REGULATION OF GRANULOMA IN TUBERCULOSIS

Project Details

Description

This proposal is designed to characterize the granulomatous response of
tuberculosis. Although generally viewed as a critical element in host
defense against M. tuberculosis, little is known about the tuberculous
granuloma at the cellular, molecular, and biochemical level. The
unusually high incidence of disseminated tuberculosis and the markedly
deficient granulomatous response seen in AIDS patients suggest a
significant role for T-cells in the regulation of granuloma formation.
We have recently developed a murine experimental tuberculosis model of
protein calorie malnutrition (PCM) in which mice receiving a protein-
deficient diet experienced fulminant and rapidly fatal infection
associated with markedly increased bacterial burden and poorly formed
granuloma. In contrast, control animals fed a regular diet develop a
vigorous granulomatous response and remain clinically well for months.
Thus, our PCM model provides a system which allows comparative studies
on the granulomatous reaction during the course of tuberculous infection.
The goals of this proposal are: i) to characterize the cellular
components that participate in the granulomatous reaction by
immunocytochemical and electron microscopic studies; ii) to evaluate the
role of T-lymphocyte subsets in the regulation of the granulomatous
reaction by T-cell cloning, examination of the differentiation of this
immune cell in the granuloma, adoptive transfer studies, and analysis of
T-cell receptor usage; iii) to study the expression of cytokines in the
tuberculous granuloma by immunohistochemical, in situ hybridization, and
competitive RT-PCR techniques; and iv) to examine the interaction between
granulomatous macrophages and T-cells. It is hoped that these studies
would allow identification of immunological elements whose roles in the
granulomatous reaction can be tested in vivo. We believe that results
generated from these studies would help gain insight into the host
defense mechanisms against the tubercle bacillus, and ultimately, to
enable appropriate manipulation of the granulomatous response in various
disease states that translate into therapeutic augmentation of resistance
against pathogens, or abatement of immunopathologic processes triggered
by this reaction.
StatusFinished
Effective start/end date4/1/973/31/03

Funding

  • National Heart, Lung, and Blood Institute: $406,761.00
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute: $446,520.00
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute: $29,250.00
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute

ASJC

  • Infectious Diseases
  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Immunology

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