Neal N Iwakoshi

Emory University, Atlanta, Georgia, United States

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Publications (50)406.42 Total impact

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    ABSTRACT: We have established a model of sensitization in non-human primates and tested two immunosuppressive regimens. Animals underwent fully mismatched skin transplantation, donor-specific antibody (DSA) response was monitored by flow crossmatch. Sensitized animals subsequently underwent kidney transplantation from their skin donor. Immunosuppression included tacrolimus, mycophenolate and methylprednisolone. Three animals received basiliximab induction, compared to non-sensitized animals they showed a shorter mean survival time (MST, 4.7±3.1 vs. 187±88 days). Six animals were treated with T-cell depletion (anti-CD4/CD8 mAbs), which prolonged survival (MST=21.6±19.0 days). All pre-sensitized animals showed antibody-mediated rejection (AMR). In 2/3 basiliximab animals cellular rejection (ACR) was prominent. After T cell depletion, 3/6 monkeys experienced early acute rejection within 8 days with histological evidence of thrombotic microangiopathy and AMR. The remaining three survived 27 to 44 days, with mixed AMR and ACR. Most T-cell depleted animals experienced a rebound of DSA that correlated with deteriorating kidney function. We also found an increase in proliferating memory B cells (CD20+CD27+IgD-Ki67+), lymph node follicular helper T cells (ICOS+PD-1hiCXCR5+CD4+) and germinal center response. Depletion controlled cell-mediated rejection in sensitized non-human primates better than basiliximab, yet grafts were rejected with concomitant DSA rise. This model provides an opportunity to test novel desensitization strategies.
    No preview · Article · Jan 2016 · Transplant International
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    ABSTRACT: We have established a model of sensitization in non-human primates and tested two immunosuppressive regimens. Animals underwent fully mismatched skin transplantation, donor-specific antibody (DSA) response was monitored by flow crossmatch. Sensitized animals subsequently underwent kidney transplantation from their skin donor. Immunosuppression included tacrolimus, mycophenolate and methylprednisolone. Three animals received basiliximab induction, compared to non-sensitized animals they showed a shorter mean survival time (MST, 4.7±3.1 vs. 187±88 days). Six animals were treated with T-cell depletion (anti-CD4/CD8 mAbs), which prolonged survival (MST=21.6±19.0 days). All pre-sensitized animals showed antibody-mediated rejection (AMR). In 2/3 basiliximab animals cellular rejection (ACR) was prominent. After T cell depletion, 3/6 monkeys experienced early acute rejection within 8 days with histological evidence of thrombotic microangiopathy and AMR. The remaining three survived 27 to 44 days, with mixed AMR and ACR. Most T-cell depleted animals experienced a rebound of DSA that correlated with deteriorating kidney function. We also found an increase in proliferating memory B cells (CD20+CD27+IgD-Ki67+), lymph node follicular helper T cells (ICOS+PD-1hiCXCR5+CD4+) and germinal center response. Depletion controlled cell-mediated rejection in sensitized non-human primates better than basiliximab, yet grafts were rejected with concomitant DSA rise. This model provides an opportunity to test novel desensitization strategies. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · American Journal of Transplantation
  • Neal N. Iwakoshi · Robert A. Bray · Howard M. Gebel

    No preview · Article · Oct 2015 · Human Immunology
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    ABSTRACT: Belatacept, a B7-specific fusion protein, blocks CD28-B7 costimulation and prevents kidney allograft rejection. However, it is ineffective in a sizable minority of patients. Although T-cell receptor and CD28 engagement are known to initiate T-cell activation, many human antigen-experienced T-cells lose CD28, and can be activated independent of CD28 signals. We posit that these cells are central drivers of costimulation blockade resistant rejection (CoBRR) and propose that CoBRR might relate to an accumulation of CD28(-) T-cells resulting from viral antigen exposure. We infected C57BL/6 mice with polyomavirus (a BK virus analog), murine cytomegalovirus (a human cytomegalovirus analog), and gammaherpesvirus (HV68; an Epstein-Barr virus analog) and assessed for CD28 expression relative to mock infection controls. We then used mixed lymphocyte reaction (MLR) assays to assess the alloreactive response of these mice against major histocompatibility complex-mismatched cells. We demonstrated that infection with polyomavirus, murine CMV, and HV68 can induce CD28 downregulation in mice. We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic, costimulation blockade resistant, alloreactive response against major histocompatibility complex-mismatched cells without prior alloantigen exposure. Further analysis revealed that gammherpesvirus-induced oligoclonal T-cell expansion is required for the increased alloreactivity. Virus exposure results in reduced T-cell expression of CD28, the target of costimulation blockade therapy. These viruses also contribute to increased alloreactivity. Thus, CD28 downregulation after viral infection may play a seminal role in driving CoBRR. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Feb 2015 · Journal of Surgical Research
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    ABSTRACT: Unlabelled: Gammaherpesviruses display tropism for B cells and, like all known herpesviruses, exhibit distinct lytic and latent life cycles. One well-established observation among members of the gammaherpesvirus family is the link between viral reactivation from latently infected B cells and plasma cell differentiation. Importantly, a number of studies have identified a potential role for a CREB/ATF family member, X-box binding protein 1 (XBP-1), in trans-activating the immediate early BZLF-1 or BRLF1/gene 50 promoters of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), respectively. XBP-1 is required for the unfolded protein response and has been identified as a critical transcription factor in plasma cells. Here, we demonstrate that XBP-1 is capable of trans-activating the murine gammaherpesvirus 68 (MHV68) RTA promoter in vitro, consistent with previous observations for EBV and KSHV. However, we show that in vivo there does not appear to be a requirement for XBP-1 expression in B cells for virus reactivation. The MHV68 M2 gene product under some experimental conditions plays an important role in virus reactivation from B cells. M2 has been shown to drive B cell differentiation to plasma cells, as well as interleukin-10 (IL-10) production, both of which are dependent on M2 induction of interferon regulatory factor 4 (IRF4) expression. IRF4 is required for plasma cell differentiation, and consistent with a role for plasma cells in MHV68 reactivation from B cells, we show that IRF4 expression in B cells is required for efficient reactivation of MHV68 from splenocytes. Thus, the latter analyses are consistent with previous studies linking plasma cell differentiation to MHV68 reactivation from B cells. The apparent independence of MHV68 reactivation from XBP-1 expression in plasma cells may reflect redundancy among CREB/ATF family members or the involvement of other plasma cell-specific transcription factors. Regardless, these findings underscore the importance of in vivo studies in assessing the relevance of observations made in tissue culture models. Importance: All known herpesviruses establish a chronic infection of their respective host, persisting for the life of the individual. A critical feature of these viruses is their ability to reactivate from a quiescent form of infection (latency) and generate progeny virus. In the case of gammaherpesviruses, which are associated with the development of lymphoproliferative disorders, including lymphomas, reactivation from latently infected B lymphocytes occurs upon terminal differentiation of these cells to plasma cells-the cell type that produces antibodies. A number of studies have linked a plasma cell transcription factor, XBP-1, to the induction of gammaherpesvirus reactivation, and we show here that indeed in tissue culture models this cellular transcription factor can trigger expression of the murine gammaherpesvirus gene involved in driving virus reactivation. However, surprisingly, when we examined the role of XBP-1 in the setting of infection of mice-using mice that lack a functional XBP-1 gene in B cells-we failed to observe a role for XBP-1 in virus reactivation. However, we show that another cellular factor essential for plasma cell differentiation, IRF4, is critical for virus reactivation. Thus, these studies point out the importance of studies in animal models to validate findings from studies carried out in cell lines passaged in vitro.
    Preview · Article · Jul 2014 · Journal of Virology
  • R. Ruhil · D. Hwang · O. Bulut · L. Kean · S. Knechtle · N. Iwakoshi

    No preview · Conference Paper · Jul 2014
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    Brian T Gaudette · Neal N Iwakoshi · Lawrence H Boise
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    ABSTRACT: Although it is known that the unfolded protein response (UPR) plays a significant role in the process of plasma cell differentiation, the contribution of the individual sensors of the UPR to this process remains unclear. In this study we examine the death signals and compensatory survival signals activated during B cell activation and the first stages of plasma cell differentiation. During in vitro differentiation of both primary murine B cells and the Bcl1 cell line, we demonstrate that in addition to activation of the physiological UPR, changes in the expression of several Bcl-2 proteins occur, which are consistent with a lowering of the apoptotic threshold of the cell. Specifically, we observed decreased expression of Bcl-2 and Mcl-1 and increased expression of the proapoptotic protein Bim. However, these changes were countered by Bcl-xL induction, which is necessary to protect differentiating cells both from ER stress-induced death by tunicamycin and from the death signals inherent in differentiation. Consistent with differentiating cells becoming dependent on Bcl-xL for survival, the addition of ABT-737 resulted in apoptosis in differentiating cells through the inhibition of sequestration of Bim. Confirming this result, differentiation in the context of RNAi-mediated Bcl-xL knockdown also induced apoptosis. This cell death is C/EBP homologous protein (CHOP)-dependent, connecting these events to the UPR. Thus plasma cell differentiation proceeds through a Bcl-xL-dependent intermediate.
    Preview · Article · Jul 2014 · Journal of Biological Chemistry
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    E J Kim · J Kwun · AC Gibby · J J Hong · AB Farris · N N Iwakoshi · F Villinger · A D Kirk · S J Knechtle
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    ABSTRACT: De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+) ) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.
    Full-text · Article · Jan 2014 · American Journal of Transplantation
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    ABSTRACT: While there have been significant advances in our understanding of the autoimmune responses and the molecular nature of the target auto-antigens in primary biliary cirrhosis (PBC), unfortunately, these data have yet to be translated into new therapeutic agents. We have taken advantage of a unique murine model of autoimmune cholangitis in which mice expressing a dominant negative form of transforming growth factor β receptor II (dnTGFβRII), under the control of the CD4 promoter, develop an intense autoimmune cholangitis associated with serologic features similar to human PBC. CD40-CD40 ligand (CD40L) is a major receptor-ligand pair that provides key signals between cells of the adaptive immune system, prompting us to determine the therapeutic potential of treating autoimmune cholangitis with anti-CD40L antibody (anti-CD40L; MR-1). Four week old dnTGFβRII mice were injected intra-peritoneally with either anti-CD40L or control IgG at days 0, 2, 4, 7 and then weekly until 12 or 24 weeks of age and monitored for the progress of serologic and histologic features of PBC, including rigorous definition of liver cellular infiltrates and cytokine production. Administration of anti-CD40L significantly reduced liver inflammation through 12 weeks of age. In addition, anti-CD40L initially lowered the levels of anti-mitochondrial auto-antibodies (AMA), but these reductions were not sustained. These data indicate that anti-CD40L delays autoimmune cholangitis, but the effect wanes over time. Further dissection of the mechanisms involved, and defining the events that lead to the reduction in therapeutic effectiveness, will be critical to determining whether such efforts can be applied to PBC.
    Preview · Article · Aug 2013 · Clinical & Experimental Immunology
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    ABSTRACT: The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well-documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti-CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell-dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC-mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile.
    Preview · Article · Aug 2012 · American Journal of Transplantation
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    ABSTRACT: Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in transplantation, with mounting evidence associating alloantibodies with the development of chronic rejection. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing or eliminating, highlighting the need for a nonhuman primate model of antibody-mediated rejection. In this report, we demonstrate that depletion using anti-CD3 immunotoxin (IT) combined with maintenance immunosuppression that included tacrolimus with or without alefacept reliably prolonged renal allograft survival in rhesus monkeys. In these animals, a preferential skewing toward CD4 repopulation and proliferation was observed, particularly with the addition of alefacept. Furthermore, alefacept-treated animals demonstrated increased alloantibody production (100%) and morphologic features of antibody-mediated injury. In vitro, alefacept was found to enhance CD4 effector memory T cell proliferation. In conclusion, alefacept administration after depletion and with tacrolimus promotes a CD4+memory T cell and alloantibody response, with morphologic changes reflecting antibody-mediated allograft injury. Early and consistent de novo alloantibody production with associated histological changes makes this nonhuman primate model an attractive candidate for evaluating targeted therapeutics.
    Preview · Article · Jul 2012 · American Journal of Transplantation
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    ABSTRACT: Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection.
    Full-text · Article · Jul 2012 · American Journal of Transplantation
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    ABSTRACT: Background: Breakdown of humoral tolerance to RBC antigens may lead to autoimmune hemolytic anemia, a severe and sometimes fatal disease. The underlying mechanisms behind the breakdown of humoral tolerance to RBC antigens are poorly understood. Design and methods: In order to study the pathogenesis of autoimmune hemolytic anemia, we developed a murine model with RBC-specific expression of a model antigen carrying epitopes from hen egg lysozyme and ovalbumin. Results: Humoral tolerance was observed; this was not broken even by strong immunogenic stimulation (lysozyme or ovalbumin with adjuvant). Autoreactive CD4(+) T cells were detected by tetramer enrichment assays, but failed to activate or expand despite repeat stimulation, indicating a nonresponsive population rather than deletion. Adoptive transfer of autoreactive CD4(+) T cells (OT-II mice) led to autoantibody (anti-lysozyme) production by B cells in multiple anatomic compartments, including the bone marrow. Conclusions: These data demonstrate that B cells autoreactive to RBC antigens survive in healthy mice with normal immune systems. Furthermore, autoreactive B cells are not centrally tolerized and are receptive to T-cell help. As the autoreactive T cells are present but non-responsive, these data indicate that factors that reverse T-cell non-responsiveness may be central to the pathogenesis of autoimmune hemolytic anemia.
    Preview · Article · Jun 2012 · Haematologica
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    ABSTRACT: The role of antibodies in chronic injury to organ transplants has been suggested for many years, but recently emphasized by new data. We have observed that when immunosuppressive potency decreases either by intentional weaning of maintenance agents or due to homeostatic repopulation after immune cell depletion, the threshold of B cell activation may be lowered. In human transplant recipients the result may be donor-specific antibody, C4d+ injury, and chronic rejection. This scenario has precise parallels in a rhesus monkey renal allograft model in which T cells are depleted with CD3 immunotoxin, or in a CD52-T cell transgenic mouse model using alemtuzumab to deplete T cells. Such animal models may be useful for the testing of therapeutic strategies to prevent DSA. We agree with others who suggest that weaning of immunosuppression may place transplant recipients at risk of chronic antibody-mediated rejection, and that strategies to prevent this scenario are needed if we are to improve long-term graft and patient outcomes in transplantation. We believe that animal models will play a crucial role in defining the pathophysiology of antibody-mediated rejection and in developing effective therapies to prevent graft injury. Two such animal models are described herein.
    No preview · Article · Nov 2011 · Seminars in Immunology
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    ABSTRACT: Costimulation blockade of the CD40/CD154 pathway has been effective at preventing allograft rejection in numerous transplantation models. This strategy has largely depended on mAbs directed against CD154, limiting the potential for translation due to its association with thromboembolic events. Though targeting CD40 as an alternative to CD154 has been successful at preventing allograft rejection in preclinical models, there have been no reports on the effects of CD40-specific agents in human transplant recipients. This delay in clinical translation may in part be explained by the presence of cellular depletion with many CD40-specific mAbs. As such, the optimal biologic properties of CD40-directed immunotherapy remain to be determined. In this report, we have characterized 3A8, a human CD40-specific mAb and evaluated its efficacy in a rhesus macaque model of islet cell transplantation. Despite partially agonistic properties and the inability to block CD40 binding of soluble CD154 (sCD154) in vitro, 3A8-based therapy markedly prolonged islet allograft survival without depleting B cells. Our results indicate that the allograft-protective effects of CD40-directed costimulation blockade do not require sCD154 blockade, complete antagonism or cellular depletion, and serve to support and guide the continued development of CD40-specific agents for clinical translation.
    Full-text · Article · Sep 2011 · American Journal of Transplantation
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    ABSTRACT: Significant deficiencies in understanding of xenospecific immunity have impeded the success of preclinical trials in xenoislet transplantation. Although galactose-α1,3-galactose, the gal epitope, has emerged as the principal target of rejection in pig-to-primate models of solid organ transplant, the importance of gal-specific immunity in islet xenotransplant models has yet to be clearly demonstrated. Here, we directly compare the immunogenicity, survival and function of neonatal porcine islets (NPIs) from gal-expressing wild-type (WT) or gal-deficient galactosyl transferase knockout (GTKO) donors. Paired diabetic rhesus macaques were transplanted with either WT (n = 5) or GTKO (n = 5) NPIs. Recipient blood glucose, transaminase and serum xenoantibody levels were used to monitor response to transplant. Four of five GTKO versus one of five WT recipients achieved insulin-independent normoglycemia; transplantation of WT islets resulted in significantly greater transaminitis. The WT NPIs were more susceptible to antibody and complement binding and destruction in vitro. Our results confirm that gal is an important variable in xenoislet transplantation. The GTKO NPI recipients have improved rates of normoglycemia, likely due to decreased susceptibility of xenografts to innate immunity mediated by complement and preformed xenoantibody. Therefore, the use of GTKO donors is an important step toward improved consistency and interpretability of results in future xenoislet studies.
    Full-text · Article · Aug 2011 · American Journal of Transplantation
  • Allan D Kirk · Nicole A Turgeon · Neal N Iwakoshi
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    ABSTRACT: Transplantation tolerance is a state of immune unresponsiveness (or benign responsiveness) to the presence of specific, nonself antigens in the absence of chronic immunosuppressive therapy. Renal transplant tolerance remains a desired yet generally unattained goal that would enable transplantation to be performed without the risk of graft rejection or the need for broadly immunosuppressive drugs, which can have toxic effects. Studies published in the past few years have provided evidence that B cells have an important role in both graft rejection and transplantation tolerance. Indeed, antibody-dependent and antibody-independent functions of B cells account for both tolerogenic and rejection-promoting immune responses in transplant recipients. This Review comprises a discussion of the mechanisms involved in the induction of B-cell tolerance and a survey of current and emerging therapies that target the effects of B cells in transplant recipients.
    No preview · Article · Oct 2010 · Nature Reviews Nephrology
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    ABSTRACT: Major complications with respect to the development of gene therapy treatments for hemophilia A include low factor VIII (fVIII) expression and humoral immune responses resulting in inhibitory anti-fVIII antibodies. We previously achieved sustained curative fVIII activity levels in hemophilia A mice after nonmyeloablative transplantation of genetically-modified hematopoietic stem cells (HSCs) encoding a B-domain deleted porcine fVIII (BDDpfVIII) transgene with no evidence of an immune response. Mouse HSCs were transduced using MSCV-based recombinant virus encoding BDDpfVIII and transplanted into hemophilia A mice. Transplanted mice were followed for donor cell engraftment, fVIII expression and activity, and generation of anti-fVIII immune response. We now show that: (i) the protein expressed by hematopoietic cells has a specific activity similar to that of purified protein; (ii) BDDpfVIII expressed from hematopoietic cells effectively induces thrombus formation, which is shown using a new method of in vivo analysis of fVIII function; (iii) naïve and pre-immunized mice receiving HSC gene therapy are nonresponsive to challenges with recombinant human fVIII; (iv) nonresponsiveness is not broken after stringent challenges with BDDpfVIII; and (v) T cells from these mice are unresponsive to BDDpfVIII presentation. Furthermore, stem cells isolated from donors with high titer anti-human fVIII antibodies show no defects in donor cell engraftment or the ability to express BDDpfVIII. These results demonstrate that HSC gene therapy can be an effective alternative treatment for individuals with hemophilia A and may benefit patients by inducing immunological nonresponsiveness to fVIII replacement products.
    Full-text · Article · Apr 2010 · The Journal of Gene Medicine
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    Stuart J Knechtle · Jean Kwun · Neal Iwakoshi
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    ABSTRACT: Belying the spectacular success of solid organ transplantation and improvements in immunosuppressive therapy is the reality that long-term graft survival rates remain relatively unchanged, in large part due to chronic and insidious alloantibody-mediated graft injury. Half of heart transplant recipients develop chronic rejection within 10 years - a daunting statistic, particularly for young patients expecting to achieve longevity by enduring the rigors of a transplant. The current immunosuppressive pharmacopeia is relatively ineffective in preventing late alloantibody-associated chronic rejection. In this issue of the JCI, Kelishadi et al. report that preemptive deletion of B cells prior to heart transplantation in cynomolgus monkeys, in addition to conventional posttransplant immunosuppressive therapy with cyclosporine, markedly attenuated not only acute graft rejection but also alloantibody elaboration and chronic graft rejection. The success of this preemptive strike implies a central role for B cells in graft rejection, and this approach may help to delay or prevent chronic rejection after solid organ transplantation.
    Full-text · Article · Mar 2010 · The Journal of clinical investigation
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    ABSTRACT: Gammaherpesviruses chronically infect their host and are tightly associated with the development of lymphoproliferative diseases and lymphomas, as well as several other types of cancer. Mechanisms involved in maintaining chronic gammaherpesvirus infections are poorly understood and, in particular, little is known about the mechanisms involved in controlling gammaherpesvirus reactivation from latently infected B cells in vivo. Recent evidence has linked plasma cell differentiation with reactivation of the human gammaherpesviruses EBV and KSHV through induction of the immediate-early viral transcriptional activators by the plasma cell-specific transcription factor XBP-1s. We now extend those findings to document a role for a gammaherpesvirus gene product in regulating plasma cell differentiation and thus virus reactivation. We have previously shown that the murine gammaherpesvirus 68 (MHV68) gene product M2 is dispensable for virus replication in permissive cells, but plays a critical role in virus reactivation from latently infected B cells. Here we show that in mice infected with wild type MHV68, virus infected plasma cells (ca. 8% of virus infected splenocytes at the peak of viral latency) account for the majority of reactivation observed upon explant of splenocytes. In contrast, there is an absence of virus infected plasma cells at the peak of latency in mice infected with a M2 null MHV68. Furthermore, we show that the M2 protein can drive plasma cell differentiation in a B lymphoma cell line in the absence of any other MHV68 gene products. Thus, the role of M2 in MHV68 reactivation can be attributed to its ability to manipulate plasma cell differentiation, providing a novel viral strategy to regulate gammaherpesvirus reactivation from latently infected B cells. We postulate that M2 represents a new class of herpesvirus gene products (reactivation conditioners) that do not directly participate in virus replication, but rather facilitate virus reactivation by manipulating the cellular milieu to provide a reactivation competent environment.
    Full-text · Article · Nov 2009 · PLoS Pathogens

Publication Stats

7k Citations
406.42 Total Impact Points

Institutions

  • 2008-2015
    • Emory University
      • • Department of Surgery
      • • Emory Transplant Center
      Atlanta, Georgia, United States
  • 2003-2007
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 2005
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1998-2003
    • University of Massachusetts Medical School
      • Department of Medicine
      Worcester, Massachusetts, United States