T A Waldmann

National Institutes of Health, Maryland, United States

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Publications (541)5203.92 Total impact

  • [Show abstract] [Hide abstract]
    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;
  • Yu Ping, Richard 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 08/2014; · 4.97 Impact Factor
  • Leukemia. 06/2014;
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    ABSTRACT: 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.
    Retrovirology. 06/2014; 11(1):43.
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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; · 9.81 Impact Factor
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    ABSTRACT: Toll/IL-1R domain-containing adaptor inducing interferon-β (IFN-β) factor (TRIF) is a key adaptor for Toll-like receptor (TLR) 3 and TLR4 signaling. Using a novel cDNA isolate encoding a TRIF protein with a 21-residue deletion (Δ160-181) from its amino-terminal half, we investigated the impact of this deletion on TRIF functions. Transfection studies consistently showed higher expression levels of the (Δ160-181) TRIF compared to wild-type (wt) TRIF, an effect unrelated to apoptosis, cell lines or plasmid amplification. Colocalization of wt and (Δ160-181) TRIF proteins led to a dramatic reduction of their respective expressions, suggesting that wt/(Δ160-181) TRIF heterocomplexes are targeted for degradation. We demonstrated that wt TRIF associates with tumor necrosis factor-α receptor-associated factor 3 (TRAF3) better than (Δ160-181) TRIF, culminating in its greater ubiquitination and proteolysis. This explains, in part, the differential expression levels of the two TRIF proteins. Despite higher expression levels in transfected cells, (Δ160-181) TRIF inefficiently transactivated the IFN pathway, whereas the nuclear factor-κB (NF-κB) pathway activation remained similar to that by wt TRIF. In coexpression studies, (Δ160-181) TRIF marginally contributed to the IFN pathway activation, but still enhanced NF-κB signaling with wt TRIF. Therefore, this 21 amino acid sequence is crucial for TRAF3 association, modulation of TRIF stability and activation of the IFN pathway. © 2014 S. Karger AG, Basel.
    Journal of Innate Immunity 02/2014; · 4.46 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 01/2014; 9(8):e102793. · 3.73 Impact Factor
  • Thomas A Waldmann
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    ABSTRACT: IL-15 has a pivotal role in life and death of natural killer (NK) and CD8 memory T cells. IL-15 signals through a heterotrimeric receptor involving the common gamma chain (γc) shared with IL-2, IL-4, IL-7, IL-9, and IL-21, IL-2/IL-15 receptor β (IL-15Rβ) shared with IL-2 and a private IL-15Rα subunit. IFN- or CD40 ligand-stimulated dendritic cells coordinately express IL-15 and IL-15Rα. Cell surface IL-15Rα presents IL-15 in trans to cells that express IL-2/IL-15Rβ and γc. IL-15 is being used to treat patients with metastatic malignancy. However, IL-15 is an inflammatory cytokine involved in immunological memory including that to self, thereby playing a role in autoimmune diseases. These insights provide the scientific basis for clinical strategies directed toward diminishing IL-15 action. Dysregulated IL-15 expression was demonstrated in patients with rheumatoid arthritis, inflammatory bowel disease, psoriasis, celiac disease, and alopecia areata. The monoclonal antibody Hu-Mik-β-1 targets the cytokine receptor subunit IL-2/IL-15Rβ (CD122), blocks IL-15 transpresentation, and is being used in clinical trials in patients with autoimmune diseases. In parallel, clinical trials have been initiated involving the Jak2/3 (Janus kinase-2/3) inhibitor tofacitinib and Jak1/2 inhibitor ruxolitinib to block IL-15 signaling.
    Journal of Investigative Dermatology Symposium Proceedings 12/2013; 16(1):S28-30. · 3.73 Impact Factor
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    ABSTRACT: Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15Rα levels in human T1D. To investigate the role of IL-15/IL-15Rα in the pathogenesis of T1D, we generated double transgenic mice with pancreatic β-cell expression of IL-15 and IL-15Rα. The mice developed hyperglycemia, marked mononuclear cell infiltration, β-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibiting IL-15 signaling with anti-IL2/IL15Rβ (anti-CD122), which blocks IL-15 transpresentation. Furthermore, the diabetes could be reversed by administration of the Janus kinase 2/3 inhibitor tofacitinib, which blocks IL-15 signaling. In an alternative diabetes model, nonobese diabetic mice, IL15/IL-15Rα expression was increased in islet cells in the prediabetic stage, and inhibition of IL-15 signaling with anti-CD122 at the prediabetic stage delayed diabetes development. In support of the view that these observations reflect the conditions in humans, we demonstrated pancreatic islet expression of both IL-15 and IL-15Rα in human T1D. Taken together our data suggest that disordered IL-15 and IL-15Rα may be involved in T1D pathogenesis and the IL-15/IL15Rα system and its signaling pathway may be rational therapeutic targets for early T1D.
    Proceedings of the National Academy of Sciences 07/2013; · 9.81 Impact Factor
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    ABSTRACT: An intense effort has been launched to develop a more optimal anthrax vaccine that can be rapidly deployed because of the inadequacies associated with the currently licensed vaccine. Protective antigen (PA)-based vaccines are most favored as immune responses directed against PA are singularly protective, although the actual protective mechanism remains to be unraveled. Herein we show that contrary to the prevailing view, an efficacious PA-based vaccine confers protection against inhalation anthrax by preventing the establishment of a toxin-releasing systemic infection. Equally importantly, antibodies measured by the in vitro lethal toxin neutralization activity assay (TNA) that is considered as a reliable correlate of protection, especially for PA protein-based vaccines adjuvanted with aluminum salts appear to be not absolutely essential for this protective immune response.
    Human vaccines & immunotherapeutics. 06/2013; 9(9).
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    ABSTRACT: Adult T-cell leukemia/lymphoma (ATLL) is etiologically linked to infection with the human T-cell leukemia/lymphoma virus type 1 (HTLV-I). ATLL is classified into four distinct clinical diseases: acute, lymphoma, chronic and smoldering. Acute ATL is the most aggressive form, representing 60% of cases and has a 4 year survival of less than 5%. A frequent complication and cause of death in acute ATL patients is the presence of lytic bone lesions and hypercalcemia. We analyzed the Wnt/β-catenin pathway due to its common role in cancer and bone remodeling. Our study demonstrated that ATL cells do not express high levels of β-catenin, but displayed high levels of LEF-1/TCF genes along with elevated levels of β-catenin (LEF-1/TCF-target genes) responsive genes. By profiling Wnt gene expression we discovered that ATL patient leukemia cells shifted expression towards the non-canonical Wnt pathway. Interestingly, ATL cells over-expressed the osteolytic-associated genes, Wnt5a, PTHLH and RANKL. We further show that Wnt5a secreted by ATL cells favors osteoclast differentiation and expression of RANK. Our results suggest that Wnt5a is a major contributing factor to the increase in osteolytic bone lesions and hypercalcemia found in ATL patients. Anti-Wnt5a therapy may prevent or reduce osteolytic lesions found in ATL patients and improve therapy outcome.
    Blood 05/2013; · 9.78 Impact Factor
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    ABSTRACT: Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus I (HTLV-1). Currently, there is no accepted curative therapy for ATL. In gene expression profiling the anti-apoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). YM155, a selective small-molecule survivin suppressant, is currently in phase 2 trials in solid tumors and B-cell malignancies. In this study, we investigated the anti-tumor activity of YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P<0.001) and prolonged the survival of tumor-bearing mice (P<0.0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive anti-tumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared to monotherapy with either YM155 (P<0.001) or alemtuzumab (P<0.05). More significantly, all mice that received the combination therapy survived and were tumor-free more than 6 months after treatment. Our data supports a clinical trial of the combination of YM155 with alemtuzumab in patients with ATL. Clinicaltrials.gov NCT00061048.
    Blood 01/2013; · 9.78 Impact Factor
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  • Nirali N Shah, Thomas A Waldmann
    Blood 01/2013; 121(1):6-7. · 9.78 Impact Factor
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    ABSTRACT: Long-lived memory T cells are able to persist in the host in the absence of antigen; however, the mechanism by which they are maintained is not well understood. Recently, a subset of human T cells, stem cell memory T cells (TSCM cells), was shown to be self-renewing and multipotent, thereby providing a potential reservoir for T cell memory throughout life. However, their in vivo dynamics and homeostasis still remain to be defined due to the lack of suitable animal models. We identified T cells with a TSCM phenotype and stem cell-like properties in nonhuman primates. These cells were the least-differentiated memory subset, were functionally distinct from conventional memory cells, and served as precursors of central memory. Antigen-specific TSCM cells preferentially localized to LNs and were virtually absent from mucosal surfaces. They were generated in the acute phase of viral infection, preferentially survived in comparison with all other memory cells following elimination of antigen, and stably persisted for the long term. Thus, one mechanism for maintenance of long-term T cell memory derives from the unique homeostatic properties of TSCM cells. Vaccination strategies designed to elicit durable cellular immunity should target the generation of TSCM cells.
    The Journal of clinical investigation 01/2013; · 15.39 Impact Factor
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    ABSTRACT: Celiac disease (CD) is an immune-mediated, inflammatory disorder of the small intestines with a defined genetic etiological component associated with the expression of HLA-DQ2 and/or HLA-DQ8 haplotypes. The dietary consumption of gluten-rich cereals triggers a gluten-specific immune response in genetically susceptible individuals leading to a spectrum of clinical manifestations ranging from an inapparent subclinical disease, to overt enteropathy that can in some individuals progress to enteropathy-associated T cell lymphoma (EATL). The tissue-destructive pathologic process of CD is driven by activated NK-like intraepithelial CD8(+) lymphocytes and the proinflammatory cytokine IL-15 has emerged to be pivotal in orchestrating this perpetual tissue destruction and inflammation. Moreover, transgenic mice that over-express human IL-15 from an enterocyte-specific promoter (T3(b)-hIL-15 Tg) recapitulate many of the disease-defining T and B cell-mediated pathologic features of CD, further supporting the evolving consensus that IL-15 represents a valuable target in devising therapeutic interventions against the form of the disease that is especially refractory to gluten-free diet. In the present study, we evaluated the potential efficacy of tofacitinib, a pan-JAK inhibitor that abrogates IL-15 signaling, as a therapeutic modality against CD using T3(b)-hIL-15 Tg mice. We demonstrate that tofacitinib therapy leads to a lasting reversal of pathologic manifestations in the treated mice, thereby highlighting the potential value of tofacitininb as a therapeutic modality against refractory CD for which no effective therapy exists currently. Additionally, the visceral adiposity observed in the tofacitinib-treated mice underscores the importance of continued evaluation of the drug's impact on the lipid metabolism.
    Journal of Clinical Immunology 12/2012; · 3.38 Impact Factor
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    ABSTRACT: Hu-Mikβ1, a humanized monoclonal antibody directed at the shared IL-2/IL-15Rβ subunit (CD122) was evaluated in patients with T-cell large granular lymphocytic leukemia (T-LGL). Hu-Mikβ1 blocked transpresentation of interleukin-15 (IL-15) to T-cells expressing IL-2/IL-15R beta and the common gamma chain (CD132), but did not block IL-15 action in cells that expressed the heterotrimeric IL-15 receptor in cis. There was no significant toxicity associated with Hu-Mikβ1 administration in patients with T-cell LGL, but no major clinical responses were observed. One patient who had previously received murine Mikβ1 developed a measurable antibody response to the infused antibody. Nevertheless the safety profile of this first in-human study of the humanized monoclonal antibody to IL-2/IL-15Rβ (CD122) supports its evaluation in disorders such as refractory celiac disease where IL-15 and its receptor have been proposed to play a critical role in the pathogenesis and maintenance of disease activity. The protocol is in clinical trial registry CT.gov with NCI number NCT 00076180.
    Blood 12/2012; · 9.78 Impact Factor
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    ABSTRACT: Species-specific differences of post-translational modifications suggested the existence of human IL-15Rα isoforms. We identified eight new isoforms that are predicted to modify the intracellular C-termini of IL-15Rα, and another N-terminal exon ″Ex2A″ that was consistently present in all but one of the C-terminal isoforms. Ex2A encodes a 49-amino acid domain that allowed the transfer of IL-15/IL-15Rα complex to the cell surface but prevented its cleavage from cell membranes and its secretion thus facilitating the transpresentation of IL-15 as part of the immunological synapse. The Ex2A domain also affected the O-glycosylation of IL-15Rα that explained the species-specific differences. The Ex2A domain appeared to be removed from major IL-15Rα species during protein maturation, but both Ex2A and IL-15Rα appeared on the surface of monocytic cells upon activation. The membrane-associated form of the only C-terminal isoform that lacked Ex2A (IC3) was retained inside the cell, but soluble IL-15/IL-15Rα complexes were readily released from cells that expressed IL-15/IL-15Rα-IC3 thus limiting this IL-15/IL-15Rα isoform to act as a secreted molecule. These data suggest that splice versions of IL-15Rα determine the range of IL-15 activities.
    Journal of Biological Chemistry 10/2012; · 4.65 Impact Factor

Publication Stats

26k Citations
5,203.92 Total Impact Points

Institutions

  • 1967–2014
    • National Institutes of Health
      • • Branch of Metabolism
      • • Branch of Radiation Oncology
      • • Laboratory of Molecular Biology
      • • Molecular Targets Laboratory
      • • Laboratory of Cell Biology
      Maryland, United States
  • 1964–2014
    • National Cancer Institute (USA)
      • • Center for Cancer Research
      • • Metabolism Branch
      • • Radiation Oncology Branch
      • • Laboratory of Molecular Biology
      Maryland, United States
  • 2013
    • Kansas City VA Medical Center
      Kansas City, Missouri, United States
  • 2006–2013
    • NCI-Frederick
      Maryland, United States
  • 1990–2013
    • U.S. Food and Drug Administration
      • Center for Biologics Evaluation and Research
      Washington, Washington, D.C., United States
  • 2012
    • University of Cincinnati
      • Division of Hematology Oncology
      Cincinnati, OH, United States
  • 2009–2012
    • Tokyo Metropolitan Institute of Medical Science
      Edo, Tōkyō, Japan
    • Lands Department of The Government of the Hong Kong Special Administrative Region
      Hong Kong, Hong Kong
  • 2009–2011
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 2010
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 2006–2010
    • University of Kansas
      • • Department of Pathology
      • • Department of Microbiology, Molecular Genetics and Immunology
      Kansas City, KS, United States
  • 1986–2010
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 2005–2009
    • Hospital of the University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, PA, United States
  • 2007
    • National Eye Institute
      Maryland, United States
  • 1998–2006
    • Beth Israel Deaconess Medical Center
      • Division of Hematology/Oncology
      Boston, MA, United States
  • 1987–2005
    • University of Debrecen
      • • Department of Biophysics and Cell Biology
      • • Medical and Health Science Centre
      Debrecen, Hajdu-Bihar, Hungary
  • 2004
    • Tufts Medical Center
      Boston, Massachusetts, United States
    • Hungarian Academy of Sciences
      • Solar Physics Research Group
      Budapest, Budapest fovaros, Hungary
  • 2002
    • Oak Ridge National Laboratory
      • Life Sciences Division
      Oak Ridge, Florida, United States
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
  • 2001
    • The University of the West Indies at Mona
      • Department of Pathology
      Kingston, Kingston, Jamaica
  • 2000
    • Miyazaki Prefectural Wood Utilization Research Center
      Миядзаки, Miyazaki, Japan
  • 1999
    • The EMMES Corporation
      Maryland, United States
  • 1986–1996
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1994
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
  • 1976–1993
    • National Heart, Lung, and Blood Institute
      Maryland, United States
    • Uganda Cancer Institute
      Kampala, Central Region, Uganda
  • 1989
    • Emory University
      • Department of Pathology and Laboratory Medicine
      Atlanta, GA, United States
  • 1988
    • Johns Hopkins University
      • Department of Biology
      Baltimore, MD, United States
  • 1970
    • Baylor College of Medicine
      Houston, Texas, United States