The purpose of these studies is to elucidate the mechanisms by which vaccination affects the cellular and cytokine responses associated with pulmonary granulomas in guinea pigs following respiratory exposure to virulent Mycobacterium tuberculosis. Using in situ and ex vivo approaches, the temporal and anatomical sequence of events in the lung will be dissected to reveal unique features of the local host-pathogen interface. During the previous funding period, we subcloned several guinea pig cytokine and chemokine genes and produced reagents and assays with which to study their involvement in the host response to mycobacterial infection. In this renewal application, we will study immune cells in granulomas in situ using novel laser capture microdissection methodology and ex vivo using lung digest cell isolation techniques. These experimental approaches will allow us to make novel observations regarding the determinants of vaccine-induced immunity in granulomas. In addition, we will take advantage of our extensive experience with the dietary modulation of immune cell membranes and alteration of proinflammatory T cell functions by n-3 polyunsaturated fatty acids (PUFA), to delineate the mechanisms by which dietary n-3 PUFA modulate vaccine-induced resistance to tuberculosis.
The specific aims of this competing renewal application are:
Aim 1 : To elucidate the mechanisms by which vaccination promotes the accumulation of a protective cellular response in the lungs of guinea pigs;
Aim 2 : To compare the cellular and cytokine responses of primary and secondary pulmonary granulomas in vaccinated and non-vaccinated guinea pigs following virulent pulmonary challenge;
Aim 3 : To interpret the cytokine cross-talk between immune lymphocytes and infected macrophages which results in the control of mycobacterial accumulation;
and Aim 4 : To determine the mechanisms by which an anti-inflammatory, T cell-suppressive diet, enriched in n-3 polyunsaturated fatty adds (PUFA), will impair innate and vaccine-induced resistance to pulmonary tuberculosis.
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