BCG-Induced Granuloma Formation in Murine Tissues

BCG infection of mice provides a convenient model to study natural and cellular immunity to mycobacteria and the mechanisms of granuloma formation and repair. We have used a range of macrophage (MΦ) membrane molecules and secretory products to investigate resident MΦ-pathogen interactions and T lymphocyte-dependent recruitment and activation of MΦ in different tissues of immature, normal adult and gamma interferon deficient animals. In situ hybridization (ISH), RT-PCR and immunocytochemical analysis of MΦ gene and product expression have been correlated with in vitro study of endocytic and secretory activity in which biogel polyacrylamide beadelicited peritoneal MΦ are exposed to Th1 and Th2 cytokines, LPS, BCG and other stimuli. The role of resident and newly recruited MΦ responding to BCG in liver, spleen, lung and brain has been defined by means of antigen markers expressed by MΦ (F4/80, 7/4, CR3, macrosialin, sialoadhesin and scavenger receptor) and/or T and B lymphoid cells (MHC Class II, CD4, CD8, B220). Heterogeneity in MΦ secretory activity was revealed by ISH analysis of lysozyme, TNF-α, IL-1 IL-6 and MCP-1, by in vitro assay of NO and superoxide anion production, and by RT-PCR studies of Th1 (interferon gamma) and Th2 (IL-4, IL-13, IL-10) lymphokine mRNA in tissues. Our studies confirm the importance of interferon gamma as a critical mediator of host resistance to mycobacterial infection and raise intriguing questions in regard to T cell and MΦ functional heterogeneity in distinct tissue microenvironments.