Geoffrey R Hill

Sir Charles Gairdner Hospital, Perth City, Western Australia, Australia

Are you Geoffrey R Hill?

Claim your profile

Publications (73)527.55 Total impact

  • [Show abstract] [Hide abstract]
    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. · 2.52 Impact Factor
  • [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;
  • [Show abstract] [Hide abstract]
    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.
    The Journal of clinical investigation. 08/2014;
  • [Show abstract] [Hide abstract]
    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; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    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; · 15.39 Impact Factor
  • [Show abstract] [Hide abstract]
    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; · 5.52 Impact Factor
  • [Show abstract] [Hide abstract]
    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; · 5.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic Graft vs. Host Disease (cGVHD) is a common complication following allogeneic stem cell transplantation (SCT). Past studies have implicated the persistence of host antigen presenting cells (APCs) in GVHD. Our objective was to determine the frequency of host Langerhans cells (LCs) in normal skin post SCT and ask if their persistence could predict cGVHD. Biopsies of normal skin from 124 sex-mismatched T cell replete allogenic SCT recipients were taken 100 days post-transplant. Patients with acute GVHD and those with less than 9 months of follow-up were excluded and prospective follow-up information was collected from remaining 22 patients. CD1a staining and X&Y chromosome in-situ hybridization were performed to label LCs and to identify their host or donor origin. At 3 months 59±5% of LCs were host derived. The density of LCs and the proportion of host derived LCs was similar between patients that did or did not develop cGVHD. Most LCs in the skin remained of host origin 3 months after SCT regardless of cGVHD status. This finding is in line with the redundant role of LCs in acute GVHD initiation uncovered in recent experimental models. This article is protected by copyright. All rights reserved.
    Experimental Dermatology 12/2013; · 3.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Malaria is a highly prevalent disease caused by infection by Plasmodium spp., which infect hepatocytes and erythrocytes. Blood-stage infections cause devastating symptoms and can persist for years. Antibodies and CD4(+) T cells are thought to protect against blood-stage infections. However, there has been considerable difficulty in developing an efficacious malaria vaccine, highlighting our incomplete understanding of immunity against this disease. Here, we used an experimental rodent malaria model to show that PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8(+) T cells. Furthermore, in contrast to widely held views, parasite-specific CD8(+) T cells are required to control both acute and chronic blood-stage disease even when parasite-specific antibodies and CD4(+) T cells are present. Our findings provide a molecular explanation for chronic malaria that will be relevant to future malaria-vaccine design and may need consideration when vaccine development for other infections is problematic.
    Cell Reports 12/2013; · 7.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cytomegalovirus latently infects myeloid cells; however, the acute effects of the virus on this cell subset are poorly characterised. We demonstrate that systemic cytomegalovirus infection induced rapid activation of monocytes in the bone marrow, characterised by upregulation of CD69, CD11c, Ly6C and M-CSF receptor. Activated bone marrow monocytes were more sensitive to M-CSF and less sensitive to GM-CSF in vitro, resulting in the generation of more macrophages and fewer dendritic cells, respectively. Monocyte activation was also observed in the periphery and resulted in significant accumulation of monocytes in the spleen. MyD88 expression was required within the haematopoietic compartment to initiate monocyte activation and recruitment. However, monocytes lacking MyD88 were activated and recruited in the presence of MyD88-sufficient cells in mixed bone marrow chimeras, indicating that once initiated, the process was MyD88-independent. Interestingly, we found that monocyte activation occurred in the absence of the common inflammatory cytokines, namely type I interferons (IFNs), IL-6, TNF-α, and IL-1 as well as the NLRP3 inflammasome adaptor protein, ASC. We also excluded a role for the chemokine-like protein MCK-2 (m131/129) expressed by MCMV. Taken together, these results challenge the notion that a single inflammatory cytokine mediates activation and recruitment of monocytes in response to infection. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 10/2013; · 4.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Natural regulatory T cells (nTregs) play an important role in tolerance; however, the small numbers of cells obtainable potentially limit the feasibility of clinical adoptive transfer. Therefore, we studied the feasibility and efficacy of using murine-induced regulatory T cells (iTregs) for the induction of tolerance after bone marrow transplantation. iTregs could be induced in large numbers from conventional donor CD4 and CD8 T cells within 1 wk and were highly suppressive. During graft-versus-host disease (GVHD), CD4 and CD8 iTregs suppressed the proliferation of effector T cells and the production of proinflammatory cytokines. However, unlike nTregs, both iTreg populations lost Foxp3 expression within 3 wk in vivo, reverted to effector T cells, and exacerbated GVHD. The loss of Foxp3 in iTregs followed homeostatic and/or alloantigen-driven proliferation and was unrelated to GVHD. However, the concurrent administration of rapamycin, with or without IL-2/anti-IL-2 Ab complexes, to the transplant recipients significantly improved Foxp3 stability in CD4 iTregs (and, to a lesser extent, CD8 iTregs), such that they remained detectable 12 wk after transfer. Strikingly, CD4, but not CD8, iTregs could then suppress Teff proliferation and proinflammatory cytokine production and prevent GVHD in an equivalent fashion to nTregs. However, at high numbers and when used as GVHD prophylaxis, Tregs potently suppress graft-versus-leukemia effects and so may be most appropriate as a therapeutic modality to treat GVHD. These data demonstrate that CD4 iTregs can be produced rapidly in large, clinically relevant numbers and, when transferred in the presence of systemic rapamycin and IL-2, induce tolerance in transplant recipients.
    The Journal of Immunology 10/2013; · 5.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To further define the relative impact of immunotherapy and subsequent development of graft-versus-host disease (GVHD) on survival in patients with relapsed acute leukaemia postallogeneic hematopoietic stem cell transplant (SCT), we performed a single-centre retrospective analysis of 32 actively treated patients between 2003 and 2011. A total of 13 patients were identified who were treated actively with cessation of immunosuppression ± Fludarabine, Cytarabine, G-CSF (FLAG) induction, but no donor leucocyte infusion (DLI) (non-DLI group) and 19 patients received the same step-wise therapy plus G-CSF mobilized DLI (G-DLI group). Groups were not statistically different with regards to baseline characteristics; however, the G-DLI group contained more sibling donors as opposed to unrelated donors than the non-DLI group. With a median follow-up of 47 months, the median overall survival (OS) of the non-DLI and G-DLI groups was not statistically different (8 months vs. 9 months, respectively, P = 0.5). Survival at 3 years was <10% in both groups. Univariate analysis identified response to FLAG, and new onset chronic GVHD as the only factors associated with improved OS. Second donor stem cell infusions are unwarranted in the treatment of relapse after allogeneic SCT and therapeutic strategies should focus on cytoreduction followed by immune modulation with the aim of invoking chronic GVHD.
    International journal of laboratory hematology 09/2013; · 1.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: MHC class I-restricted T cell immunity is essential to control infection with cytomegalovirus (CMV), a clinically important virus that causes significant morbidity and mortality in immunocompromized individuals. Cross-presentation is considered the primary mode of antigen-presentation to generate protective anti-viral CD8(+) T cell immunity. CMV and other herpesviruses (eg Herpes Simplex Virus) encode numerous proteins that interfere with direct antigen presentation, leading to the paradigm that T cell immunity to these pathogens necessitates cross-presentation. However, the antigen presentation requirements needed to generate a protective T cell response to CMV remain unknown. Here, we show that a fully functional anti-viral CD8(+) T cell response can be generated in a system where cross-presentation is shut down by pre-treatment with CpG. Notably, in this setting CD8(+) T cells demonstrate accelerated control of infection, and organ pathology is limited. These data indicate that protective anti-viral T cell immunity to CMV is generated by direct presentation and can be enhanced by pre-treatment with CpG.
    Blood 05/2013; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Donor T cells play pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects following bone marrow transplantation (BMT). DNAX accessory molecule 1 (DNAM-1) is a co-stimulatory and adhesion molecule, expressed mainly by NK cells and CD8(+) T cells at steady state to promote adhesion to ligand-expressing targets and enhance cytolysis. We have analyzed the role of this pathway in GVHD and GVL. The absence of DNAM-1 on the donor graft attenuated GVHD in MHC-mismatched and MHC-matched BMT following conditioning with lethal and sublethal irradiation. In contrast, DNAM-1 was not critical for GVL effects against ligand (CD155)-expressing and non-expressing leukemia. The effects on GVHD following myeloablative conditioning were independent of CD8(+) T cells and dependent on CD4(+) T, and specifically donor FoxP3(+) regulatory T cells (T(reg)). The absence of DNAM-1 promoted the expansion and suppressive function of T(reg) after BMT. These findings provide support for therapeutic DNAM-1 inhibition to promote tolerance in relevant inflammatory based diseases characterized by T cell activation.
    Blood 02/2013; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Microglial cells are the resident macrophages of the central nervous system and participate in both innate and adaptive immune responses but can also lead to exacerbation of neurodegenerative pathologies after viral infections. Microglia in the outer layers of the retina and the subretinal space are thought to be involved in retinal diseases where low-grade chronic inflammation and oxidative stress play a role. This study investigated the effect of systemic infection with murine cytomegalovirus on the distribution and dynamics of retinal microglia cells. Systemic infection with murine cytomegalovirus elicited a significant increase in the number of microglia in the subretinal space and an accumulation of iris macrophages, along with morphological signs of activation. Interferon γ (IFN-γ)-deficient mice failed to induce changes in microglia distribution. Bone marrow chimera experiments confirmed that microglial cells in the subretinal space were not recruited from the circulating monocyte pool, but rather represented an accumulation of resident microglial cells from within the retina. Our results demonstrate that a systemic viral infection can lead to IFN-γ-mediated accumulation of microglia into the outer retinal layers and offer proof of concept that systemic viral infections alter the ocular microenvironment and therefore, may influence the course of diseases such as macular degeneration, diabetic retinopathy, or autoimmune uveitis, where low-grade inflammation is implicated.
    American Journal Of Pathology 01/2013; · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anti-viral immunity and cross-presentation is mediated constitutively through CD8α(+) and CD103(+) DCs. Development of these DC subsets is thought to require the transcription factors Irf8, Id2, Nfil3 and Batf3 although how this network is regulated is poorly defined. We have addressed the nature of the differentiation blocks observed in the absence of these factors and found that while all four factors are required for CD103(+) DC development, only Irf8 is essential for CD8α(+) DC. CD8α(+) DCs emerged in the absence of Id2, Nfil3 and Batf3 in short-term bone marrow reconstitution. These 'induced' CD8α(+) DCs exhibit several hallmarks of classical CD8α(+) DCs including the expression of CD24, Tlr3, Xcr1, Clec9A and the capacity to cross-present soluble, cell-associated antigens and viral antigens even in the absence of Batf3. Collectively, these results uncover a previously undescribed pathway by which CD8α(+) DCs emerge independent of Id2, Nfil3 and Batf3, but dependent on Irf8.
    Blood 01/2013; · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The reconstitution of anti-viral cellular immunity following hematopoietic stem cell transplantation (HSCT) is crucial in preventing cytomegalovirus (CMV)-associated complications. Thus immunological monitoring has emerged as an important tool to better target pre-emptive anti-viral therapies. However, traditional laboratory-based assays are too cumbersome and complicated to implement in a clinical setting. Here we conducted a prospective study of a new whole blood assay (referred to as QuantiFERON-CMV®) to determine the clinical utility of measuring CMV-specific CD8+ T-cell responses as a prognostic tool. Forty-one evaluable allogeneic HSCT recipients underwent weekly immunological monitoring from day 21 post-transplant and of these 21 (51.2%) showed CMV reactivation and 29 (70.7%) developed acute graft-versus-host disease (GvHD). Patients with acute GvHD (grade≥2) within 6 weeks of transplant showed delayed reconstitution of CMV-specific T-cell immunity (p = 0.013) and a higher risk of CMV viremia (p = 0.026). The median time to stable CMV-specific immune reconstitution was 59 days and the incidence of CMV reactivation was lower in patients who developed this than those who did not (27% versus 65%; p = 0.031). Furthermore, a failure to reconstitute CMV-specific immunity soon after the onset of CMV viraemia was associated with higher peak viral loads (5685 copies/ml versus 875 copies/ml; p = 0.002). Hence, QuantiFERON-CMV® testing in the week following CMV viremia can be useful in identifying HSCT recipients at risk of complicated reactivation.
    PLoS ONE 01/2013; 8(10):e74744. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone marrow (BM) or hematopoietic stem cell (HSC) transplantation is used as curative therapy for hematological malignancies. Incorporation of gene-therapy to drive tolerogenic expression of antigens is a promising strategy to overcome the limited long-term efficacy of autologous HSC transplantation for autoimmune diseases. HSC engraftment and tolerance induction is readily achieved after myeloablative or immune-depleting conditioning regardless of the cellular compartment in which antigen is expressed. It is unclear whether the efficiency of engraftment and tolerance induction is influenced by targeting antigen to specific cellular compartments. This is particularly important when using clinically-feasible low-intensity conditioning aimed at preserving infectious immunity in individuals where immunological memory exists to the autoantigen to be expressed. Here we demonstrate that, under immune-preserving conditions, confining expression of a transgenically-expressed antigen to dendritic cells permits stable, long-term engraftment of genetically-modified BM even when recipients are immune to the expressed antigen. In contrast, broader expression within the hematopoietic compartment leads to graft rejection and therapeutic failure due to antigen expression in HSC. These findings are relevant to the clinical application of genetically-engineered HSC and provide evidence that careful selection of promoters for HSC-mediated gene therapy is important, particularly where tolerance is sought under immune-preserving conditions.
    Blood 12/2012; · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: FoxP3(+) confers suppressive properties and is confined to regulatory T cells (T(reg)) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4(+) T(reg) are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8(+) population of FoxP3(+) T(reg) that convert from CD8(+) conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8(+) T(reg) undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4(+)FoxP3(+) population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8(+)FoxP3(+) T(reg) are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8(+)FoxP3(+) T(reg) thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation.
    Blood 04/2012; 119(24):5898-908. · 9.78 Impact Factor
  • Renee J Robb, Geoffrey R Hill
    [Show abstract] [Hide abstract]
    ABSTRACT: The therapeutic GVL effect after allogeneic stem cell transplantation is limited by the development of GVHD. The ultimate aim of current research is to separate the 2 processes in a meaningful fashion. The IFNs are a pleiotropic group of cytokines that were originally recognized because of their ability to interfere with viral replication. However, it is now established that these cytokines play an important role in orchestrating both innate and adaptive immunity. Multiple studies have investigated the effects of both types I and II IFN on GVHD and GVL in preclinical transplant models. The results indicate variable effects that are dependent on the period of activity within the developing immune response, the presence and type of pretransplant conditioning and the differential mechanisms, and IFN sensitivity of immune pathology within individual target organs during GVHD. This Perspective discusses the current literature on the IFNs and their potential modulation within clinical transplantation, focusing particularly on enhancing the therapeutic GVL effects.
    Blood 04/2012; 119(23):5351-8. · 9.78 Impact Factor

Publication Stats

2k Citations
527.55 Total Impact Points

Institutions

  • 2013
    • Sir Charles Gairdner Hospital
      Perth City, Western Australia, Australia
  • 2010–2013
    • University of Western Australia
      • Lions Eye Institute
      Perth, Western Australia, Australia
  • 2004–2013
    • Queensland Institute of Medical Research
      • • Bone Marrow Transplantation Laboratory
      • • Immunology and Infection Laboratory
      Brisbane, Queensland, Australia
  • 2012
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States
  • 2011
    • University of Sydney
      • Discipline in Dermatology
      Sydney, New South Wales, Australia
  • 2001–2008
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
  • 2005–2007
    • Royal Brisbane Hospital
      Brisbane, Queensland, Australia
  • 2003
    • University of Queensland
      Brisbane, Queensland, Australia
  • 1999
    • Dana-Farber Cancer Institute
      • Department of Pediatric Oncology
      Boston, MA, United States