Medicine and Health Sciences Commons^™

Occupational Exposure To Hepatitis C Virus: Early T-Cell Responses In The Absence Of Seroconversion In A Longitudinal Cohort Study., Theo Heller, Jens Martin Werner, Fareed Rahman, Eishiro Mizukoshi, Yuji Sobao, Ann Marie Gordon, Arlene Sheets, Averell H. Sherker, Ellen Kessler, Kathleen S. Bean, Steven K. Herrine, M'Lou Stevens, James Schmitt, Barbara Rehermann

Division of Gastroenterology and Hepatology Faculty Papers

BACKGROUND: T-cell responses have been described in seronegative patients who test negative for hepatitis C virus (HCV) RNA despite frequent HCV exposure. However, the cross-sectional design of those studies did not clarify whether T cells were indeed induced by low-level HCV exposure without seroconversion or whether they resulted from regular acute infection with subsequent antibody loss.

METHODS: Over a 10-year period, our longitudinal study recruited 72 healthcare workers with documented HCV exposure. We studied viremia and antibody and T-cell responses longitudinally for 6 months.

RESULTS: All healthcare workers remained negative for HCV RNA and antibodies. However, 48% developed proliferative T-cell …

Autoimmune Enteropathy With A Cd8+ Cd7- T-Cell Small Bowel Intraepithelial Lymphocytosis: Case Report And Literature Review, Shrinivas Bishu, Violeta Arsenescu, Eun Y. Lee, H. David Vargas, Willem J. S. De Villiers, Razvan Arsenescu

Surgery Faculty Publications

Background

Adult onset autoimmune enteropathy (AIE) is a rare condition characterized by diarrhea refractory to dietary therapy diagnosed in patients with evidence of autoimmune conditions. Auto-antibodies to gut epithelial cells and other tissues are commonly demonstrated. Despite increasing awareness, the pathogenesis, histologic, immunologic and clinical features of AIE remain uncertain. There remains controversy regarding the diagnostic criteria, the frequency and types of auto-antibodies and associated autoimmune conditions, and the extent and types of histologic and immunologic abnormalities. CD4+ T-cells are thought to at least responsible for this condition; whether other cell types, including B- and other T-cell subsets are involved, …

Tacrolimus And Cyclosporine A Inhibit Allostimulatory Capacity And Cytokine Production Of Human Myeloid Dendritic Cells, Gyongyi Szabo, C. Gavala, Pranoti Mandrekar

Gyongyi Szabo

Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigens and, therefore, in the induction of allograft rejection. Induction of alloreactive T cell proliferation by myeloid DCs depends on the maturation of DCs, the expression of costimulatory molecules, and the cytokine environment. This study investigated the effects of tacrolimus and cyclosporine A (CsA) on DC maturation and allostimulatory capacity. Myeloid DCs were propagated from normal blood monocytes with interleukin (IL) 4 and GM-CSF for 7 days in the presence or absence of tacrolimus (FK506; 10 nM) or CsA (1 microg/mL). Exposure of DCs during maturation to tacrolimus or CsA …

Reduced Alloreactive T-Cell Activation After Alcohol Intake Is Due To Impaired Monocyte Accessory Cell Function And Correlates With Elevated Il-10, Il-13, And Decreased Ifngamma Levels, Gyongyi Szabo, Pranoti Mandrekar, Angela Dolganiuc, Donna Catalano, Karen Kodys

Gyongyi Szabo

BACKGROUND: Immunosuppression associated with chronic alcohol use is characterized by reduced antigen-specific T-cell response and impaired delayed type hypersensitivity. Increasing evidence suggests in chronic alcohol consumption models that reduced antigen-specific T-cell proliferation is due to insufficient accessory cell function. Accessory cell function, a critical step in recognition of viral antigens, is reduced in chronic hepatitis C. The severity of hepatitis C is increased by alcohol consumption. Thus, we investigated the effects of alcohol consumption on accessory cell activity of monocytes in supporting alloreactive T-cell proliferation. METHODS: Alloreactive T-cell proliferation was evaluated in a one-way mixed lymphocyte reaction (MLR). Mononuclear cells …

Human Macrophages Degrade Tryptophan Upon Induction By Interferon-Gamma, Ernst Werner, Gabriele Bitterlich, Dietmar Fuchs, Arno Hausen, Gilbert Reibnegger, Gyongyi Szabo, Manfred Dierich, Helmut Wachter

Gyongyi Szabo

Human peripheral blood mononuclear cells, monocytes-macrophages and T-cells were stimulated with human recombinant interferon-gamma, interferon-alpha and phytohemagglutinin. The culture supernatants were analyzed for tryptophan, kynurenine, 3-hydroxyanthranilic acid, anthranilic acid and neopterin by high performance liquid chromatography. Tryptophan was decreased and the four other compounds were increased in supernatants of peripheral blood mononuclear cells activated by interferon-gamma (250 U/ml), interferon-alpha (10.000 U/ml) and phytohemagglutinin (1 microgram/ml). After splitting of peripheral blood mononuclear cells by adherence, the monocytes and macrophages but not the T-cells degraded tryptophan upon stimulation by interferon-gamma in a dose dependent manner. Supernatants of phytohemagglutinin stimulated but not of …

Ethanol-Mediated Regulation Of Transcription Factors In Immunocompetent Cells, Gyongyi Szabo, Pranoti Mandrekar

Gyongyi Szabo

The immunomodulatory effects of acute and chronic alcohol use are characterized by impaired antigen-specific immune activation and by increased susceptibility to infections due to alterations in innate immune responses and inflammatory mediator production. The central feature of cellular responses to inflammatory and stress signals is the activation of the nuclear regulatory kappa B/Rel family of transcriptional factors via various surface receptor systems in immunocompetent cells. Activation of NF-kappa B, however, is regulated at multiple levels including I-kappa B degradation, nuclear translocation, and by interaction of NF-kappa B/Rel with other transcription factors. Data from our and other laboratories demonstrate that acute …

Additive Inhibition Of Dendritic Cell Allostimulatory Capacity By Alcohol And Hepatitis C Is Not Restored By Dc Maturation And Involves Abnormal Il-10 And Il-2 Induction, Angela Dolganiuc, Karen Kodys, Andrea Kopasz, Christopher Marshall, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: Excessive alcohol use results in impaired immunity, and it is associated with increased incidence and progression of chronic hepatitis C virus (HCV) infection. Here we investigated the effects of HCV infection and alcohol on myeloid dendritic cells (DC) that are critical in antiviral immunity.

METHODS: Immature and mature DCs were generated from monocytes of chronic HCV infected patients (HCV-DC) and controls (N-DC) with IL-4 plus granulocyte-macrophage colony stimulating factor (GM-CSF) in the presence or absence of alcohol (25 mM). DC allostimulatory capacity was tested in mixed lymphocyte reaction (MLR) and cytokine production by ELISA.

RESULTS: Allostimulatory capacity of HCV-DCs …

Hepatitis C And Innate Immunity: Recent Advances, Gyongyi Szabo, Angela Dolganiuc

Gyongyi Szabo

Eradication of hepatitis C virus (HCV) infection requires a complex and coordinated interplay between innate and adaptive immune responses that, when it fails, leads to chronic infection. In this review, the innate immune mechanisms by which HCV is sensed and by which HCV undermines host defense are discussed. The critical role of dendritic cells in antigen presentation and T-cell activation in addition to type I interferon production and interference of HCV with innate immune cell functions are reviewed. Finally, current and emerging therapeutic approaches targeting innate immune pathways are evaluated.