T A Waldmann

NCI-Frederick, Фредерик, Maryland, United States

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Publications (589)5766.29 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin-2 (IL-2) regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. IL-2 is of considerable therapeutic interest, but harnessing its actions in a controllable manner remains a challenge. Previously, we have engineered an IL-2 "superkine" with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as "receptor signaling clamps." They retained high affinity for IL-2Rβ, inhibiting binding of endogenous IL-2, but their interaction with γc was weakened, attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogs acted as partial agonists and differentially affected lymphocytes poised at distinct activation thresholds. Moreover, one variant, H9-RETR, antagonized IL-2 and IL-15 better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft-versus-host disease and blocked spontaneous proliferation of smoldering adult T cell leukemia (ATL) T cells. This receptor-clamping approach might be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 05/2015; 42(5):826-38. DOI:10.1016/j.immuni.2015.04.018 · 19.75 Impact Factor
  • Thomas A Waldmann
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    ABSTRACT: IL2 and IL15, members of the 4α-helix bundle family of cytokines, play pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of IL2 through maintenance of fitness of regulatory T cells and activation-induced cell death is the elimination of self-reactive T cells to prevent autoimmunity. In contrast with IL2, IL15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. Blockade of IL2 and IL15 using monoclonal antibodies has been reported to be of value in the treatment of patients with leukemia, autoimmune disorders, and in the prevention of allograft rejection. IL2 has been approved by the FDA for the treatment of patients with malignant renal cell cancer and metastatic malignant melanoma. Clinical trials involving recombinant human IL15 given by bolus infusions have been completed, and studies assessing subcutaneous and continuous intravenous infusions are under way in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL15 with IL15Rα(+/-) IgFc. Cancer Immunol Res; 3(3); 219-27. ©2015 AACR. ©2015 American Association for Cancer Research.
    03/2015; 3(3):219-227. DOI:10.1158/2326-6066.CIR-15-0009
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    ABSTRACT: Lymphodepleting regimens are used before adoptive immuno-therapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic " cytokine sinks. " These conditioning modalities, however, are often associated with severe tox-icities. We found that microRNA-155 (miR-155) enabled tumor-specific CD8 + T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-abla-tion. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic γc cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serine-threonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a reca-pitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be used to increase the effectiveness of adop-tive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers.
    Proceedings of the National Academy of Sciences 01/2015; 112(2). DOI:10.1073/pnas.1422916112 · 9.81 Impact Factor
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    ABSTRACT: Adult T cell leukemia/lymphoma (ATLL) is an aggressive malignancy caused by human T cell lymphotropic virus type-I (HTLV-I) without curative treatment at present. To illuminate the pathogenesis of ATLL we performed whole transcriptome sequencing of purified ATLL patient samples and discovered recurrent somatic mutations in CCR4, encoding CC chemokine receptor 4. CCR4 mutations were detected in 14/53 ATLL samples (26%) and consisted exclusively of nonsense or frameshift mutations that truncated the coding region at C329, Q330, or Y331 in the carboxy terminus. Functionally, the CCR4-Q330 nonsense isoform was gain-of-function because it increased cell migration toward the CCR4 ligands CCL17 and CCL22, in part by impairing receptor internalization. This mutant enhanced PI(3) kinase/AKT activation after receptor engagement by CCL22 in ATLL cells and conferred a growth advantage in long-term in vitro cultures. These findings implicate somatic gain-of-function CCR4 mutations in the pathogenesis of ATLL and suggest that inhibition of CCR4 signaling might have therapeutic potential in this refractory malignancy.
    Journal of Experimental Medicine 12/2014; 211(13). DOI:10.1084/jem.20140987 · 13.91 Impact Factor
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    ABSTRACT: Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. We performed a first in-human trial of Escherichia coli-produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration. © 2014 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 11/2014; 33(1). DOI:10.1200/JCO.2014.57.3329 · 18.43 Impact Factor
  • 11/2014; 2(Suppl 3):P79-P79. DOI:10.1186/2051-1426-2-S3-P79
  • 11/2014; 2(Suppl 3):P167-P167. DOI:10.1186/2051-1426-2-S3-P167
  • 11/2014; 2(Suppl 3):P80-P80. DOI:10.1186/2051-1426-2-S3-P80
  • Yu Ping, Richard N. Bamford, Thomas A. Waldmann
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    ABSTRACT: Interleukin-15 (IL-15) is an inflammatory cytokine whose role in autoimmune diseases has not been fully elucidated. Th17 cells have been shown to play critical roles in experimental autoimmune encephalomyelitis (EAE) models. In this study, we demonstrate that blockade of IL-15 signaling by TMβ-1 mAb treatment aggravated EAE severity. The key mechanism was not NK-cell depletion but depletion of CD8+CD122+ T cells. Adoptive transfer of exogenous CD8+CD122+ T cells to TMβ-1-treated mice rescued animals from severe disease. Moreover, transfer of pre-activated CD8+CD122+ T cells prevented EAE development and significantly reduced IL-17 secretion. Naïve effector CD4+CD25− T cells cultured with either CD8+CD122+ T cells from wild-type mice or IL-15 transgenic mice displayed lower frequencies of IL-17A production with lower amounts of IL-17 in the supernatants when compared with production by effector CD4+CD25− T cells cultured alone. Addition of a neutralizing antibody to IL-10 led to recovery of IL-17A production in Th17 cultures. Furthermore, co-culture of CD8+CD122+ T cells with effector CD4+ T cells inhibited their proliferation significantly, suggesting a regulatory function for IL-15 dependent CD8+CD122+ T cells. Taken together, these observations suggest that IL-15, acting through CD8+CD122+ T cells, has a negative regulatory role in reducing IL-17 production and Th17-mediated EAE inflammation.This article is protected by copyright. All rights reserved
    European Journal of Immunology 11/2014; 44(11). DOI:10.1002/eji.201444675 · 4.52 Impact Factor
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    ABSTRACT: IL-15 supports improved antitumor immunity. How to best incorporate IL-15 into vaccine formulations for superior cancer immunotherapy remains a challenge. DC-derived IL-15 (DCIL-15) notably has the capacity to activate DC, to substitute for CD4(+) Th and to potentiate vaccine efficacy making IL-15-based therapies attractive treatment options. We observed in transplantable melanoma, glioma and metastatic breast carcinoma models that DCIL-15-based DNA vaccines in which DC specifically express IL-15 and simultaneously produce tumor Aghsp70 were able to mediate potent therapeutic efficacy that required both host Batf3(+) DC and CD8(+) T cells. In an inducible Braf(V600E)/Pten-driven murine melanoma model, DCIL-15 (not rIL-15)-based DNA vaccines elicited durable therapeutic CD8(+) T cell-dependent antitumor immunity. DCIL-15 was found to be superior to rIL-15 in "licensing" both mouse and human DC, and for activating CD8(+) T cells. Such activation occurred even in the presence of Treg, without a need for CD4(+) Th, but was IL-15/IL-15Rα-dependent. A single low-dose of DCIL-15 (not rIL-15)-based DC vaccines induced therapeutic antitumor immunity. CD14(+) DC emigrating from human skin explants genetically-immunized by IL-15 and Aghsp70 were more effective than similar DC emigrating from the explants genetically-immunized by Aghsp70 in the presence of rIL-15 in expressing membrane-bound IL-15/IL-15Rα and activating CD8(+) T cells. These results support future clinical use of DCIL-15 as a therapeutic agent in battling cancer.
    OncoImmunology 11/2014; 3(10):e959321. DOI:10.4161/21624011.2014.959321 · 6.28 Impact Factor
  • Thomas A Waldmann
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    ABSTRACT: IL-15 is a 14–15 kDa member of the four α-helix bundle of cytokines that acts through a heterotrimeric receptor involving IL-2/IL-15R β, γc and the IL-15 specific receptor subunit IL-15R α. IL-15 stimulates the proliferation of T, B and NK cells, and induces stem, central and effector memory CD8 T cells. In rhesus macaques, continuous infusion of recombinant human IL-15 at 20 μg/kg/day was associated with approximately a 10-fold increase in the numbers of circulating NK, γ/δ cells and monocytes, and an 80- to 100-fold increase in the numbers of effector memory CD8 T cells. IL-15 has shown efficacy in murine models of malignancy. Clinical trials involving recombinant human IL-15 given by bolus infusions have been completed and by subcutaneous and continuous intravenous infusions are underway in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL-15 with IL-15R α+/- IgFc.
    Expert Review of Clinical Immunology 10/2014; 10(12). DOI:10.1586/1744666X.2014.973856 · 3.34 Impact Factor
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    ABSTRACT: The interleukin-9 receptor (IL-9R) consists of an α subunit and a γc chain that are shared with other cytokine receptors, including interleukin-2 receptor (IL-2R), an important regulator of T cells. We previously showed that IL-2R is expressed in common clusters with major histocompatibility complex (MHC) glycoproteins in lipid rafts of human T lymphoma cells, which raised the question about what the relationship between clusters of IL-2R/MHC and IL-9R is. Confocal microscopy colocalization and fluorescence resonance energy transfer experiments capable of detecting membrane protein organization at different size scales revealed nonrandom association of IL-9R with IL-2R/MHC clusters at the surface of human T lymphoma cells. Accommodation of IL-9Rα in membrane areas segregated from the IL-2R/MHC domains was also detected. The bipartite nature of IL-9R distribution was mirrored by signal transducer and activator of transcription (STAT) activation results. Our data indicate that co-compartmentalization with MHC glycoproteins is a general property of γc receptors. Distribution of receptor chains between different membrane domains may regulate their function.
    ChemPhysChem 10/2014; DOI:10.1002/cphc.201402501 · 3.36 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2575-2575. DOI:10.1158/1538-7445.AM2014-2575 · 9.28 Impact Factor
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    ABSTRACT: Interleukin-2 receptor α chain (CD25) is overexpressed in human T-cell leukemia virus 1 associated adult T-cell leukemia/lymphoma (ATL). Daclizumab a humanized monoclonal antibody blocks IL-2 binding by recognizing the interleukin-2 receptor α chain (CD25). We conducted a phase I/II trial of daclizumab in 34 patients with ATL. Saturation of surface CD25 on circulating ATL cells was achieved at all doses; however saturation on ATL cells in lymph nodes required 8 mg/kg. Up to 8 mg/kg of daclizumab administered every 3 weeks was well tolerated. No responses were observed in 18 patients with acute or lymphoma ATL; however, 6 partial responses were observed in 16 chronic and smoldering ATL patients. The pharmacokinetics/pharmacodynamics of daclizumab suggest that high-dose daclizumab would be more effective than low-dose daclizumab in treatment of lymphoid malignancies and autoimmune diseases (e.g., multiple sclerosis) since high-dose daclizumab is required to saturate IL-2R alpha in extravascular sites.
    Clinical Immunology 09/2014; DOI:10.1016/j.clim.2014.09.012 · 3.99 Impact Factor
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    ABSTRACT: Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell lymphotropic virus I (HTLV-1). There is no accepted curative therapy for ATL. We have reported that certain ATL patients have increased Notch-1 signaling along with constitutive activation of the NF-κB pathway. Physical and functional interaction between these two pathways provides the rationale to combine the γ-secretase inhibitor Compound E with the proteasome inhibitor Bortezomib. Moreover, Romidepsin, a histone deacetylase inhibitor, has demonstrated major antitumor action in leukemia/ lymphoma. In this study, we investigated the therapeutic efficacy of the single agents and combinations of these agents in a murine model of human ATL, the MT-1 model. Single and double agents inhibited tumor growth as monitored by tumor size (P<0.05), and prolonged survival of leukemia-bearing mice (P<0.05) compared with the control group. The combination of three agents significantly enhanced the antitumor efficacy as assessed by tumor size, tumor markers in the serum (human sIL-2 Rα and β2M), and survival of the MT-1 tumor bearing mice, compared with all other treatment groups (P<0.05). Improved therapeutic efficacy obtained by combining Compound E, Bortezomib and Romidepsin supports a clinical trial of this combination in the treatment of ATL.Leukemia accepted article preview online, 14 August 2014; doi:10.1038/leu.2014.241.
    Leukemia 08/2014; 29(3). DOI:10.1038/leu.2014.241 · 9.38 Impact Factor
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    Jürgen R Müller, Thomas A Waldmann, Sigrid Dubois
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    ABSTRACT: NK cells are able to form a functional memory suggesting that some NK cells are surviving the activation process. We hypothesized that NK cell activation causes the development of a distinct NK cell subset and studied the fate of murine post-activation NK cells. Activation was achieved by in vivo and in vitro exposures to the melanoma tumor cell line B16 that was followed by differentiation in IL-2. When compared with control NK cells, post-activation CD25+ NK cells expressed little granzyme B or perforin and had low lysis activity. Post-activation NK cells expressed CD27, CD90, CD127, and were low for CD11b suggesting that tumor-induced activation is restricted to an early NK cell subset. Activation of NK cells led to decreases of CD16, CD11c and increases of CD62L and the IL-18 receptor. In vivo activated but not control NK cells expressed a variety of cytokines that included IFNγ, TNFα, GM-CSF and IL-10. These data suggest that the exposure of a subset of peripheral NK cells to the B16 tumor environment caused an exhaustion of their cytolytic capacity but also a gain in their ability to produce cytokines.
    PLoS ONE 08/2014; 9(8):e102793. DOI:10.1371/journal.pone.0102793 · 3.53 Impact Factor
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    Leukemia 06/2014; DOI:10.1038/leu.2014.200 · 9.38 Impact Factor
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    ABSTRACT: Background Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of CD4+CD25+ lymphocytes caused by human T-cell lymphotropic virus type 1. While much progress has been made in understanding the mechanisms of cellular dysregulation, the prognosis for aggressive ATL still remains poor. Therefore, new therapeutic approaches need to be developed. Results Previously, we demonstrated that the viral protein Tax inactivates p53 in HTLV-1-infected T-cells. Here we show that 9-aminoacridine (9AA) through p53 reactivation and NF-κB inhibition has selective toxicity for infected leukemic cells independent of their p53 status. We further demonstrate that 9AA activates caspase-3/7 resulting in PARP cleavage. Next we investigated the efficacy of 9AA in the MET-1 ATL model. Alone, 9AA did not cause significant drops in surrogate tumor markers, soluble IL-2Rα or β2-micorglobulin (β2μ) levels with only a slight increase in survival of MET-1-bearing mice. However, in combination with Campath-1H, 9AA treatment resulted in low soluble IL-2Rα and β2μ levels at 2 and 4 weeks. Consistent with reduced tumor cell burden, combination treatment significantly increased survival of MET-1-bearing mice compared to mice treated with either drug alone. Splenic cells isolated from 9AA or combination treated mice showed increased p53 protein levels and transcriptional activity. Consistent with increased tumor suppressor activity, we found increased PARP-1 cleavage in 9AA and combination treated cells. Conclusion Our results indicate that targeting reactivation of p53 and inhibition of NF-κB with acridine-derivatives in combination with other chemotherapeutics could result in increased efficacy and selective killing of tumor cells.
    Retrovirology 06/2014; 11(1):43. DOI:10.1186/1742-4690-11-43 · 4.77 Impact Factor
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    ABSTRACT: Current influenza vaccines are ineffective against novel viruses and the source or the strain of the next outbreak of influenza is unpredictable; therefore, establishing universal immunity by vaccination to limit the impact of influenza remains a high priority. To meet this challenge, a novel vaccine has been developed using the immunogenic live vaccinia virus as a vaccine vector, expressing multiple H5N1 viral proteins (HA, NA, M1, M2, and NP) together with IL-15 as a molecular adjuvant. Previously, this vaccine demonstrated robust sterile cross-clade protection in mice against H5 influenza viruses, and herein its use has been extended to mediate heterosubtypic immunity toward viruses from both group 1 and 2 HA lineages. The vaccine protected mice against lethal challenge by increasing survival and significantly reducing lung viral loads against the most recent human H7N9, seasonal H3N2, pandemic-2009 H1N1, and highly pathogenic H7N7 influenza A viruses. Influenza-specific antibodies elicited by the vaccine failed to neutralize heterologous viruses and were unable to confer protection by passive transfer. Importantly, heterologous influenza-specific CD4(+) and CD8(+) T-cell responses that were elicited by the vaccine were effectively recalled and amplified following viral challenge in the lungs and periphery. Selective depletion of T-cell subsets in the immunized mice revealed an important role for CD4(+) T cells in heterosubtypic protection, despite low sequence conservation among known MHC-II restricted epitopes across different influenza viruses. This study illustrates the potential utility of our multivalent Wyeth/IL-15/5Flu as a universal influenza vaccine with a correlate of protective immunity that is independent of neutralizing antibodies.
    Proceedings of the National Academy of Sciences 03/2014; DOI:10.1073/pnas.1403684111 · 9.81 Impact Factor
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    ABSTRACT: A number of antitumor vaccines have recently shown promise in upregulating immune responses against tumor antigens and improving patient survival. In this study, we examine the effectiveness of vaccination using interleukin (IL)-15-expressing tumor cells and also examine their ability to upregulate immune responses to tumor antigens. We demonstrated that the coexpression of IL-15 with its receptor, IL-15Rα, increased the cell-surface expression and secretion of IL-15. We show that a gene transfer approach using recombinant adenovirus to express IL-15 and IL-15Rα in murine TRAMP-C2 prostate or TS/A breast tumors induced antitumor immune responses. From this, we developed a vaccine platform, consisting of TRAMP-C2 prostate cancer cells or TS/A breast cancer cells coexpressing IL-15 and IL-15Rα that inhibited tumor formation when mice were challenged with tumor. Inhibition of tumor growth led to improved survival when compared with animals receiving cells expressing IL-15 alone or unmodified tumor cells. Animals vaccinated with tumor cells coexpressing IL-15 and IL-15Rα showed greater tumor infiltration with CD8(+) T and natural killer (NK) cells, as well as increased antitumor CD8(+) T-cell responses. Vaccination with IL-15/IL-15Rα-modified TS/A breast cancer cells provided a survival advantage to mice challenged with unrelated murine TUBO breast cancer cells, indicating the potential for allogeneic IL-15/IL-15Rα-expressing vaccines.Gene Therapy advance online publication, 27 February 2014; doi:10.1038/gt.2014.10.
    Gene therapy 02/2014; 21(4). DOI:10.1038/gt.2014.10 · 4.20 Impact Factor

Publication Stats

36k Citations
5,766.29 Total Impact Points


  • 1981–2015
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 1967–2015
    • National Institutes of Health
      • • Center for Cancer Research
      • • Branch of Metabolism
      • • Branch of Radiation Oncology
      • • Laboratory of Molecular Biology
      • • Laboratory of Pathology
      • • Laboratory of Cell Biology
      베서스다, Maryland, United States
  • 1964–2015
    • National Cancer Institute (USA)
      • • Experimental Transplantation and Immunology Branch
      • • Metabolism Branch
      • • Center for Cancer Research
      • • Radiation Oncology Branch
      • • Basic Research Laboratory
      베서스다, Maryland, United States
  • 2013
    • Kansas City VA Medical Center
      Kansas City, Missouri, United States
  • 2012
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2010
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 2008
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
  • 2006
    • University of Kansas
      Lawrence, Kansas, United States
  • 2003–2006
    • The Rockefeller University
      New York, New York, United States
  • 1997–2005
    • Northern Inyo Hospital
      BIH, California, United States
  • 2002
    • Lady Davis Institute for Medical Research
      Montréal, Quebec, Canada
  • 2001
    • University of Debrecen
      • Medical and Health Science Centre
      Debrecen, Hajdu-Bihar, Hungary
  • 1999
    • The EMMES Corporation
      Maryland, United States
  • 1994–1996
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
  • 1976–1993
    • National Heart, Lung, and Blood Institute
      Maryland, United States
    • University of New Mexico
      • Division of Hospital Medicine
      Albuquerque, New Mexico, United States
    • Uganda Cancer Institute
      Kampala, Central Region, Uganda
  • 1986–1989
    • Duke University Medical Center
      • Department of Pediatrics
      Durham, North Carolina, United States
  • 1986–1988
    • Emory University
      • School of Medicine
      Atlanta, GA, United States
  • 1971–1988
    • Johns Hopkins University
      • Department of Biology
      Baltimore, MD, United States
  • 1982
    • Geisel School of Medicine at Dartmouth
      Hanover, New Hampshire, United States
  • 1979
    • University of Vermont
      Burlington, Vermont, United States
    • Keck School of Medicine USC
      Los Ángeles, California, United States
  • 1975
    • The Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States
    • Yale University
      • School of Medicine
      New Haven, Connecticut, United States
  • 1973
    • National Institute of Child Health and Human Development
      Maryland, United States