Host factors, including malnutrition, significantly impair the protection afforded by BCG vaccination, currently the only practical means of controlling tuberculosis world-wide. The ultimate objective of this investigation is to determine the mechanisms by which nutritional deficiencies interfere with tuberculosis vaccine efficacy, and to define the immunologic defects in cellular and molecular terms.
The specific aims of this proposal are to examine five hypothetical mechanisms of diet- induced T lymphocyte dysfunction in a guinea pig model of respiratory tuberculosis. A direct effect of protein-deficiency on the thymus will be assessed by studying thymic architecture, expression of phenotypic markers of T cell maturity including CD2, and circulating levels of thymulin. We will study the impact of protein deprivation on FC gamma receptor-bearing T cells (T gamma) and their role in down-regulation of anti-mycobacterial immunity. An antigen-specific suppressor role for T gamma cells will be sought in vitro and in vivo. The antigens utilized will include tuberculin (PPD) and two recombinant mycobacterial heat shock protein, M. bovis BCG hsp 65 and M. tuberculosis hsp 70. Trapping of antigen-reactive lymphocytes in the bronchotracheal lymph nodes of malnourished, tuberculous guinea pigs will be investigated by comparing the phenotype and function of lymphocytes in blood, lymph nodes and thoracic duct lymph, and by examining the characteristics of lymphocytes capable of trafficking into a pleural effusion induced by mycobacterial antigens. The differential effect of protein deficiency on secondary, but not primary, immunity to infection with M. tuberculosis will be assessed in experiments designed to demonstrate the presence and function of memory cells following BCG vaccination. Finally, the kinetics and mechanisms of the rapid recovery of anti-mycobacterial immunity following transfer of malnourished guinea pigs to a complete diet will be studied, changes in the proportions, distribution or antigen-specific function of T lymphocytes will be correlated with recovery of immune function. Taken together, these experiments should provide evidence for the contribution of some or all of these mechanisms in diet-induced loss of BCG vaccine efficacy. This knowledge will support a rational strategy for successful vaccination of malnourished populations against tuberculosis.
Showing the most recent 10 out of 55 publications
