Bruce R Blazar

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

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Publications (577)3973.29 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic graft-versus-host disease (cGVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy despite limited efficacy and long-term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in cGVHD. We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3 mg/m(2) IV on days 1, 8, 15, 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at 0.5-1 mg/kg/day with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity, 20 were evaluable for response. Bortezomib plus prednisone therapy was well-tolerated, with one occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ-specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50 mg/day to 20 mg/day at week 15 (p < 0.001). The combination of bortezomib and prednisone for initial treatment of cGVHD is feasible and well-tolerated. We observed a high response rate to combined bortezomib and prednisone therapy, but, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2014; · 3.15 Impact Factor
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    ABSTRACT: Chronic graft versus host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) has emerged as a predominant complication following HSCT and has a distinct etiology. We and others have previously demonstrated that bortezomib, a proteasome inhibitor, can prevent but not treat acute GVHD in mice. To assess the effects of bortezomib on cGVHD, a mouse minor histocompatibility antigen-mismatched strain combination was used to mimic clinical cGVHD sclerodermatous pathogenesis and phenotype. Treatment of ongoing cGVHD with bortezomib ameliorated cutaneous lesions, which were also associated with a reduction in total numbers of germinal center B cells and lower B-cell activating factor (BAFF) gene expression levels in cutaneous tissues. Importantly, lymphoma-bearing mice receiving allogeneic HSCT with bortezomib preserved graft versus tumor (GVT) effects. Based on these animal studies, we initiated an intra-patient dose escalation clinical trial in patients with extensive steroid intolerant, dependent or resistant cGVHD. Marked clinical improvement was observed in patients, which was also associated with reductions of peripheral B cells and minimal toxicity. These results indicate that bortezomib can be of significant use in the treatment of cGVHD and may also allow for maintenance of GVT. This study was registered at ClinicalTrials.gov, identifier: NCT01672229.
    Blood 07/2014; · 9.78 Impact Factor
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    ABSTRACT: There is accumulating evidence that mesenchymal stem cells (MSC) have their origin as perivascular cells (PVC) in vivo, but precisely identifying them has been a challenge, as they have no single definitive marker and are rare. We have developed a fluorescent transgenic vertebrate model in which PVC can be visualized in vivo based upon sdf1 expression in the zebrafish. Prospective isolation and culture of sdf1(DsRed) PVC demonstrated properties consistent with MSC including prototypical cell surface marker expression; mesodermal differentiation into adipogenic, osteogenic and chondrogenic lineages; and the ability to support hematopoietic cells. Global proteomic studies performed by 2-dimensional liquid chromatography and tandem mass spectrometry revealed a high degree of similarity to human MSC and discovery of novel markers (CD99, CD151 and MYOF) that were previously unknown to be expressed by hMSC. Dynamic in vivo imaging during fin regeneration showed that PVC may arise from undifferentiated mesenchyme providing evidence of a PVC - MSC relationship. This is the first model, established in zebrafish, in which MSC can be visualized in vivo and will allow us to better understand their function in a native environment. Stem Cells 2014.
    Stem Cells 06/2014; · 7.70 Impact Factor
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    ABSTRACT: Development of T cells in the thymus requires continuous importation of T lineage progenitors from the bone marrow via the circulation. Following bone marrow transplant (BMT), recovery of a normal peripheral T cell pool depends on production of naïve T cells in the thymus; however, delivery of progenitors to the thymus limits T lineage reconstitution. Here, we examine homing of intravenously-delivered progenitors to the thymus following irradiation and bone marrow reconstitution. Surprisingly, following host conditioning by irradiation, we find that homing of lymphoid-primed multipotent progenitors (LMPP) and common lymphoid progenitors (CLP) to the thymus decreases more than ten-fold relative to unirradiated mice. The reduction in thymic homing in irradiated mice is accompanied by a significant reduction in CCL25, an important chemokine ligand for thymic homing. We show that pretreatment of bone marrow progenitors with CCL25 and CCL21 corrects the defect in thymic homing after irradiation and promotes thymic reconstitution. These data suggest new therapeutic approaches to promote T-cell regeneration.
    Blood 05/2014; · 9.78 Impact Factor
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    ABSTRACT: CD4 regulatory T cells play a critical role in establishment of immune tolerance and prevention of graft versus host disease after allogeneic hematopoietic stem cell transplantation. The recovery and maintenance of regulatory T cells is dependent on homeostatic factors including the generation of naive regulatory T cells from hematopoietic precursor cells, the proliferation and expansion of mature regulatory T cells and the survival of regulatory T cells in vivo. In this study, quantitation of mitochondrial apoptotic priming was used to compare susceptibility of regulatory T cells, conventional CD4 T cells and CD8 T cells to intrinsic pathway apoptosis in 57 patients after allogeneic hematopoietic stem cell transplantation and 25 healthy donors. In healthy donors, regulatory T cells are more susceptible to mitochondrial priming than conventional T cells. Mitochondrial priming is increased after hematopoietic stem cell transplantation in all T cell subsets and particularly in patients with chronic graft versus host disease. Regulatory T cells express high levels of CD95 and are also more susceptible than conventional T cells to apoptosis through the extrinsic pathway. However, CD95 expression and extrinsic pathway apoptosis is not increased after hematopoietic stem cell transplantation. Decreased expression of BCL2 and increased expression of BIM, a mitochondrial cell death activator protein, in regulatory T cells contributes to increased mitochondrial priming in this T cell subset but additional factors likely contribute to increased mitochondrial priming following hematopoietic stem cell transplantation.
    Haematologica 05/2014; · 5.94 Impact Factor
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    ABSTRACT: Chronic GVHD (cGVHD) is a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Having previously shown that germinal center (GC) formation and tissue immunoglobulin deposition is required for multi-organ system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased Tfh frequency correlated with increased GC B cells, cGVHD and BOS. Although administering a highly depletionary anti-CD20 mAb to mice with established cGVHD resulted in marked peripheral B-cell depletion, B-cells remained in the lung and BOS was not reversed. BOS could be treated by eliminating production of IL21 by donor T-cells or IL21R signaling of donor B cells. Development of BOS was dependent upon T-cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL21/IL-21R, ICOS/ICOS-ligand, and CD40L/CD40 hindered GC formation and cGVHD development. These data provide novel insights into cGVHD pathogenesis, indicate an essential role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cell generation, trafficking and function to reverse established cGVHD and associated BOS.
    Blood 05/2014; · 9.78 Impact Factor
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    ABSTRACT: NK cell efficacy correlates with in vivo proliferation and we hypothesize that NK cell product manipulations may optimize this endpoint. Xenotransplantation was used to compare GMP grade freshly activated NK cells (FA-NK) and ex vivo expanded NK cells (Ex-NK). Cells were infused into NSG mice followed by IL-2, IL-15, or no cytokines. Evaluation of blood, spleen and marrow showed that persistence and expansion was cytokine dependent, IL-15 being superior to IL-2. Cryopreservation and immediate infusion resulted in less cytotoxicity and fewer NK cells in vivo and this could be rescued in FA-NK by overnight culture and testing the next day. Marked differences in the kinetics and homing of FA-NK versus Ex-NK were apparent: FA-NK cells preferentially homed to spleen, and persisted longer after cytokine withdrawal. These data would suggest that cryopreservation of FA-NK and Ex-NK is detrimental and that culture conditions profoundly affect homing, persistence and expansion of NK cells in vivo. The NSG mouse model is an adjuvant to in vitro assays prior to clinical testing.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2014; · 3.15 Impact Factor
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    ABSTRACT: In recent years, immune-based therapies have become an increasingly attractive treatment option for patients with cancer. Cancer immunotherapy is often used in combination with conventional chemotherapy for synergistic effects. The alkylating agent cyclophosphamide (CTX) has been included in various chemoimmunotherapy regimens due to its well-known immunostimulatory effects. Paradoxically, CTX can also induce suppressor cells that inhibit immune responses. However, the identity and biological relevance of these suppressor cells are poorly defined. Here we report that CTX treatment drives the expansion of inflammatory monocytic myeloid cells (CD11b+Ly6ChiCCR2hi) that possess immunosuppressive activities. In mice with advanced lymphoma, adoptive transfer (AT) of tumor-specific CD4+ T cells following CTX treatment (CTX+CD4 AT) provoked a robust initial antitumor immune response, but also resulted in enhanced expansion of monocytic myeloid cells. These therapy-induced monocytes inhibited long-term tumor control and allowed subsequent relapse by mediating functional tolerization of antitumor CD4+ effector cells through the PD-1/PD-L1 axis. PD-1/PD-L1 blockade after CTX+CD4 AT therapy led to persistence of CD4+ effector cells and durable antitumor effects. Depleting proliferative monocytes by administering low dose gemcitabine effectively prevented tumor recurrence after CTX+CD4 AT therapy. Likewise, targeting inflammatory monocytes by disrupting the CCR2 signaling pathway markedly potentiated the efficacy of CTX-based therapy. Besides CTX, we found that melphalan and doxorubicin can also induce monocytic myeloid suppressor cells. These findings reveal a counter-regulation mechanism elicited by certain chemotherapeutic agents, and highlight the importance of overcoming this barrier to prevent late tumor relapse after chemoimmunotherapy.
    Cancer Research 04/2014; · 9.28 Impact Factor
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    ABSTRACT: Haploidentical natural killer (NK) cell infusions can induce remissions in some patients with AML but regulatory T-cell (Treg) suppression may reduce efficacy. We treated 57 refractory AML patients with lymphodepleting cyclophosphamide and fludarabine followed by NK cell infusion and interleukin (IL)-2 administration. In 42 patients, donor NK cell expansion was detected in 10%, whereas in 15 patients receiving host Treg depletion with the IL-2-diphtheria fusion protein (IL2DT) the rate was 27%, with a median absolute count of 1000 NK cells/µL blood. IL2DT was associated with improved complete remission rates at day 28 (53% versus 21%; P=0.02) and disease-free survival at 6 months (33% versus 5%; P<0.01). In the IL2DT cohort, NK cell expansion correlated with higher post-chemotherapy serum IL-15 levels (P=0.002), effective peripheral blood Treg depletion (< 5%) at day 7 (P<0.01) and decreased IL-35 levels at day 14 (P=0.02). In vitro assays demonstrated that Tregs co-cultured with NK cells inhibit their proliferation by competition for IL-2, but not for IL-15. Together with our clinical observations this supports the need to optimize the in vivo cytokine milieu where adoptively transferred NK cells compete with other lymphocytes to improve clinical efficacy in patients with refractory AML. This study is registered at clinicaltrials.gov, identifiers: NCT00274846 and NCT01106950.
    Blood 04/2014; · 9.78 Impact Factor
  • Blood 03/2014; 123(12):1967-9. · 9.78 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) are stem cell disorders that can progress to acute myeloid leukemia (AML). While hematopoietic cell transplantation (HCT) can be curative, additional therapies are needed for a disease that disproportionally afflicts the elderly. We tested the ability of a CD16xCD33 BiKE to induce natural killer (NK) cell function from 67 MDS patients. Compared to age-matched normal controls, CD7(+) lymphocytes, NK cells, and CD16 expression were markedly decreased in MDS patients. Despite this, reverse-antibody dependent cell-mediated cytotoxicity (R-ADCC) assays showed potent degranulation and cytokine production when resting MDS-NK cells were triggered with an agonistic CD16 mAb. Blood and marrow MDS-NK cells treated with BiKE significantly enhanced degranulation, TNF-α and IFN-γ production against HL-60 and endogenous CD33(+) MDS targets. MDS patients had a significantly increased proportion of immunosuppressive CD33(+) myeloid derived suppressor cells (MDSC) that negatively correlated with MDS lymphocyte populations and CD16 loss on NK cells. Treatment with the CD16xCD33 BiKE successfully reversed MDSC immunosuppression of NK cells and induced MDSC target cell lysis. Lastly, the BiKE induced optimal MDS-NK cell function irrespective of disease stage. Our data suggest that the CD16xCD33 BiKE functions against both CD33(+) MDS and MDSC targets and may be therapeutically beneficial for MDS patients.
    Blood 03/2014; · 9.78 Impact Factor
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    ABSTRACT: Acquisition of a functional NK cell repertoire, known as education or licensing, is a complex process mediated through inhibitory receptors that recognize self. We found that NK cells containing self-killer Ig-like receptors for cognate HLA ligand in vivo were less susceptible to apoptosis. In vitro IL-15 withdrawal showed that uneducated NK cells upregulated Bim and Fas. Conversely, educated NK cells upregulated Fas ligand (FasL) under these conditions. Induction of cell death and Bim expression on uneducated cells correlated with increased IL-2Rα expression. Overexpression and knockdown studies showed that higher IL-2Rα limits NK cell survival in a novel manner that is independent from the role of IL-2 in activation-induced cell death. To study the role of FasL in induction of IL-2Rα(hi) NK cell death, a coculture assay with FasL-blocking Abs was used. IL-15 withdrawal led to FasL-dependent killing of IL-2Rα(hi) NK cells by more educated IL-2Rα(lo) NK cells. Finally, CMV reactivation induces a potent long-lasting population of licensed NK cells with enhanced survival. These findings show that education-dependent NK cell survival advantages and killing of uneducated NK cells result in the maintenance of a functional repertoire, which may be manipulated to exploit NK cells for cancer immunotherapy.
    The Journal of Immunology 03/2014; · 5.52 Impact Factor
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    ABSTRACT: Excessive levels of B Cell Activating Factor (BAFF) are found in patients with active chronic graft versus host disease (cGVHD). In mice, BAFF has been shown to be essential for B cell recovery after myeloablation. To assess how BAFF levels relate to transplant factors and subsequent cGVHD development, we prospectively monitored 412 patients in the first year after allogeneic peripheral blood or bone marrow (PB/BM) hematopoietic stem cell transplantation (HSCT) and censored data at time of cGVHD onset. In patients who did not develop cGVHD, we affirmed a temporal pattern of gradual BAFF level decrease as the B cell numbers increase after myeloablative conditioning (MAC). By contrast, after reduced intensity conditioning (RIC), BAFF levels remained high throughout the first post-HSCT year, suggesting that the degree of myeloablation resulted in delayed B cell recovery associated with persistence of higher BAFF levels. Since high BAFF/B ratios have been associated with active cGVHD, we examined differences in early BAFF/B ratios and found significantly different BAFF/B ratios at 3 months post-HSCT only after MAC in patients who subsequently developed cGVHD. In addition to HSCT conditioning type, use of sirolimus was significantly associated with higher BAFF levels after HSCT and this was also potentially related to lower B cell numbers. Together, our results are important for interpretation of BAFF measurements in cGVHD biomarker studies.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2014; · 3.15 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GvHD) is a systemic inflammatory response due to the recognition of MHC disparity between donor and recipient after hematopoietic stem cell transplantation (HSCT). T cell activation is critical to the induction of GvHD and data from our group and others have shown that regulatory T cells (Tregs) prevent GvHD when given at the time of HSCT. Using multiphoton laser-scanning microscopy (MPLSM), we examined the single cell dynamics of donor T cells and dendritic cells (DCs) with or without Tregs post-allogeneic transplantation. We found that donor conventional T cells (Tcons) spent very little time screening host DCs. Tcons formed stable contacts with DCs very early after transplantation and only increased velocity in the lymph node at 20 hours after transplant. We also observed that Tregs reduced the interaction time between Tcons and DCs, which was dependent on the generation of IL-10 by Tregs. Imaging using inducible Tregs (iTregs) showed similar disruption of Tcon-DC contact. Additionally, we found that donor Tregs induce host DC death and down-regulate surface proteins required for donor T cell activation. These data indicate that Tregs use multiple mechanisms that affect host DC numbers and function to mitigate acute GvHD.
    Blood 01/2014; · 9.78 Impact Factor
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    ABSTRACT: Bortezomib, a proteasome inhibitor capable of direct anti-tumor effects, has been shown to prevent acute graft-versus-host disease (aGVHD) when administered in a short course immediately after bone marrow transplantation (BMT) in mice. However, when given continuously, CD4+ T cell mediated gastrointestinal tract damages increase GVHD mortality. To investigate the protective effects of bortezomib on other organs, we have used a CD8 dependent aGVHD model of C3H.SW donor T cells engrafted into irradiated C57BL/6 recipients (minor MHC mismatch), which lack significant gut GVHD. Our data in this model show that bortezomib can be given continuously to prevent and treat aGVHD mediated by CD8+ T cells, but this effect is organ-specific such that only skin, but not liver, protection was observed. Despite the lack of hepatic protection, bortezomib still significantly improved survival primarily due to its skin protection. Reduced skin GVHD by bortezomib was correlated with reduced serum and skin IL-6 levels. Administration of a blocking IL-6 antibody in this model also resulted in similar cutaneous GVHD protection. These results indicate that bortezomib or blockade of IL-6 may prevent CD8+ T cell mediated cutaneous aGVHD.
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 01/2014;
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    ABSTRACT: We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent "bystander-activated" (CD8+CD44high) T cells displaying a CD25-NKG2D+ phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4+ T cell help for antigen-specific CD8+ T cell expansion, little is known regarding the role of CD4+ T cells in antigen-nonspecific bystander-memory CD8+ T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non-CD4 depleted mice. Expanded bystander-memory CD8+ T cells upregulated PD-1 in the absence of CD4+ T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8+ T cells. Interestingly, compared to CD8+ T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced) cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8+ response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8+ T cell expansion, CD4+ T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8+ T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion.
    PLoS ONE 01/2014; 9(8):e102709. · 3.73 Impact Factor
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    ABSTRACT: We tested the hypothesis that a novel vaccine developed from autologous dendritic cells (DC) loaded with cells from a unique allogeneic brain tumor cell line (GBM6-AD) would be well-tolerated and would generate an immune response. Patients with recurrent primary brain tumors underwent vaccination with GBM6-AD/DC vaccine. Subjects were treated at escalating DC cell doses: 5 × 10(6) (one patient), 10 × 10(6) (one patient) and 15 × 10(6) (6 patients). Subcutaneous injections were planned for days 0, 14, 28, 42, 56, and monthly thereafter. The primary endpoint was the safety of the GBM6-AD/DC vaccination. The secondary endpoints were immune response, measured by flow cytometry, and the clinical outcome of tumor response defined by time to progression and overall survival. Eight patients were treated. The first three patients were treated in the dose escalation phase of the trial; the remaining five patients received the maximum dose of 15 × 10(6) DC. No dose limiting toxicity was observed. The best response per modified McDonald criteria was partial response in one patient. Flow cytometric immune profiling revealed significant differences in CD4(+)IL17(+) lymphocytes and myeloid derived suppressor cell populations between patients characterized as having stable vs. non-stable disease. This first-in-human study shows that the GBM6-AD/DC vaccine was well tolerated and was associated with an immune response in a subset of patients. No MTD was achieved in this trial. This small-scale pilot provides information for larger scale investigations into the use of this allogeneic vaccine source.
    Journal for immunotherapy of cancer. 01/2014; 2:4.
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    ABSTRACT: Nfatc2 and Tob1 are intrinsic negative regulators of T cell activation. Nfatc2-deficient and Tob1-deficient T cells show reduced thresholds of activation; however, whether these factors have independent or overlapping roles in negative regulation of T cell responses has not been previously examined. Here, we show that Nfatc2 knockout (KO) but not Tob1 KO mice have age-associated accumulation of persistently activated T cells in vivo and expansion of the CD44+ memory cell compartment and age-associated lymphocytic infiltrates in visceral organs, without significant changes in numbers of CD4+CD25+Foxp3+ regulatory T cells (Treg). In vitro, CD4+CD25- "conventional" T cells (Tconvs) from both KO strains showed greater proliferation than wild type (WT) Tconvs. However, while Tregs from Nfatc2 KO mice retained normal suppressive function, Tregs from Tob1 KOs had enhanced suppressive activity. Nfatc2 KO Tconvs expanded somewhat more rapidly than WT Tconvs under conditions of homeostatic proliferation, but their accelerated growth capacity was negated, at least acutely, in a lymphoreplete environment. Finally, Nfatc2 KO mice developed a previously uncharacterized increase in B-cell malignancies, which was not accelerated by the absence of Tob1. The data thus support the prevailing hypothesis that Nfatc2 and Tob1 are non-redundant regulators of lymphocyte homeostasis.
    PLoS ONE 01/2014; 9(6):e100629. · 3.73 Impact Factor
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    ABSTRACT: Spontaneous reversion of disease-causing mutations has been observed in some genetic disorders. In our clinical observations of severe generalized recessive dystrophic epidermolysis bullosa (RDEB), a currently incurable blistering genodermatosis caused by loss-of-function mutations in COL7A1 that results in a deficit of type VII collagen (C7), we have observed patches of healthy-appearing skin on some individuals. When biopsied, this skin revealed somatic mosaicism resulting from the self-correction of C7 deficiency. We believe this source of cells could represent an opportunity for translational "natural" gene therapy. We show that revertant RDEB keratinocytes expressing functional C7 can be reprogrammed into induced pluripotent stem cells (iPSCs) and that self-corrected RDEB iPSCs can be induced to differentiate into either epidermal or hematopoietic cell populations. Our results give proof in principle that an inexhaustible supply of functional patient-specific revertant cells can be obtained-potentially relevant to local wound therapy and systemic hematopoietic cell transplantation. This technology may also avoid some of the major limitations of other cell therapy strategies, eg, immune rejection and insertional mutagenesis, which are associated with viral- and non-viral-mediated gene therapy. We believe this approach should be the starting point for autologous cellular therapies using "natural" gene therapy in RDEB and other diseases.Journal of Investigative Dermatology accepted article preview online, 6 December 2013. doi:10.1038/jid.2013.523.
    Journal of Investigative Dermatology 12/2013; · 6.19 Impact Factor
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    ABSTRACT: Acute graft-versus-host disease (aGVHD) occurs in 40-60% of recipients of partially matched umbilical cord blood transplantation (UCB). In a phase I study, adoptive transfer of expanded CD4+CD25+Foxp3+ natural regulatory T cells (nTregs) resulted in a reduced incidence of grade II-IV GVHD. To investigate potential mechanisms responsible for the reduced GVHD risk, we analyzed peripheral blood mononuclear cell (PBMC) mRNA expression of a tolerance gene set previously identified in operational tolerant kidney transplant recipients, comparing healthy controls to patients who received no nTregs or nTregs with and without GVHD. Samples from patients receiving nTregs regardless of GVHD showed increased Foxp3, but also B cell related tolerance marker expression. This correlated with early B cell recovery, predominately of naïve B cells, and nearly normal T cell reconstitution. CD8+ T cells showed reduced signs of activation (HLA-DR+ expression) in comparison to conventionally treated patients developing GVHD. In contrast, patients with GVHD had significantly increased whereas nTreg-treated patients without GVHD had reduced TLR5 mRNA expression. We identified Lin-HLADR-CD33+CD16+ cells and CD14++CD16- monocytes as main TLR5 producers especially in samples of conventionally treated patients developing GVHD. Together, these data reveal interesting similarities and differences between tolerant organ and nTreg-treated hematopoietic stem cell transplant recipients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2013; · 3.15 Impact Factor

Publication Stats

22k Citations
3,973.29 Total Impact Points

Institutions

  • 2004–2014
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
  • 1990–2014
    • University of Minnesota Duluth
      • • Medical School
      • • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2013
    • Regent University
      Virginia Beach, Virginia, United States
    • Charité Universitätsmedizin Berlin
      • Institute of Medical Immunology
      Berlín, Berlin, Germany
  • 2012–2013
    • University of California, Davis
      • Department of Dermatology
      Davis, CA, United States
    • University of Leuven
      Louvain, Flanders, Belgium
  • 2004–2013
    • University of Nevada, Reno
      • Department of Microbiology and Immunology
      Reno, Nevada, United States
  • 2000–2013
    • University of North Carolina at Chapel Hill
      • • Department of Medicine
      • • Lineberger Comprehensive Cancer Center
      • • Department of Microbiology and Immunology
      Chapel Hill, NC, United States
  • 2007–2012
    • Universität Basel
      • Department of Biomedicine
      Basel, BS, Switzerland
    • Anthony Nolan Research Institute
      Londinium, England, United Kingdom
  • 2006–2012
    • University of Pennsylvania
      • • Department of Microbiology (Medicine)
      • • Department of Pathology and Laboratory Medicine
      Philadelphia, PA, United States
  • 1999–2012
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • Massachusetts General Hospital
      • Transplantation Biology Research Center
      Boston, MA, United States
  • 1993–2012
    • University of Minnesota Twin Cities
      • • Department of Pediatrics
      • • Department of Therapeutic Radiology
      • • Department of Medicine
      Minneapolis, MN, United States
    • Emory University
      • • Department of Surgery
      • • Department of Pediatrics
      • • School of Medicine
      • • Department of Pathology and Laboratory Medicine
      Atlanta, GA, United States
  • 2011
    • Kagawa University
      Takamatu, Kagawa, Japan
  • 1988–2011
    • University of Minnesota Medical Center, Fairview
      Minneapolis, Minnesota, United States
  • 2010
    • Medical College of Georgia
      Augusta, Georgia, United States
  • 2008–2010
    • Hannover Medical School
      • Department of Paediatric Haematology and Oncology
      Hanover, Lower Saxony, Germany
    • University of Michigan
      Ann Arbor, Michigan, United States
  • 2007–2010
    • Georgia Health Sciences University
      • Medical College of Georgia
      Augusta, Georgia, United States
  • 2005–2010
    • University of Miami Miller School of Medicine
      • Department of Microbiology and Immunology
      Miami, FL, United States
  • 2009
    • University of South Florida
      Tampa, Florida, United States
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2006–2009
    • Weizmann Institute of Science
      • Department of Immunology
      Israel
  • 2001–2009
    • Dana-Farber Cancer Institute
      • • Division of Hematologic Malignancies
      • • Department of Medical Oncology
      Boston, MA, United States
  • 2004–2008
    • University of Nevada School of Medicine
      Reno, Nevada, United States
  • 1988–2007
    • Children's Hospitals and Clinics of Minnesota
      Minneapolis, Minnesota, United States
  • 2003
    • Dartmouth–Hitchcock Medical Center
      Lebanon, New Hampshire, United States
    • University of Iowa
      • Department of Pathology
      Iowa City, IA, United States
  • 2002–2003
    • Dartmouth Medical School
      • Department of Microbiology and Immunology
      Hanover, NH, United States
    • NCI-Frederick
      Maryland, United States
    • Medical College of Wisconsin
      • Department of Pediatrics
      Milwaukee, WI, United States
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 1998–2003
    • National Cancer Institute (USA)
      • Center for Cancer Research
      Bethesda, MD, United States
    • Dartmouth College
      • Department of Microbiology and Immunology
      Hanover, New Hampshire, United States
    • University of Texas Southwestern Medical Center
      • Department of Pathology
      Dallas, TX, United States
  • 1999–2002
    • Leidos Biomedical Research
      Maryland, United States
  • 1995
    • Visalia Medical Clinic
      Visalia, California, United States