Thomas J Waldschmidt

University of Iowa, Iowa City, Iowa, United States

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Publications (113)602.54 Total impact

  • No preview · Article · Sep 2015 · Clinical Cancer Research

  • No preview · Conference Paper · Nov 2014
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    ABSTRACT: Loyola University Chicago, Health Sciences Campus in Maywood, Illinois hosted the 18th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting on November 22, 2013. This year’s meeting emphasized alcohol’s effect on inflammatory responses in diverse disease states and injury conditions. The meeting consisted of three plenary sessions demonstrating the adverse effects of alcohol, specifically, liver inflammation, adverse systemic effects, and alcohol’s role in infection and immunology. Researchers also presented insight on modulation of microRNAs and stress proteins following alcohol consumption. Additionally, researchers revealed sex- and concentration-dependent differences in alcohol-mediated pathologies.
    No preview · Article · Nov 2014 · Alcohol
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    ABSTRACT: Neutrophils play an essential role in the innate immune response to infection. Neutrophils migrate from the vasculature into the tissue in response to infection. Recently, a neutrophil cell surface receptor, CD177, was shown to help mediate neutrophil migration across the endothelium through interactions with PECAM1. We examined a publicly available gene array dataset of CD177 expression from human neutrophils following pulmonary endotoxin instillation. Among all 22,214 genes examined, CD177 mRNA was the most upregulated following endotoxin exposure. The high level of CD177 expression is also maintained in airspace neutrophils, suggesting a potential involvement of CD177 in neutrophil infiltration under infectious diseases. To determine the role of CD177 in neutrophils in vivo, we constructed a CD177-genetic knockout mouse model. The mice with homozygous deletion of CD177 have no discernible phenotype and no significant change in immune cells, other than decreased neutrophil counts in peripheral blood. We examined the role of CD177 in neutrophil accumulation using a skin infection model with Staphylococcus aureus. CD177 deletion reduced neutrophil counts in inflammatory skin caused by S. aureus. Mechanistically we found that CD177 deletion in mouse neutrophils has no significant impact in CXCL1/KC- or fMLP-induced migration, but led to significant cell death. Herein we established a novel genetic mouse model to study the role of CD177 and found that CD177 plays an important role in neutrophils. Electronic supplementary material The online version of this article (doi:10.1007/s13238-014-0109-1) contains supplementary material, which is available to authorized users.
    No preview · Article · Oct 2014 · Protein & Cell
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    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    No preview · Article · Sep 2014 · Leukemia
  • Alexander W Boyden · Allison M Frickman · Kevin L Legge · Thomas J Waldschmidt
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    ABSTRACT: Influenza A virus (IAV) infection represents a significant global public health burden in addition to its potential as a pandemic killer. Accordingly, the immune response within the respiratory tract and associated lymphoid tissues has been a focus of study for decades. Murine model systems have led to a relatively clear understanding that while innate and T-cell responses are essential for clearance of an initial infection, high affinity neutralizing antibodies (Abs) generated by long-lived Ab forming cells and memory B cells are critical for protection from reinfection and are the goal of classic vaccination strategies. Indeed, the local and systemic IAV-specific Ab response after primary pulmonary infection has been well studied in mice. However, the highly organized microenvironments responsible for producing long-lived, high affinity responses, namely germinal center (GC) reactions, have been less well studied. Recently, work from our laboratory and others has provided new insights into the induction and character of IAV-specific GC responses in the secondary lymphoid organs and the lung. Of interest, these studies have demonstrated IAV reactive GCs to persist for extended periods in both draining lymph nodes and lung tissue. Herein, the primary adaptive response to IAV is reviewed with an emphasis on GC B-cell responses. In addition, data are shown demonstrating the persistence of GCs in the respiratory tract after IAV infection, and key factors that drive their maintenance.
    No preview · Article · May 2014 · Immunologic Research
  • Corey P Parlet · Thomas J Waldschmidt · Annette J Schlueter
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    ABSTRACT: Chronic alcoholism is associated with increased incidence and severity of cutaneous infection. Skin-resident T cells orchestrate numerous immunological functions that are critically involved in both tissue homeostasis and cutaneous immunity. The impact of chronic ethanol (EtOH) exposure on skin T cells has not previously been examined; given their important role in maintaining the immune barrier function of the skin further study is warranted. Mice were administered EtOH in the drinking water for 12 to 16 weeks. Flow cytometry was used to evaluate impact of EtOH feeding on skin T cell numbers, rates of proliferation, and apoptosis as well as activation marker expression and cytokine production after ex vivo stimulation. Chronic EtOH feeding caused a baseline reduction in dendritic epidermal T cell (DETC) numbers that corresponded with reduced expression of the activation marker JAML following phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. Chronic EtOH feeding did not alter total numbers of dermal T cells, but specific subset loss was observed in Foxp3(+) regulatory T cells (Tregs) as well as CD3hi, Vγ3(+) and CD3int, Vγ3(-) dermal γδ T cells. EtOH-induced dysfunction in the latter population, which represents prototypical interleukin-17 (IL-17)-producing dermal γδT17s, was made evident by diminished IL-17 production following anti-CD3 stimulation. Additionally, the capacity of lymph node γδ T cells to produce IL-17 following anti-CD3 and PMA/ionomycin stimulation was impaired by chronic EtOH feeding. Chronic EtOH feeding induced defects in both numbers and function of multiple skin T cell subsets. The decreased density and poor responsiveness of DETCs and γδT17 cells in particular would be expected to compromise immune effector mechanisms necessary to maintain a protective barrier and restrict pathogen invasion. These findings demonstrate the sensitivity of skin T cells to EtOH and provide new mechanisms to help explain the propensity of alcoholics to suffer skin infection.
    No preview · Article · Feb 2014 · Alcoholism Clinical and Experimental Research
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    ABSTRACT: Gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of B cell lymphomas. These viruses are thought to co-opt the process of B cell differentiation to latently infect a fraction of circulating memory B cells, resulting in the establishment of a stable latency setpoint. However, little is known about how this infected memory B cell compartment is maintained throughout the life of the host. We have previously demonstrated that immature and transitional B cells are long-term latency reservoirs for murine gammaherpesvirus 68 (MHV68), suggesting that infection of developing B cells contributes to the maintenance of lifelong latency. During hematopoiesis, immature and transitional B cells are subject to B cell receptor (BCR)-mediated negative selection, which results in the clonal deletion of autoreactive B cells. Interestingly, numerous gammaherpesviruses encode homologs of the anti-apoptotic protein Bcl-2, suggesting that virus inhibition of apoptosis could subvert clonal deletion. To test this, we quantified latency establishment in mice inoculated with MHV68 vBcl-2 mutants. vBcl-2 mutant viruses displayed a marked decrease in the frequency of immature and transitional B cells harboring viral genome, but this attenuation could be rescued by increased host Bcl-2 expression. Conversely, vBcl-2 mutant virus latency in early B cells and mature B cells, which are not targets of negative selection, was remarkably similar to wild-type virus. Finally, in vivo depletion of developing B cells during chronic infection resulted in decreased mature B cell latency, demonstrating a key role for developing B cells in the maintenance of lifelong latency. Collectively, these findings support a model in which gammaherpesvirus latency in circulating mature B cells is sustained in part through the recurrent infection and vBcl-2-mediated survival of developing B cells.
    Full-text · Article · Feb 2014 · PLoS Pathogens
  • Kevin L. Legge · Thomas J. Waldschmidt
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    ABSTRACT: It is well established that alcoholics have an increased incidence of respiratory diseases. Further, chronic alcoholism predisposes for more severe disease following respiratory infections. While many studies have detailed the increase in disease severity during respiratory infections in alcoholics, much less is understood about the underlying mechanisms through which chronic alcohol consumption mediates this increase in disease severity or how alcohol alters pulmonary adaptive immune responses. It is well accepted that chronic alcohol ingestion is immunosuppressive and exerts inhibitory effects on adaptive immunity. However, these studies have largely focused on examining the immunosuppression of cell-mediated immunity in the spleen, skin, and liver. Importantly, for many pathogens the type of immune response generated in the respiratory and intestinal mucosa is distinct from that generated following intravenous, intraperitoneal, or subcutaneous exposures. Therefore, the type and extent of lesions that exist in the respiratory adaptive immune system of alcoholics and the consequences of these lesions, particularly during infections, remain in question. This chapter highlights and discusses the field’s current knowledge on chronic alcohol-induced lesions within the pulmonary dendritic cell and T cell compartments and the relationship of these lesions to increased respiratory disease.
    No preview · Chapter · Jan 2014
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    ABSTRACT: (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMyc(ΔEμ) gene insertion and the widely expressed H2-L(d)-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage- and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma.
    Full-text · Article · Nov 2013 · Blood Cancer Journal
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    ABSTRACT: Infection caused by Human Immunodeficiency Virus (HIV) is one of the greatest challenges for researchers around the world. Since its outbreak in 1981, more than 25 million people have died of Acquired Immunodeficiency Deficiency Syndrome (AIDS). An ideal strategy to stop the spread of the virus is to develop a prophylactic or therapeutic intervention against HIV-1that can be easily administered and distributed and elicits a robust and balanced immune response in order to avoid the infection of the host. Due to the high mutation rate of the virus and multiple mechanisms used to evade the immune response, HIV remains a daunting challenge. A current focus in vaccine development is the design of novel adjuvant formulations and delivery systems that can elicit strong and balanced immune responses towards a variety of pathogens. Active targeting of these adjuvants can help in the design of efficacious vaccines since the use of subunit proteins as antigens requires developing delivery platforms that will provide the appropriate environment to preserve the structure of these novel antigens, and at the same time, offers the prospect of enhancing the typically modest ability of these immunogens to elicit specific immune responses. Our work is focused on the gp41-54Q-GHC immunogen, which is based on the membrane proximal external region of an HIV-1 glycoprotein (gp41) that elicits broadly neutralizing antibodies for epitopes conserved in different virus isolates. The main goal of this study is to design a biodegradable nanoparticle-based delivery platform for gp41-54Q-GHC that stimulates a robust immune response. In particular, polyanhydride nanoparticles exhibit desirable characteristics as adjuvants and delivery vehicles, including immune modulation, activation of antigen presenting cells, induction of high titer and highly avid antibodies, sustained antigen release, and stabilization of protein antigens. In this work, polyanhydride copolymers based on 1,6-bis(p-carboxyphenoxy) hexane (CPH) and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) and CPH were synthesized via melt polycondensation. CPTEG:CPH nanoparticles encapsulating gp41-54Q-GHC protein were fabricated using an anti-solvent nanoencapsulation method. Surface functionalization of the antigen-loaded nanoparticles was carried out using an amine-carboxylic acid coupling reaction. Di-mannose (i.e. alpha-D-mannopyranosyl-(1,2)-D-mannopyranoside) and glycolic acid (linker) modified nanoparticles were characterized using zeta potential measurements and a phenol-sulfuric acid assay. Subcutaneous administration of these particles using footpad injections in BALB/c mice was performed. Germinal center formation and isotype switching analysis were analyzed following injection of these particles. These studies lay the groundwork for using the targeted nanovaccine platform as a dual adjuvant/delivery system for gp41-54Q-GHC in future studies.
    No preview · Conference Paper · Nov 2013
  • E.A. Hemann · J.L. McGill · T.J. Waldschmidt · K.L. Legge

    No preview · Article · Nov 2013 · Alcohol
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    Alexander W Boyden · Kevin L Legge · Thomas J Waldschmidt
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    ABSTRACT: Protection from influenza A virus (IAV) challenge requires switched, high affinity Abs derived from long-lived memory B cells and plasma cells. These B cell subsets are generated in germinal centers (GCs), hallmark structures of T helper cell-driven B cell immunity. A full understanding of the GC reaction after respiratory IAV infection is lacking, as is the characterization of T follicular helper (T(FH)) cells that support GCs. Here, GC B cell and T(FH) cell responses were studied in mice following pulmonary challenge with IAV. Marked GC reactions were induced in draining lymph nodes (dLNs), lung, spleen and nasal-associated lymphoid tissue (NALT), although the magnitude and kinetics of the response was site-specific. Examination of switching within GCs demonstrated IgG2(+) cells to compose the largest fraction in dLNs, lung and spleen. IgA(+) GC B cells were infrequent in these sites, but composed a significant subset of the switched GC population in NALT. Further experiments demonstrated splenectomized mice to withstand a lethal recall challenge, suggesting the spleen to be unnecessary for long-term protection in spite of strong GC responses in this organ. Final studies showed that T(FH) cell numbers were highest in dLNs and spleen, and peaked in all sites prior to the height of the GC reaction. T(FH) cells purified from dLNs generated IL-21 and IFNγ upon activation, although CD4(+)CXCR5(-) T effector cells produced higher levels of all cytokines. Collectively, these findings reveal respiratory IAV infection to induce strong T helper cell-driven B cell responses in various organs, with each site displaying unique attributes.
    Preview · Article · Jul 2012 · PLoS ONE
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    ABSTRACT: On November 18, 2011, the 16th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at Loyola University Medical Center in Maywood, Illinois. The focus of this year's meeting was alcohol's effect on epigenetic changes and possible outcomes induced by these changes. Two sessions, which consisted of talks from invited speakers as well as presentations of selected abstracts, were held in addition to a poster session. Participants presented information on alcohol-induced alterations in histone modifications and gene expression along with immunologic responses to alcohol. Speakers shared new research specifically on histone deacetylase enzyme expression and modifications due to alcohol and the downstream effect of these modifications may have on gene expression and tissue damage. Additional studies suggested that alcohol exacerbates inflammation when combined with other insults such as infection, trauma, inhalation injury, and disease.
    No preview · Article · Jun 2012 · Alcohol (Fayetteville, N.Y.)
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    ABSTRACT: Co-infection of C3HeB/FeJ (C3H) mice with both Leishmania major and Leishmania amazonensis leads to a healed footpad lesion, whereas co-infection of C57BL/6 (B6) mice leads to non-healing lesions. This inability to heal corresponds to a deficiency in B cell stimulation of the macrophage-mediated killing of L. amazonensis in vitro and a less robust antibody response. The mechanism that leads to healing of these lesions is not completely known, although our studies implicate the B cell response as having an important effector function in killing L. amazonensis. To understand more completely this disparate clinical outcome to the same infection, we analyzed the draining lymph node germinal center B cell response between co-infected C3H and B6 mice. There were more germinal center B cells, more antibody isotype-switched germinal center B cells, more memory B cells, and more antigen-specific antibody-producing cells in co-infected C3H mice compared to B6 mice as early as 2 weeks postinfection. Interleukin (IL)-21 production and IL-21 receptor expression in both mouse strains, however, were similar at 2 weeks, suggesting that the difference in the anti-Leishmania response in these mouse strains may be due to differences in T follicular cell commitment or intrinsic B cell differences. These data support the idea that functional B cells are important for healing L. amazonensis in this infectious disease model.
    Full-text · Article · Mar 2012 · American Journal Of Pathology

  • No preview · Article · Mar 2012 · Alcohol (Fayetteville, N.Y.)
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    ABSTRACT: Infection of erythrocytes with Plasmodium species induces clinical malaria. Parasite-specific CD4(+) T cells correlate with lower parasite burdens and severity of human malaria and are needed to control blood-stage infection in mice. However, the characteristics of CD4(+) T cells that determine protection or parasite persistence remain unknown. Here we show that infection of humans with Plasmodium falciparum resulted in higher expression of the inhibitory receptor PD-1 associated with T cell dysfunction. In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.
    Full-text · Article · Dec 2011 · Nature Immunology
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    ABSTRACT: Germinal centre (GC) reactions are central features of T-cell-driven B-cell responses, and the site where antibody-producing cells and memory B cells are generated. Within GCs, a range of complex cellular and molecular events occur which are critical for the generation of high affinity antibodies. These processes require exquisite regulation not only to ensure the production of desired antibodies, but to minimize unwanted autoreactive or low affinity antibodies. To assess whether T regulatory (Treg) cells participate in the control of GC responses, immunized mice were treated with an anti-glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) monoclonal antibody (mAb) to disrupt Treg-cell activity. In anti-GITR-treated mice, the GC B-cell pool was significantly larger compared with control-treated animals, with switched GC B cells composing an abnormally high proportion of the response. Dysregulated GCs were also observed regardless of strain, T helper type 1 or 2 polarizing antigens, and were also seen after anti-CD25 mAb treatment. Within the spleens of immunized mice, CXCR5(+) and CCR7(-) Treg cells were documented by flow cytometry and Foxp3(+) cells were found within GCs using immunohistology. Final studies demonstrated administration of either anti-transforming growth factor-β or anti-interleukin-10 receptor blocking mAb to likewise result in dysregulated GCs, suggesting that generation of inducible Treg cells is important in controlling the GC response. Taken together, these findings indicate that Treg cells contribute to the overall size and quality of the humoral response by controlling homeostasis within GCs.
    Full-text · Article · Jun 2011 · Immunology
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    ABSTRACT: Reactive oxygen species (ROS) are critical in a broad spectrum of cellular processes including signaling, tumor progression, and innate immunity. The essential nature of ROS signaling in the immune systems of Drosophila and zebrafish has been demonstrated; however, the role of ROS, if any, in mammalian adaptive immune system development and function remains unknown. This work provides the first clear demonstration that thymus-specific elevation of mitochondrial superoxide (O(2)(•-)) disrupts normal T cell development and impairs the function of the mammalian adaptive immune system. To assess the effect of elevated mitochondrial superoxide in the developing thymus, we used a T-cell-specific knockout of manganese superoxide dismutase (i.e., SOD2) and have thus established a murine model to examine the role of mitochondrial superoxide in T cell development. Conditional loss of SOD2 led to increased superoxide, apoptosis, and developmental defects in the T cell population, resulting in immunodeficiency and susceptibility to the influenza A virus H1N1. This phenotype was rescued with mitochondrially targeted superoxide-scavenging drugs. These findings demonstrate that loss of regulated levels of mitochondrial superoxide lead to aberrant T cell development and function, and further suggest that manipulations of mitochondrial superoxide levels may significantly alter clinical outcomes resulting from viral infection.
    Full-text · Article · Feb 2011 · Free Radical Biology and Medicine
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    ABSTRACT: As initiators of immune responses, dendritic cells (DCs) are required for antigen (Ag)-specific activation of naïve T cells in the defense against infectious agents. The increased susceptibility to and severity of infection seen in chronic alcoholics could be because of impaired DCs initiation of naïve T-cell responses. Specifically, these DCs may not provide adequate Signals 1 (Ag presentation), 2 (costimulation), or 3 (cytokine production) to these T cells. Using the Meadows-Cook murine model of chronic alcohol abuse, the ability of ethanol (EtOH)-exposed DCs to stimulate T-cell proliferation, acquire and process Ag, express costimulatory molecules, and produce inflammatory cytokines was assessed. Normal naïve T cells primed by EtOH-exposed DCs showed decreased proliferation in vitro and in vivo, compared to water-fed control mice. These EtOH-exposed DCs, after activation by CpG or tumor necrosis factor alpha (TNFα), were less able to upregulate costimulatory molecules CD40, CD80, or CD86, and produced less IL-12 p40, TNFα, and IFNα than DCs from water-fed mice. TLR9 and TNF receptor expression were also reduced in/on EtOH-exposed DCs. No evidence of defective Ag acquisition or processing as a result of EtOH feeding was identified. Inadequate proliferation of normal T cells following stimulation by EtOH-exposed DCs is likely a result of diminished Signal 2 and Signal 3. Lack of adequate inflammatory stimulation of EtOH-exposed DCs because of diminished receptors for inflammatory mediators appears to be at least partially responsible for their dysfunction. These findings provide a mechanism to explain increased morbidity and mortality from infectious diseases in alcoholics and suggest targets for therapeutic intervention.
    Full-text · Article · Oct 2010 · Alcoholism Clinical and Experimental Research

Publication Stats

9k Citations
602.54 Total Impact Points


  • 1990-2014
    • University of Iowa
      • • Department of Pathology
      • • Department of Internal Medicine
      • • Department of Microbiology
      Iowa City, Iowa, United States
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States
  • 2007
    • University of Nebraska Medical Center
      • Department of Pathology and Microbiology
      Omaha, Nebraska, United States
  • 1995
    • Geisel School of Medicine at Dartmouth
      Hanover, New Hampshire, United States
  • 1987
    • Johns Hopkins University
      Baltimore, Maryland, United States