http://www.loc.gov/mods/v3 http://www.loc.gov/standards/mods/v3/mods-3-2.xsd
role of tumor necrosis factor-Alpha (TNF-α) in host resistance to experimental pulmonary tuberculosis
xii, 130 leaves : illustrations ; 28 cm.
The purpose of this study was to examine the role of TNF-α in host immunity using an experimental model of pulmonary tuberculosis. In this study, we focused on three leukocyte-rich guinea pig cell populations, bronchoalveolar lavage (BAL) cells, resident peritoneal cells (PC), and splenocytes (SPC). Each cell population was stimulated with either live attenuated M. tuberculosis H37Ra, or live/heat-killed virulent M. tuberculosis H37Rv (MOI 1:100). Each cell population was determined to proliferate in response to heat-killed virulent H37Rv, whereas no measurable proliferative response could be detected upon stimulation with live mycobacteria. Additionally, this proliferative capacity was enhanced significantly upon prior vaccination with M. bovis BCG in the case of SPC and PC populations. Accordingly, in a parallel set of experiments we found a strong positive correlation between bioactive TNF-α production and prior vaccination with BCG. Although, this same correlation was not detected at the mRNA level, we determined this to be purely antigen-specific process, whereby a non-specific stimulus, lipopolysaccharide (LPS), failed to induce this effect on BAL-cells, SPC, and PC. While the same vaccination-specific effect was observed in BAL-cell, SPC, and PC populations stimulated with M. tuberculosis PPD, we determined that upon prior aerosol challenge with M. tuberculosis H37Rv, the opposite was true. That is, BAL-cells, SPC and PC obtained from non-vaccinated guinea pigs produced higher levels of bioactive TNF-α than their BCG-vaccinated counterparts. Furthermore, both recombinant guinea pig TNF-α (rgpTNF-α) and polyclonal rabbit anti- rgpTNF-α reagents were developed and utilized to modulate TNF-α availability in a series of in vitro and in vivo experiments. We determined that the in vitro effect of TNF-α on PPD-induced T-cell proliferation is highly dependent on the concentration of TNF-α. While PPD-induced proliferation from SPC correlated with persistent levels of TNF-α in the supernatant, further addition of TNF-α (with rgpTNF-α) suppressed this proliferative effect, whereby neutralization (with anti-rgpTNF-α) led to a hyperproliferative response in SPC. Lastly, the administration of anti-rgpTNF-α to M.tuberculosis-infected guinea pigs did not affect mycobacterial replication in the tissues; however, pronounced splenomegaly developed in BCG-vaccinated guinea pigs, and interestingly, a dramatic influx of plasma cells into the pulmonary granulomas was also observed.
Issued also on microfiche from University Microfilm Inc.
Includes bibliographical references (leaves 117-129).