Bruce R Blazar

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

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Publications (688)4871.47 Total impact

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    ABSTRACT: Purpose: The effectiveness of NK cell infusions to induce leukemic remission is limited by lack of both antigen specificity and in vivo expansion. To address the first issue we previously generated a bispecific killer engager (BiKE) containing single chain scFV against CD16 and CD33 to create an immunologic synapse between NK cells and CD33+ myeloid targets. We have now incorporated a novel modified human IL-15 crosslinker, producing a 161533 trispecific killer engager (TriKE) to induce expansion, priming, and survival, which we hypothesize will enhance clinical efficacy. Methods: Reagents were tested in proliferation and functional assays and in an in vivo xenograft model of AML. Results: When compared to the 1633 BiKE, the 161533 TriKE induced superior NK cell cytotoxicity, degranulation, and cytokine production against CD33+ HL-60 targets and increased NK survival and proliferation. Specificity was shown by the ability of a 1615EpCAM TriKE to kill CD33-EpCAM+ targets. Using NK cells from patients after allogeneic stem cell transplantation when NK cell function is defective, the 161533 TriKE restored potent NK function against primary AML targets and induced specific NK cell proliferation. These results were confirmed in an immunodeficient mouse HL-60-Luc tumor model where the 161533 TriKE exhibited superior anti-tumor activity and induced in vivo persistence and survival of human NK cells for at least 3 weeks. Conclusions: Off-the-shelf 161533 TriKE imparts antigen specificity and promotes in vivo persistence, activation, and survival of NK cells. These qualities are ideal for NK cell therapy of myeloid malignancies or targeting antigens of solid tumors.
    No preview · Article · Feb 2016 · Clinical Cancer Research
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    ABSTRACT: Caveolin-1 (Cav-1) is a key organizer of membrane specializations and a scaffold protein that regulates signalling in multiple cell types. We found increased Cav-1 expression in human and murine T cells after allogeneic hematopoietic cell transplantation. Indeed, Cav-1(-/-) donor T cells caused less severe acute Graft-versus-Host Disease (GVHD) and yielded higher numbers of regulatory T cells (Treg) compare to controls. Depletion of Treg from the graft abrogated this protective effect. Correspondingly, Treg frequencies increased when Cav-1(-/-) T cells were exposed to TGF-β/TCR/CD28-activation or alloantigen-stimulation in vitro compared to wt T cells. Mechanistically, we found that the phosphorylation of Cav-1 is dispensable for the control of T cell fate by using a non-phosphorylatable Cav-1 (Y14F/Y14F) point-mutation-variant. Moreover, the close proximity of lymphocyte-specific protein tyrosine kinase (Lck) to the TCR induced by TCR-activation was reduced in Cav-1(-/-) T cells. Therefore, less TCR/Lck-clustering results in suboptimal activation of the downstream signalling events, which correlates with the preferential development into a Treg phenotype. Overall, we report a novel role for Cav-1 in TCR/Lck spatial distribution upon TCR triggering, which controls T cell fate towards a regulatory phenotype. This alteration translated into a significant increase in the frequency of Treg and reduced GVHD in vivo.
    No preview · Article · Feb 2016 · Blood
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    ABSTRACT: B cell anti-host antibody production plays a central role in chronic graft-vs-host disease (cGVHD). T follicular helper (TFH) cells drive B cell responses and are implicated in this process. Given differences in cGVHD incidence between umbilical cord blood (UCB) and adult donor transplant recipients, we evaluated TFH cell reconstitution kinetics to define graft source differences and their potential pathogenic role in cGVHD. Although we observed significantly fewer TFH cells in the blood of UCB recipients (vs. matched related donors (MRD)) early after transplantation, by 1 year the numbers of TFH cells were similar. Additionally, at both early (day 60) and late (1 year) time points, TFH cell phenotype was predominantly central memory cells in both cohorts. TFH cells were functional and able to produce multiple cytokines (INF-γ, TNF-α, IL-2, IL-17 and IL-21) following stimulation. In contrast to mouse models where an enhanced frequency of splenic TFH cells contributes to cGVHD, patients with cGVHD showed significantly depleted circulating TFH cells following both UCB and MRD transplantation. Low numbers of TFH cells early after UCB transplantation could directly contribute to less cGVHD in this cohort. Additionally, systemic therapy (including steroids and calcineurin inhibitors) may contribute to decreases in TFH cells in patients with cGVHD. These data provide further evidence supporting the importance of TFH cells in cGVHD pathogenesis.
    No preview · Article · Jan 2016 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: There is little data regarding the incidence, clinical manifestations, risk factors and outcomes of late acute GVHD (aGVHD). We evaluated patients with late aGVHD after allogeneic HCT between 2007 and 2012 and compared their outcomes to patients with early onset aGVHD. Of the 511 allogeneic HCT recipients, 75 developed late aGVHD (cumulative incidence: 14.7% (95% CI: 11.6-17.8) versus 248 with early onset aGVHD (cumulative incidence: 49% (95% CI: 45-53). Amongst those with late aGVHD, 52% had persistent, 39% recurrent and 9% de-novo late aGVHD. Advanced (grade III-IV) early onset aGVHD was associated with a higher risk of developing late aGVHD (HR 1.9, 95% CI: 1.2 -3.1, p= 0.01). 48% (95% CI: 36-60%) of late aGVHD versus only 31% (95% CI: 26-37%) of early onset aGVHD progressed to chronic GVHD by 2 years. Higher proportion of persistent (53%) as compared to recurrent (39%) and de-novo (46%) late aGVHD progressed to cGVHD at 2 years. The overall survival was 59% (95% CI: 49-72) in late aGVHD and 50% (95% CI: 44-57%) in early onset aGVHD. Persistent late aGVHD had worse OS and NRM (45% and 39%) as compared to recurrent (74% and 18%) and de-novo (83% and 0%) late aGVHD. Compared to HLA-identical sibling HCT, unrelated donor transplants were associated with a higher risk of mortality in patients developing late aGVHD (HR 6.1, 95% CI: 2.3-16.2, p<0.01). In a landmark analysis (evaluating 100 day survivors among early onset aGVHD), no difference was seen in late mortality (after 100 days) between early onset and late aGVHD (HR 0.96, 95% CI: 0.59-1.55, p= 0.85), however the risk of cGVHD was nearly doubled (HR 1.81, 95% CI: 1.16-2.82, p=0.01) in patients with late aGVHD. Conclusions: Late aGVHD is a relatively common complication after allogeneic HCT. Poorer outcomes in those with persistent late aGVHD imply need for more effective therapy in this group to improve transplant outcomes. A higher risk of subsequent chronic GVHD needs further evaluation and close monitoring.
    No preview · Article · Dec 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Clinical application of umbilical cord blood (UCB) as a source of hematopoietic stem cells for transplantation is limited by low CD34+ cell dose, increased risk of graft failure, and slow hematopoietic recovery. While the cell dose limitation is partially mitigated by using two UCB units, larger-dosed single units would be preferable. We have evaluated the feasibility and safety of StemRegenin-1 (SR-1), an aryl hydrocarbon receptor antagonist that expands CD34+ cells, by placing one of the two units in expansion culture. SR-1 produced a 330-fold increase in CD34+ cells and led to engraftment in 17/17 patients at a median of 15 days for neutrophils and 49 days for platelets, significantly faster than in patients treated with unmanipulated UCB. Taken together, the marked expansion, absence of graft failure, and enhanced hematopoietic recovery support testing of SR-1 expansion as a stand-alone graft and suggest it may ameliorate a limitation of UCB transplant.
    No preview · Article · Dec 2015 · Cell stem cell
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    ABSTRACT: Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of nonhuman primate (NHP) T cells during acute GVHD. Utilizing microarray technology, we measured the expression profiles of CD3(+) T cells from five cohorts: allogeneic transplant recipients receiving (i) no immunoprophylaxis (No Rx), (ii) sirolimus monotherapy (Siro), (iii) tacrolimus-methotrexate (Tac-Mtx), as well as (iv) autologous transplant recipients (Auto) and (v) healthy controls (HC). This comparison allowed us to identify transcriptomic signatures specific for alloreactive T cells and determine the impact of both mTOR (mechanistic target of rapamycin) and calcineurin inhibition on GVHD. We found that the transcriptional profile of unprophylaxed GVHD was characterized by significant perturbation of pathways regulating T cell proliferation, effector function, and cytokine synthesis. Within these pathways, we discovered potentially druggable targets not previously implicated in GVHD, prominently including aurora kinase A (AURKA). Utilizing a murine GVHD model, we demonstrated that pharmacologic inhibition of AURKA could improve survival. Moreover, we found enrichment of AURKA transcripts both in allo-proliferating T cells and in sorted T cells from patients with clinical GVHD. These data provide a comprehensive elucidation of the T cell transcriptome in primate acute GVHD and suggest that AURKA should be considered a target for preventing GVHD, which, given the many available AURKA inhibitors in clinical development, could be quickly deployed for the prevention of GVHD.
    No preview · Article · Nov 2015 · Science translational medicine
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    ABSTRACT: A disodium phosphonooxymethyl prodrug of the antitumor agent triptolide was prepared from the natural product in three steps (39% yield) and displayed excellent aqueous solubility at pH 7.4 (61 mg/mL) compared to the natural product (17 μg/mL). The estimated shelf life (t90) for hydrolysis of the prodrug at 4 °C and pH 7.4 was found to be two years. In a mouse model of human colon adenocarcinoma (HT-29), the prodrug administered intraperitoneally was effective in reducing or eliminating xenograft tumors at dose levels as low as 0.3 mg/kg when given daily and at 0.9 mg/kg when given less frequently. When given via intraperitoneal and oral routes at daily doses of 0.6 and 0.9 mg/kg, the prodrug was also effective and well tolerated in a mouse model of human ovarian cancer (A2780).
    Preview · Article · Nov 2015 · Journal of Medicinal Chemistry
  • Brent H Koehn · Robert Zeiser · Bruce R Blazar

    No preview · Article · Nov 2015 · Oncotarget
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    ABSTRACT: We studied the safety and clinical outcomes of patients treated with umbilical cord blood (UCB) derived regulatory T cells that expanded in cultures stimulated with K562 cells modified to express the high affinity Fc receptor (CD64) and CD86, the natural ligand of CD28 (KT64/86). Eleven patients were treated with Treg doses from 3 to 100 x 10(6) Treg/kg. The median proportion of CD4+FoxP3+CD127- in the infused product was 87% (r, 78-95%) and we observed no dose limiting infusional adverse events. Clinical outcomes were compared to contemporary controls (n=22) who received the same conditioning regimen with sirolimus and mycophenolate mofetil immune suppression. The incidence of grade II-IV acute graft-vs.-host disease (GVHD) at 100 days was 9% (95%CI, 0-25%) vs. 45% (95%CI, 24-67%) in controls (p=.05). Chronic GVHD at 1 year was zero in Tregs and 14% in controls. Hematopoietic recovery and chimerism, cumulative density of infections, non-relapse mortality, relapse and disease-free survival were similar in the Treg recipients and controls. KT64/86 expanded UCB Tregs were safe and resulted in low risk of acute GVHD.
    No preview · Article · Nov 2015 · Blood
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    ABSTRACT: The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted.
    Full-text · Article · Nov 2015 · Science Advances
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    Full-text · Article · Nov 2015
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    ABSTRACT: Present adoptive immunotherapy strategies are based on the re-targeting of autologous T-cells to recognize tumor antigens. As T-cell properties may vary significantly between patients, this approach can result in significant variability in cell potency that may affect therapeutic outcome. More consistent results could be achieved by generating allogeneic cells from healthy donors. An impediment to such an approach are the endogenous T-cell receptors present on T-cells, which have the potential to direct dangerous off-tumor anti-host reactivity. To address these limitations, we assessed the ability of three different TCR-alpha targeted nucleases to disrupt T-cell receptor expression in primary human T-cells. We optimized the conditions for the delivery of each reagent, and assessed off target cleavage. The megaTAL and CRISPR/Cas9 reagents exhibited the highest disruption efficiency combined with low levels of toxicity and off target cleavage and we used them for a translatable manufacturing process to produce safe cellular substrates for next generation immunotherapies.Molecular Therapy (2015); doi:10.1038/mt.2015.197.
    Full-text · Article · Oct 2015 · Molecular Therapy
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    ABSTRACT: The human intestine contains 10 bacteria, which outnumber the mammalian cells 10-fold. Certain other commensal or infectious agents, like helminthic parasites, become members of this microbial ecosystem, especially in populations living under less hygienic conditions. Intestinal microbes, also called the microbiome or microbiota, shape the host immune reactivity to self and nonself throughout life. Changes in microbiome composition may impair the maturation of immune regulatory pathways and predispose the host to develop various forms of inflammatory disorders, like Crohn's disease or ulcerative colitis. The microbiome is also critical to successful transplantation of organs or grafts. After allogeneic hematopoietic stem cell transplantation, when the new donor cells, such as T lymphocytes learn to discriminate "the new self from nonself" in the transplant recipient, they need healthy microbiota-derived signals to preserve the immune homeostasis. Restoring microbiota through intestinal delivery of bacterial strains, helminths, fecal microbiota transplantation, or stool substitutes have the potential to improve and correct aberrant immune reactivity in various disorders.
    No preview · Article · Oct 2015 · Inflammatory Bowel Diseases
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    ABSTRACT: Graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We previously identified high plasma soluble suppression of tumorigenicity 2 (sST2) as a biomarker of the development of GVHD and death. sST2 sequesters interleukin-33 (IL-33), limiting its availability to T cells expressing membrane-bound ST2 (mST2) [T helper 2 (TH2) cells and ST2+ FoxP3+ regulatory T cells]. We report that blockade of sST2 in the peritransplant period with a neutralizing monoclonal antibody (anti-ST2 mAb) reduced GVHD severity and mortality. We identified intestinal stromal cells and T cells as major sources of sST2 during GVHD. ST2 blockade decreased systemic interferon-g, IL-17, and IL-23 but increased IL-10 and IL-33 plasma levels. ST2 blockade also reduced sST2 production by IL-17-producing T cells while maintaining protective mST2-expressing T cells, increasing the frequency of intestinal myeloid-derived suppressor cells, and decreasing the frequency of intestinal CD103 dendritic cells. Finally, ST2 blockade preserved graft-versus-leukemia activity in a model of green fluorescent protein (GFP)-positive MLL-AF9 acute myeloid leukemia. Our findings suggest that ST2 is a therapeutic target for severe GVHD and that the ST2/IL-33 pathway could be investigated in other T cell-mediated immune disorders with loss of tolerance.
    No preview · Article · Oct 2015 · Science translational medicine
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    ABSTRACT: The impact of allele level HLA mismatch is uncertain in recipients of double umbilical cord blood transplantation (dUCBT). We report a single center retrospective study of the clinical effect of using allele-level HLA mismatch HLA-A, -B, -C, -DRB1 and -DQB1 of the two UCB units. We studied 342 patients with hematological malignancy. Donor-recipient pairs were grouped according to the number of matched HLA alleles with 32 matched at 9-10/10, 202 at 6-8/10 and 108 at 2-5/10 alleles. The incidence of hematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), and non-relapse mortality (NRM) and treatment failure was similar between groups. In an exploratory analysis of 174 patients with acute leukemia, after adjusting for length of first remission and cytogenetic risk group, 2-5/10 HLA match was associated with lower risk of relapse and treatment failure. These data indicate that a high degree of allele level HLA mismatch does not adversely affect transplant outcomes and may be associated with reduced relapse risk in patients with acute leukemia.
    No preview · Article · Oct 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL-2) and anti-CD40 (αCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of negative regulators such as cytotoxic T lymphocyte antigen-4 (CTLA-4) could simultaneously prolong CD8(+) T cell responses and augment T cell anti-tumor effects. We devised a regimen in which anti-CTLA-4 was administered late so as to delay contraction and minimize toxicities. This late administration both enhanced and prolonged CD8 T cell activation without the need for additional IL-2. The quality of the T cell response was improved with increased frequency of effector/effector memory phenotype cells along with improved lytic ability and bystander expansion. This enhanced CD8 response translated to improved anti-tumor responses both at the primary and metastatic sites. Importantly, toxicities were not exacerbated with combination. This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities.
    No preview · Article · Oct 2015 · Cancer Immunology and Immunotherapy
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    ABSTRACT: We have recently described a specialized subset of human natural killer (NK) cells with a CD56(dim)CD57(+)NKG2C(+) phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% [17-35%], p=0.05) and superior disease-free survival (DFS) (55% [45-65%] p=0.04) 1 year after reduced intensity conditioning (RIC) compared to CMV seronegative recipients who experienced higher relapse rates (35% [27-43%]) and lower DFS (46% [38-54%]). This protective effect was independent of age and graft-versus-host disease (GvHD) and was not observed in recipients who received myeloablative (MA) regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56(dim)CD57(+)NKG2C(+) NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months post-transplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on post-transplant relapse is in part driven by adaptive NK cell responses.Leukemia accepted article preview online, 29 September 2015. doi:10.1038/leu.2015.260.
    No preview · Article · Sep 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: Allogeneic hematopoietic cell transplantation is often complicated by graft-versus-host disease (GVHD). We analyzed the incidence and risk factors for acute and chronic graft-versus-host disease (GVHD), and their impact on disease relapse and survival, among recipients of single umbilical cord blood (sUCB, n=295), double umbilical cord blood (dUCB, n=416), and matched sibling donor (MSD, n=469) allografts. The incidence of grade II-IV aGVHD and chronic GVHD among dUCB, sUCB, and MSD was 56%, 26% and 37% and 26%, 7%, and 40%, respectively. Development of acute GVHD had no effect on relapse, non-relapse mortality, or overall survival among UCB recipients, but was associated with worse non-relapse mortality and survival in MSD recipients. Development of cGVHD was only associated with lower relapse in dUCBT. In multivariate analysis of GVHD incidence, age > 18 years was associated with higher incidence of aGVHD and cGVHD across all cohorts, while worse HLA match and prior aGVHD were associated with higher risks of aGVHD in both UCB cohorts. Non-myeloablative conditioning limited the risk of aGVHD compared to myeloablative conditioning in dUCB recipients. Cyclosporine A and mycophenolate mofetil as GVHD prophylaxis lowered the risk of cGVHD compared to steroids with cyclosporine A among sUCB recipients. This large contemporary analysis suggests similarity of risks and consequences of GVHD for UCB and MSD recipients. Limiting the severity of aGVHD remains important in all groups. Increasing the UCB inventory or developing strategies that reduce the cell-dose threshold and thereby increase the chance of identifying an adequately dosed, better HLA-matched single UCB unit may further limit risks of acute GVHD after UCB transplantation.
    No preview · Article · Sep 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • Beau R. Webber · Jakub Tolar · Michael Kyba · Bruce R. Blazar

    No preview · Conference Paper · Sep 2015
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    ABSTRACT: Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30–60 minutes after 4–5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing non-inflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1high neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses towards the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation.
    No preview · Article · Aug 2015 · OncoImmunology

Publication Stats

33k Citations
4,871.47 Total Impact Points

Institutions

  • 2005-2015
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
    • Neural Stem Cell Institute
      رنسلیر، نیویورک, New York, United States
  • 1988-2015
    • University of Minnesota Duluth
      • • Medical School
      • • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States
  • 2013
    • American Cancer Society
      Atlanta, Georgia, United States
  • 2005-2013
    • University of North Carolina at Chapel Hill
      • • Department of Medicine
      • • Lineberger Comprehensive Cancer Center
      North Carolina, United States
  • 2012
    • ICL
      Londinium, England, United Kingdom
    • University of California, Davis
      • Department of Dermatology
      Davis, CA, United States
    • Universität Basel
      • Department of Biomedicine
      Bâle, Basel-City, Switzerland
  • 2011
    • Harvard Medical School
      • Department of Pathology
      Boston, MA, United States
    • Georgia Health Sciences University
      • Cancer Center
      Augusta, GA, United States
  • 2001-2010
    • Emory University
      • • Department of Surgery
      • • Department of Biochemistry
      Atlanta, Georgia, United States
    • University of Cambridge
      • Department of Pathology
      Cambridge, England, United Kingdom
    • Baylor College of Medicine
      Houston, Texas, United States
  • 2009
    • University of South Florida
      • Department of Oncologic Sciences
      Tampa, Florida, United States
  • 1990-2009
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2008
    • Yale-New Haven Hospital
      • Department of Laboratory Medicine
      New Haven, Connecticut, United States
    • Yale University
      • Department of Laboratory Medicine
      New Haven, Connecticut, United States
  • 1986-2007
    • Children's Hospitals and Clinics of Minnesota
      Minneapolis, Minnesota, United States
  • 2006
    • Weizmann Institute of Science
      • Department of Immunology
      Israel
    • Loyola University Medical Center
      مايوود، إلينوي, Illinois, United States
  • 2001-2005
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2004
    • University of Nevada, Reno
      • Department of Microbiology and Immunology
      Reno, Nevada, United States
    • University of Nevada School of Medicine
      Reno, Nevada, United States
    • Children's Hospital Los Angeles
      Los Ángeles, California, United States
    • Mayo Clinic - Rochester
      • Department of Immunology
      Рочестер, Minnesota, United States
  • 2002
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
    • Medical College of Wisconsin
      • Department of Microbiology and Molecular Genetics
      Milwaukee, Wisconsin, United States
    • Università degli Studi di Perugia
      • Department of Clinical and Experimental Medicine
      Perugia, Umbria, Italy
  • 1998-2002
    • Dartmouth College
      • Department of Microbiology and Immunology
      Hanover, New Hampshire, United States
  • 1999
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • Dong-A University
      Tsau-liang-hai, Busan, South Korea
  • 1997
    • University of Minnesota Twin Cities
      • Department of Pediatrics
      Minneapolis, MN, United States
  • 1995
    • Laval University
      Quebec City, Quebec, Canada