent findings have demonstrated a crucial role for autophagy in haematopoietic stem cell survival and function, antigen presentation, T-cell differentiation and response to cytokine stimulation. Given the critical requirement for each of these processes in HSCT and subsequent complications, it is surprising that the contribution of autophagy to HSCT per se is relatively unexplored. In addition, the increasing use of autophagy-modulating drugs in the clinic further highlights the need to understand the role of autophagy in allogeneic HSCT. This review will cover established and implicated roles of autophagy in HSCT, suggesting this pathway as an important therapeutic target for improving transplant outcomes.Immunology and Cell Biology advance online publication, 4 November 2014; doi:10.1038/icb.2014.95.
    Immunology and Cell Biology 11/2014; 93(1). DOI:10.1038/icb.2014.95 · 4.21 Impact Factor
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    ABSTRACT: Natural killer (NK) cell prevention of tumor initiation and metastases requires regulation by both immune receptors and cytokines of the interferon (IFN) family. Recently we first described the ability of the Ig superfamily member CD96 to compete with CD226 (DNAM-1) and to negatively control cytokine responses by NK cells. Now we have evaluated anti-CD96 monoclonal antibody as a novel cancer immunotherapy, alone and in the context of conventional therapies such as surgery, targeted therapies (Her2/neu), doxorubicin, and checkpoint blockade (CTLA-4 or PD-1). Our data demonstrate the general utility of this new immunotherapy in enhancing NK and T cell IFN-g effector function, independently of ADCC, against experimental and spontaneous metastases and established transplanted and de novo primary tumors. We will also describe early studies to compare the activity of co-blockade of CD96 and TIGIT, which both, like CD226 bind CD155. NK cells also have an intrinsic dependence upon type I IFN priming to execute their effector functions. Type III IFN (IFN-l) shares some common functions with IFN-ab, but a more restricted cellular expression. By using the IL-28Ra gene-targeted strain, we demonstrate for the first time, the ability of IFN-l to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-ab signalling.
    Cytokine 11/2014; 70(1):26. DOI:10.1016/j.cyto.2014.07.244 · 2.87 Impact Factor
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    ABSTRACT: Natural killer (NK) cells have been reported to control adaptive immune responses that occur in lymphoid organs at the early stages of immune challenge. The physiological purpose of such regulatory activity remains unclear, because it generally does not confer a survival advantage. We found that NK cells specifically eliminated activated CD4(+) T cells in the salivary gland during chronic murine cytomegalovirus (MCMV) infection. This was dependent on TNF-related apoptosis inducing ligand (TRAIL) expression by NK cells. Although NK cell-mediated deletion of CD4(+) T cells prolonged the chronicity of infection, it also constrained viral-induced autoimmunity. In the absence of this activity, chronic infection was associated with a Sjogren's-like syndrome characterized by focal lymphocytic infiltration into the glands, production of autoantibodies, and reduced saliva and tear secretion. Thus, NK cells are an important homeostatic control that balances the efficacy of adaptive immune responses with the risk of developing autoimmunity.
    Immunity 10/2014; 41(4):646-56. DOI:10.1016/j.immuni.2014.09.013 · 19.75 Impact Factor
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    ABSTRACT: Primary defects in host immune responses have been hypothesised to contribute towards an inability of subjects with cystic fibrosis (CF) to effectively clear pulmonary infections. Innate T-lymphocytes provide rapid pathogen-specific responses prior to the development of classical MHC class I and II restricted T-cell responses and are essential to the initial control of pulmonary infection. We aimed to examine the relationship between peripheral blood lymphocyte phenotype and clinical outcomes in adults with CF.
    PLoS ONE 10/2014; 9(10):e109891. DOI:10.1371/journal.pone.0109891 · 3.53 Impact Factor
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    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
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    ABSTRACT: Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17-dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80+CSF-1R+CD206+iNOS-). Cutaneous cGVHD developed in a CSF-1/CSF-1R-dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r-/- mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80+ macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and lung cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti-CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD.
    Journal of Clinical Investigation 08/2014; 124(10). DOI:10.1172/JCI75935 · 13.77 Impact Factor
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    ABSTRACT: The last six decades have seen major advances in the understanding of immunological diseases, driven by preclinical animal models. Indeed, bone marrow transplantation (BMT) has its genesis in rodent models dating back to the 1950's. Allogeneic BMT and its major complication, graft-versus-host disease (GVHD), represent a paradigm for the translational of preclinical concepts into clinical practice. The appreciation that GVHD can be thought of as a step-wise, escalation in immune activation characterized by eventual massive target tissue apoptosis has allowed the design of rational approaches to better manage patients. Here we describe the pathophysiology of GVHD as defined in preclinical models, focusing on the successes and failures of this research to instruct and translate clinical practice. We also provide a commentary on the limitations of these models so that they may be better appreciated and addressed in future studies. Notable preclinical successes include the definition of modern immune suppression, reductions in conditioning intensity, post-transplant cyclophosphamide and the promotion of regulatory T cell reconstitution. New strategies including naïve T cell depletion, focused cytokine and chemokine inhibition and the blockade of costimulation now also appear highly promising and very likely to translate into patients in the near future.
    Blood 06/2014; 124(3). DOI:10.1182/blood-2014-02-514745 · 9.78 Impact Factor
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    ABSTRACT: Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4+ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-γ-producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8- cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-α production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8- splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN-inducing pathogens.
    The Journal of clinical investigation 05/2014; 124(6). DOI:10.1172/JCI70698 · 13.77 Impact Factor
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    ABSTRACT: The stimulation of naive donor T cells by recipient alloantigen is central to the pathogenesis of graft-versus-host disease after bone marrow transplantation (BMT). Using mouse models of transplantation, we have observed that donor cells become "cross-dressed" in very high levels of recipient hematopoietic cell-derived MHC class I and II molecules following BMT. Recipient-type MHC is transiently present on donor dendritic cells (DCs) after BMT in the setting of myeloablative conditioning but is persistent after nonmyeloablative conditioning, in which recipient hematopoietic cells remain in high numbers. Despite the high level of recipient-derived alloantigen present on the surface of donor DCs, donor T cell proliferative responses are generated only in response to processed recipient alloantigen presented via the indirect pathway and not in response to cross-dressed MHC. Assays in which exogenous peptide is added to cross-dressed MHC in the presence of naive TCR transgenic T cells specific to the MHC class II-peptide combination confirm that cross-dressed APC cannot induce T cell proliferation in isolation. Despite failure to induce T cell proliferation, cross-dressing by donor DCs contributes to generation of the immunological synapse between DCs and CD4 T cells, and this is required for maximal responses induced by classical indirectly presented alloantigen. We conclude that the process of cross-dressing by donor DCs serves as an efficient alternative pathway for the acquisition of recipient alloantigen and that once acquired, this cross-dressed MHC can assist in immune synapse formation prior to the induction of full T cell proliferative responses by concurrent indirect Ag presentation.
    The Journal of Immunology 04/2014; 192(11). DOI:10.4049/jimmunol.1302490 · 5.36 Impact Factor
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    ABSTRACT: The majority of allogeneic stem cell transplants are currently undertaken using G-CSF mobilized peripheral blood stem cells. G-CSF has diverse biological effects on a broad range of cells and IL-10 is a key regulator of many of these effects. Using mixed radiation chimeras in which the hematopoietic or nonhematopoietic compartments were wild-type, IL-10(-/-), G-CSFR(-/-), or combinations thereof we demonstrated that the attenuation of alloreactive T cell responses after with G-CSF mobilization required direct signaling of the T cell by both G-CSF and IL-10. IL-10 was generated principally by radio-resistant tissue, and was not required to be produced by T cells. G-CSF mobilization significantly modulated the transcription profile of CD4(+)CD25(+) regulatory T cells, promoted their expansion in the donor and recipient and their depletion significantly increased graft-versus-host disease (GVHD). In contrast, stem cell mobilization with the CXCR4 antagonist AMD3100 did not alter the donor T cell's ability to induce acute GVHD. These studies provide an explanation for the effects of G-CSF on T cell function and demonstrate that IL-10 is required to license regulatory function but T cell production of IL-10 is not itself required for the attenuation GVHD. Although administration of CXCR4 antagonists is an efficient means of stem cell mobilization, this fails to evoke the immunomodulatory effects seen during G-CSF mobilization. These data provide a compelling rationale for considering the immunological benefits of G-CSF in selecting mobilization protocols for allogeneic stem cell transplantation.
    The Journal of Immunology 02/2014; 192(7). DOI:10.4049/jimmunol.1302315 · 5.36 Impact Factor

Publication Stats

2k Citations
737.67 Total Impact Points

Institutions

  • 2004–2015
    • Queensland Institute of Medical Research
      • Bone Marrow Transplantation Laboratory
      Brisbane, Queensland, Australia
    • Royal Brisbane Hospital
      Brisbane, Queensland, Australia
  • 2003–2014
    • University of Queensland
      Brisbane, Queensland, Australia
  • 2013
    • Sir Charles Gairdner Hospital
      Perth City, Western Australia, Australia
  • 2011
    • University of Sydney
      • Discipline in Dermatology
      Sydney, New South Wales, Australia
  • 2007
    • University of Adelaide
      Tarndarnya, South Australia, Australia
  • 2002
    • Mater Medical Research Institute
      South Brisbane, Queensland, Australia
  • 1999–2000
    • Dana-Farber Cancer Institute
      • Department of Pediatric Oncology
      Boston, MA, United States