Functions of transforming growth factor-[beta]1 in immune responses against Mycobacterium tuberculosis : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2002]
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| Subjects: |
| Abstract: | ABSTRACT: Tuberculosis is a leading infectious cause of morbidity and mortality worldwide. Due to the sensitivity of the lungs to inflammatory damage, the immune response to Mycobacterium tuberculosis in its preferred environment must remain tightly controlled. TGF-β1 appears to be an important regulator in these immune responses. In the first experiment of this study, we observed the effects of TGF-β1 on the interactions between alveolar macrophages and lymphocytes from BCG-vaccinated guinea pigs upon exposure to the mycobacterial specific antigen, PPD, and to a nonspecific mitogen, ConA. TGF-β1 protein levels were examined by ELISA, and lymphocyte proliferation was measured by [³H]-thymidine uptake. Alveolar macrophage / lymphocyte4 co-cultures produced TGF-β1 upon stimulation with PPD and ConA. However, suppression of lymphoproliferation was only observed in the presence of ConA. TGF-β1 removal from ConA-stimulated cultures enhanced lymphocyte proliferation, providing evidence that TGF-β1 production in these cultures was responsible for the decreased proliferation observed. Secondly, we documented cytokine mRNA kinetics and lymphocyte responses during experimental tuberculous pleurisy in guinea pigs. Pleurisy was induced by the injection of heat-killed M. tuberculosis into the pleural space of BCG-vaccinated animals. mRNA expression various cytokines was quantified by reverse transcription real time PCR. In this study, we discovered significant cellular influx into the pleural space within 24 hours of pleurisy induction. In addition, TGF-β1, TNF-α, IFN-γ, and IL-8 mRNA expression were simultaneously upregulated during the first half of the response. On the other hand, TGF-β1 protein levels continually increased, while IFN protein concentrations remained similar throughout the pleuritis. Finally, by day 3 of the response, pleural exudate cells proliferated upon stimulation with ConA and PPD. In the last experiment, we analyzed the effects of altering in vivo TGF-β1 levels in guinea pig tuberculous pleurisy. Injection of anti-TGF-β1 directly into the pleural space of pleuritic guinea pigs late in the inflammatory response enhanced lymphocyte proliferation in response to in vitro stimulation with PPD, increased production of the pro-inflammatory cytokines TNF-α and IFN-γ, and significantly altered lymphocyte and neutrophil proportions in the pleural exudate. Thus, in experimental tuberculous pleurisy, TGF-β1 is important for downregulating immune responses and protecting the host from excessive pathology associated with this intense inflammatory reaction. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Graduate School of Biomedical Sciences of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy December 2002." Approved as to style and content by: David N. McMurray, Robert S. Chapkin, Jonathan T. Skare, John M. Quarles, Vernon L. Tesh. |
| Physical Description: | xi, 120 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 103-119). |