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The opposing roles of interferon-[gamma] and IL-17 in inflammation

Mauermann, Nora Corinna. The opposing roles of interferon-[gamma] and IL-17 in inflammation. 2007, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7924

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Abstract

Inflammation is the normal immune response to infection ur injury, helping the body to fight pathogens and regain the integrity of the organism. Inflammatory processes develop in an unwanted and harmful degree in autoimmunity and chronic inflammation. The aim of the thesis was to identify the role of IFN[gamma] and T cell Th1 commitment in inflammation using two separate models; experimental autoimmune myocarditis (EAM) and graft versus host mediated idiopathic pneumonia syndrome (IPS).
Using knock out mice for Th1 (T-bet), we show that inflammatory CD4+ T cell responses in EAM depend not on Th1, but rather on newly described Th17. Neither Th1 or Th2 but only Th17 induce myocarditis in EAM and invivo IL-17 depletion markedly reduce disease severity in T-bet-/- mice. Mice deficient for both T-bet and a receptor for IL-23 (maintenance factor of the Th17 subset) were proeected from disease. While heart-infiltrating T-bet+/+ CD8+ cells secrete IFN[gamma], a negative regulator of EAM and inhibitor of IL-17 production, T-bet-/- CD8+ lymphocytes lost their capacity to release IFN[gamma] within the heart. These data show that severe IL-17-mediated EAM develops in the absence of T-bet, and that T-bet can regulate autoimmunity via the control of CD8+ T cell bystander function in the inflamed target organ.
Idiopathic pneumonia syndrome (IPS= is a major complication after allogeneic bone marrow transplantation, found in 30-50% of patients. Transplantation of bone marrow together with IFN[gamma] deficient CD4+ T cells resulted in severe pulmonary inflammation that was lethal by day 13 in our animal model. Absence of IFN[gamma] favoured the development of IL-17 producing CD4+ T cells. Blocking of IL-17 could only reduce disease severity. Protection from pulmonary graft-versus-host-disease was dependent on the presence of IFN[gamma] in donor CD4+ T cells or the IFN[gamma] receptor on pulmonary parenchymal cells. The lung tissue seems to be a uniquely sensitive organ for CD4+ T cells mediated immunopathology in absence of the protective IFN[gamma] induced signalling cascade. In addition, pulmonary host antigen-presenting cells (APC) are rapidly replaced by donor APC and do not seem to play a major role for the maintenance of the donor mediated allogeneic immune response against the host.
Advisors:Rolink, Antonius G.
Committee Members:Erikson, Urs and Finke, Daniela
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Further Research Groups at DBM > Developmental and Molecular Immunology (Rolink)
UniBasel Contributors:Rolink, Antonius G. and Finke, Daniela
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:7924
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:95
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 16:15

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