Mechanisms of granuioma formation in murine Mycobacterium avium infection: the contribution of CD4+ T cells |
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Authors: | Hansch, Holger C. R. Smith, Debbie A. Mielke, Martin E. A. Hahn, Helmut Bancroft, Gregory J. Ehlers, Stefan |
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Affiliation: | Institut für Medizinische Mikrobiologie und Infektionsimmunologie, Freie Universität Berlin Hindenburgdamm 27, 12203 Berlin, Germany 1 Department of Clinical Sciences, London School of Hygiene and Tropical Medicine Keppel Street, London WC1E7HT, UK |
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Abstract: | Infection with the virulent Mycobacterium avium strain TMC 724caused progressive Infection in C57BL/6 and BALB/c mice, whileinfection with a less virulent strain (M. avium SE 01) resultedIn chronically persistent bacterial loads. Livers of mice Infectedwith TMC 724 were characterized by progressively expanding tumor-likeInfiltrations of epithelloid macrophages, while SE 01 Inducedwell-developed, compact epithelioid granulomas that remainedconstant in size and number for at least 4 months. When C57BL/6mice were depleted of CD4+ T cells by i.p. administration ofspecific mAb at the time of infection, their capacity to Initiategranuloma formation was completely abrogated during the first4 weeks of infection. Semi-quantltatlve competitive RT-PCR ofliver homogenates obtained 3 weeks after infection revealedthat depletion of CD4+ T cells was accompanied by a 25-foldreduced expression of IFN- mRNA and a 5-fold reduced expressionof tumor necrosis factor (TNF)- mRNA when compared to controlInfected mice. Granuioma morphology in response to either TMC724 or SE 01 was similar in immunodeficlent SCID mice to thatobserved In syngeneic BALB/c mice. However, SCID mice developedgranuiomas In a delayed fashion and were less efficient in surroundingInfected Kupffer cells with an inflammatory infiltration. Thedelayed kinetics of granuioma Initiation In Infected SCID micewas paralleled by a lower mRNA expression for IFN- and TNF-compared to that observed in Infected BALB/c mice. mAb-mediatedneutralization of IFN- In BALB/c mice significantly reducedinflammatory infiltrations and granuioma formation. These datasupport the conclusion that CD4+ T cells accelerate granuiomaformation by enhancing the production of TNF- and IFN- at thesite of infection. |
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Keywords: | cytokines granuloma formation mycobacteria RT-PCR SCID mice T cell dependent T cell independent |
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