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Dive into the research topics where Mark A. Wallet is active.

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Featured researches published by Mark A. Wallet.


Oral Diseases | 2012

Triclosan alters antimicrobial and inflammatory responses of epithelial cells

Mark A. Wallet; Nadia Calderon; Tess R. Alonso; Christina S. Choe; Dana L. Catalfamo; Charles Lalane; Kathleen G. Neiva; Foti Panagakos; Shannon M. Wallet

UNLABELLEDnPeriodontal diseases are a class of pathologies wherein oral microbes induce harmful immune responses in a susceptible host. Therefore, an agent that can both reduce microbial burden and lessen pathogenesis of localized inflammation would have beneficial effects in periodontal disease; 2,4,4-trichloro-2-hydroxydiphenyl-ether [triclosan] is currently used in oral care products owing to broad spectrum antimicrobial and anti-inflammatory properties.nnnOBJECTIVEnTo determine effects of triclosan on the response of oral epithelial cells to stimulation with the inflammatory microbial product lipopolysaccharide (LPS), a ligand for toll-like receptor 4 [TLR4].nnnMATERIALS/METHODSnPrimary human oral epithelial cells were stimulated with LPS in the presence and/or absence of triclosan after which expression of pro-inflammatory cytokines, β-defensins, micro-RNAs [miRNAs], or TLR-signaling pathway proteins were evaluated.nnnRESULTSnHere, we demonstrate that triclosan is a potent inhibitor of oral epithelial cell LPS-induced pro-inflammatory responses by inducing miRNA regulation of the TLR-signaling pathway. Triclosan was not a pan-suppresser of oral epithelial cell responses as β-defensin 2 [βD2] and βD3 were upregulated by triclosan following LPS-stimulation.nnnCONCLUSIONSnThese data demonstrate both a novel antimicrobial mechanism by which triclosan improves plaque control and an additional anti-inflammatory property, which could have beneficial effects in periodontal disease resolution.


AIDS | 2010

Microbial translocation induces persistent macrophage activation unrelated to HIV-1 levels or T cell activation following therapy

Mark A. Wallet; Carina A. Rodriguez; Li Yin; Sara Saporta; Sasawan Chinratanapisit; Wei Hou; John W. Sleasman; Maureen M. Goodenow

Objective:HIV-1 replication and microbial translocation occur concomitant with systemic immune activation. This study delineates mechanisms of immune activation and CD4 T-cell decline in pediatric HIV-1 infection. Design:Cross-sectional and longitudinal cellular and soluble plasma markers for inflammation were evaluated in 14 healthy and 33 perinatally HIV-1-infected pediatric study volunteers prior to and over 96 weeks of protease-inhibitor-containing combination antiretroviral therapy (ART). All HIV-1-infected patients reconstituted CD4 T cells either with suppression of viremia or rebound of drug-resistant virus. Methods:Systemic immune activation was determined by polychromatic flow cytometry of blood lymphocytes and ELISA for plasma soluble CD27, soluble CD14, and tumor necrosis factor. Microbial translocation was evaluated by limulus amebocyte lysate assay to detect bacterial lipopolysaccharide (LPS) and ELISA for antiendotoxin core antigen immunoglobulin M (IgM) antibodies. Immune activation markers were compared with viral load, CD4 cell percentage, and LPS by regression models. Comparisons between healthy and HIV-1-infected or between different viral outcome groups were performed by nonparametric rank sum. Results:Microbial translocation was detected in healthy infants but resolved with age (P < 0.05). LPS and soluble CD14 levels were elevated in all HIV-1-infected patients (P < 0.05 and P < 0.0001, respectively) and persisted even if CD4 T cells were fully reconstituted, virus optimally suppressed, and lymphocyte activation resolved by ART. Children with CD4 T-cell reconstitution but viral rebound following ART continued to display high levels of soluble CD27. Conclusion:Microbial translocation in pediatric HIV-1 infection is associated with persistent monocyte/macrophage activation independent of viral replication or T-cell activation.


Journal of Experimental Medicine | 2008

MerTK is required for apoptotic cell-induced T cell tolerance.

Mark A. Wallet; Pradip Sen; Rafael R. Flores; Yaming Wang; Zuoan Yi; Yingsu Huang; Clayton E. Mathews; H. Shelton Earp; Glenn K. Matsushima; Bo Wang; Roland Tisch

Self-antigens expressed by apoptotic cells (ACs) may become targets for autoimmunity. Tolerance to these antigens is partly established by an ill-defined capacity of ACs to inhibit antigen-presenting cells such as dendritic cells (DCs). We present evidence that the receptor tyrosine kinase Mer (MerTK) has a key role in mediating AC-induced inhibition of DC activation/maturation. Pretreatment of DCs prepared from nonobese diabetic (NOD) mice with AC blocked secretion of proinflammatory cytokines, up-regulation of costimulatory molecule expression, and T cell activation. The effect of ACs on DCs was dependent on Gas6, which is a MerTK ligand. NOD DCs lacking MerTK expression (NOD.MerTKKD/KD) were resistant to AC-induced inhibition. Notably, autoimmune diabetes was exacerbated in NOD.MerTKKD/KD versus NOD mice expressing the transgenic BDC T cell receptor. In addition, β cell–specific CD4+ T cells adoptively transferred into NOD.MerTKKD/KD mice in which β cell apoptosis was induced with streptozotocin exhibited increased expansion and differentiation into type 1 T cell effectors. In both models, the lack of MerTK expression was associated with an increased frequency of activated pancreatic CD11c+CD8α+ DCs, which exhibited an enhanced T cell stimulatory capacity. These findings demonstrate that MerTK plays a critical role in regulating self-tolerance mediated between ACs, DCs, and T cells.


Journal of Immunology | 2011

Sepsis Induces Early Alterations in Innate Immunity That Impact Mortality to Secondary Infection

Matthew J. Delano; Terri C. Thayer; Sonia Gabrilovich; Kindra M. Kelly-Scumpia; Robert D. Winfield; Philip O. Scumpia; Alex G. Cuenca; Elizabeth A. Warner; Shannon M. Wallet; Mark A. Wallet; Kerri O'Malley; Reuben Ramphal; Michael Clare-Salzer; Philip A. Efron; Clayton E. Mathews; Lyle L. Moldawer

Sepsis, the systemic inflammatory response to microbial infection, induces changes in both innate and adaptive immunity that presumably lead to increased susceptibility to secondary infections, multiorgan failure, and death. Using a model of murine polymicrobial sepsis whose severity approximates human sepsis, we examined outcomes and defined requirements for survival after secondary Pseudomonas aeruginosa pneumonia or disseminated Listeria monocytogenes infection. We demonstrate that early after sepsis neutrophil numbers and function are decreased, whereas monocyte recruitment through the CCR2/MCP-1 pathway and function are enhanced. Consequently, lethality to Pseudomonas pneumonia is increased early but not late after induction of sepsis. In contrast, lethality to listeriosis, whose eradication is dependent upon monocyte/macrophage phagocytosis, is actually decreased both early and late after sepsis. Adaptive immunity plays little role in these secondary infectious responses. This study demonstrates that sepsis promotes selective early, impaired innate immune responses, primarily in neutrophils, that lead to a pathogen-specific, increased susceptibility to secondary infections.


Journal of Immunology | 2003

NF-κB Hyperactivation Has Differential Effects on the APC Function of Nonobese Diabetic Mouse Macrophages

Pradip Sen; Sandip Bhattacharyya; Mark A. Wallet; Carmen P. Wong; Brian Poligone; Maitreyee Sen; Albert S. Baldwin; Roland Tisch

Type 1 diabetes is characterized by a chronic inflammatory response resulting in the selective destruction of the insulin-producing β cells. We have previously demonstrated that dendritic cells (DCs) prepared from nonobese diabetic (NOD) mice, a model for spontaneous type 1 diabetes, exhibit hyperactivation of NF-κB resulting in an increased capacity to secrete proinflammatory cytokines and stimulate T cells compared with DCs of nondiabetic strains of mice. In the current study, the activational status of NF-κB and its role in regulating the APC function of macrophages (Mφ) prepared from NOD, nonobese resistant (NOR), and BALB/c mice was investigated. Independent of the stimulus, splenic and bone marrow-derived Mφ prepared from NOD mice exhibited increased NF-κB activation relative to NOR and BALB/c Mφ. This hyperactivation was detected for different NF-κB complexes and correlated with increased IκBα degradation. Furthermore, increased NF-κB activation resulted in an enhanced capacity of NOD vs NOR or BALB/c Mφ to secrete IL-12(p70), TNF-α, and IL-1α, which was inhibited upon infection with an adenoviral recombinant encoding a modified form of IκBα. In contrast, elevated NF-κB activation had no significant effect on the capacity of NOD Mφ to stimulate CD4+ or CD8+ T cells in an Ag-specific manner. These results demonstrate that in addition to NOD DCs, NOD Mφ exhibit hyperactivation of NF-κB, which correlates with an increased ability to mediate a proinflammatory response. Furthermore, NF-κB influences Mφ APC function by regulating cytokine secretion but not T cell stimulation.


Journal of Immunology | 2007

Identical β Cell-Specific CD8+ T Cell Clonotypes Typically Reside in Both Peripheral Blood Lymphocyte and Pancreatic Islets

Carmen P. Wong; Rosemary Stevens; Brian Long; Li Li; Yaming Wang; Mark A. Wallet; Kevin S. Goudy; Jeffrey A. Frelinger; Roland Tisch

A major issue regarding T cell responses in autoimmunity is how the repertoire compares between the periphery and target organ. In type 1 diabetes, the status of at-risk or diabetic individuals can be monitored by measuring β cell-specific T cells isolated from PBL, but whether these T cells accurately reflect the repertoire residing in the pancreatic islets is unclear. The TCR repertoire of disease-relevant, tetramer-sorted CD8+ T cells was examined at the single-cell level in PBL, pancreatic lymph nodes (PLN), and the islets of individual NOD mice. CDR3α and CDR3β sequences demonstrated that the same repertoire of T cells in PBL was detected in the islets and PLN, although the frequency of specific clonotypes varied. Albeit infrequent, clonotypes that were prevalent in the islets but not found in PBL were also detected. β cell Ag immunization expanded immunodominant PBL clonotypes present in the islets and PLN. These results show that insight into repertoire profiles of islet-infiltrating T cells can be obtained from PBL.


Diabetes | 2007

The Type and Frequency of Immunoregulatory CD4+ T-Cells Govern the Efficacy of Antigen-Specific Immunotherapy in Nonobese Diabetic Mice

Shannon M. Pop; Carmen P. Wong; Qiuming He; Yaming Wang; Mark A. Wallet; Kevin S. Goudy; Roland Tisch

Antigen-specific immunotherapy, an approach to selectively block autoimmune diabetes, generally declines in nonobese diabetic (NOD) mice as disease progresses. To define the parameters influencing the efficacy of antigen-specific immunotherapy once diabetes is established, plasmid DNA (pDNA) vaccination was used to suppress autoimmune-mediated destruction of syngeneic islet grafts in diabetic NOD recipients. pDNAs encoding a glutamic acid decarboxylase 65 (GAD65)-Ig molecule (pGAD65), interleukin (IL)-4 (pIL4), and IL-10 (pIL10) significantly delayed the onset of recurrent diabetes compared with pGAD65+pIL10-vaccinated recipients. Despite differences in efficacy, a similar frequency of GAD65-specific CD4+ T-cells secreting IL-4, IL-10, or interferon-γ were detected in mice treated with pGAD65+pIL4+pIL10 and pGAD65+pIL10. However, the frequency of FoxP3-expressing CD4+CD25+CD62Lhi T-cells was increased in the renal and pancreatic lymph nodes of diabetic recipients vaccinated with pGAD65+pIL4+pIL10. These immunoregulatory CD4+CD25+ T-cells (CD4+CD25+ Treg) exhibited enhanced in vivo and in vitro suppressor activity that partially was transforming growth factor-β dependent. Furthermore, duration of islet graft protection in pGAD65+pIL4+pIL10-vaccinated diabetic recipients correlated with the persistence of CD4+CD25+ Treg. These data demonstrate that the frequency and maintenance of FoxP3-expressing CD4+CD25+ Treg influence antigen-induced suppression of ongoing β-cell autoimmunity in diabetic recipients.


Proceedings of the National Academy of Sciences of the United States of America | 2009

MerTK regulates thymic selection of autoreactive T cells

Mark A. Wallet; Rafael R. Flores; Yaming Wang; Zuoan Yi; Charles J. Kroger; Clayton E. Mathews; H. Shelton Earp; Glenn K. Matsushima; Bo Wang; Roland Tisch

T cell-mediated autoimmune diseases such as type 1 diabetes (T1D) are believed to be the result in part of inefficient negative selection of self-specific thymocytes. However, the events regulating thymic negative selection are not fully understood. In the current study, we demonstrate that nonobese diabetic (NOD) mice lacking expression of the Mer tyrosine kinase (MerTK) have reduced inflammation of the pancreatic islets and fail to develop diabetes. Furthermore, NOD mice deficient in MerTK expression (Mer−/−) exhibit a reduced frequency of β cell-specific T cells independent of immunoregulatory effectors. The establishment of bone marrow chimeric mice demonstrated that the block in β cell autoimmunity required hematopoietic-derived cells lacking MerTK expression. Notably, fetal thymic organ cultures and self-peptide administration showed increased thymic negative selection in Mer−/− mice. Finally, thymic dendritic cells (DC) prepared from Mer−/− mice exhibited an increased capacity to induce thymocyte apoptosis in a peptide-specific manner in vitro. These findings provide evidence for a unique mechanism involving MerTK-mediated regulation of thymocyte negative selection and thymic DC, and suggest a role for MerTK in contributing to β cell autoimmunity.


Journal of Leukocyte Biology | 2010

Proteome bioprofiles distinguish between M1 priming and activation states in human macrophages

Joseph N. Brown; Mark A. Wallet; Bryan Krastins; David Sarracino; Maureen M. Goodenow

Macrophage activation is a dynamic process that results in diverse functional outcomes ranging from immunoregulation to inflammation. The proinflammatory, or M1, response is a complex, bimodal progression composed of a “prime,” classically through IFN‐γ, and “trigger,” such as LPS. To characterize the physiological response of M1 activation, a systems biology approach was applied to determine the intracellular proteome bioprofiles of IFN‐γ‐ and LPS‐treated primary human macrophages. Our goal was to develop intracellular proteomic fingerprints to serve as novel correlates of macrophage priming and/or activation to augment the existing approaches of analyzing secreted cytokines and cell‐surface protein expression. The majority of the proteome, ∼78%, remained stable during activation, representing the core proteome. In contrast, three distinct patterns defined response proteomes: IFN‐γ‐specific, LPS‐specific, or IFN‐γ‐ and LPS‐shared or M1‐specific. Although steady‐state expression levels of proteins involved in energy metabolism and immune response were increased during priming and triggering, changes in protein and fatty acid metabolism, signaling, and transport pathways were most apparent. Unique proteomic fingerprints distinguish among IFN‐γ‐specific, LPS‐specific, or M1‐specific activation states and provide a clear molecular, archeological profile to infer recent history of cells, as well as correlates for chronic macrophage activation in health and disease.


Journal of Virology | 2012

Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

Melissa M. Norström; Marcus Buggert; Johanna Tauriainen; Wendy Hartogensis; Mattia Prosperi; Mark A. Wallet; Frederick Hecht; Marco Salemi; Annika C. Karlsson

ABSTRACT HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1 in vivo evolution and epitope-specific CD8+ T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4+ T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8+ T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8+ T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.

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Roland Tisch

University of North Carolina at Chapel Hill

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Pradip Sen

Indian Institute of Chemical Biology

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Sandip Bhattacharyya

Cincinnati Children's Hospital Medical Center

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Albert S. Baldwin

University of North Carolina at Chapel Hill

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Glenn K. Matsushima

University of Southern California

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Yaming Wang

University of North Carolina at Chapel Hill

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