Although helper T cell subsets are believed to regulate protective vs nonprotective responses to Mycobacterium tuberculosis, control of the response is poorly understood, because of its complexity. To study regulatory pathways of the response, we prepared a model in which the complexity has been reduced to one host mutation affecting the response to M. tuberculosis, strain H37Rv, were detected; the key observation was that the S-27 mutant does not make antibodies against 27 Kda mycobacterial protein while parental C57BL/6J (B6) mice do. Others have demonstrated that 27 Kda protein is a secreted immunodominant antigen of M. tuberculosis. The S-27 mutant is linked to H-2; molecular tests showed that the second exon - second intron region of the Ab/b gene is affected by the mutation. This proposal addresses the hypothesis that the selection by the host of TH1 or TH2 response to 27 Kda antigen of M. tuberculosis is controlled by MHC class II Ab/b gene.
The Specific Aims 1 and 2 proposed here will subject this hypothesis to a rigorous test by determining the molecular basis for different resistance phenotypes of Ab/b alleles in B6 and S-27 mice and immunological mechanism(s) of resistance in S-27 mutant. Therefore, proposed experiments address fundamental questions about the nature of genetic control of resistance, its mechanisms, and th functional significance of responses against 27 Kda mycobacterial protein. We also provide evidence that in some mouse mutants resisting cancer metastasis, responses to tuberculosis infection have been altered. BCG vaccination is thought to influence cancer incidence in human. Additional experiments (Specific Aim 3) will focus on pathways of response which are common for mycobacterial infection and malignant transformation by testing resistance to tuberculosis in a group of mouse mutants resisting cancer metastasis. A rational for improved treatment of or improved vaccination against tuberculosis in humans will be provided.
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