T-CELL-INDEPENDENT GRANULOMA-FORMATION IN RESPONSE TO MYCOBACTERIUM-AVIUM - ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-GAMMA

We used Mycobacterium avium infection in severe combined immunodeficie ncy (SCID) mice to examine T-cell-independent mechanisms of inflammato ry cell recruitment. SCID mice infected with a virulent strain of M. a vium (TMC724) were able to recruit macrophages to sites of mycobacteri al replication and formed organized and coherent granulomas in the abs ence of functional T cells. Phagocyte recruitment was almost totally a blated by neutralization of either tumour necrosis factor-alpha (TNF-a lpha) or interferon-gamma (IFN-gamma) in vivo demonstrating that granu loma formation was dependent on the presence of these cytokines. This was concomitant with a reduction in the in situ cytokine mRNA levels o therwise induced in infected mice, for chemokines, pro-inflammatory an d regulatory cytokines, including TNF-alpha, IFN-gamma, macrophage inf lammatory protein-1 alpha, interleukin-1 beta (IL-1 beta) and IL-10. F urthermore, in vivo treatment of infected mice with anti-asialo GM-I a ntisera, which depletes natural killer (NK) cells, prevented recruitme nt of inflammatory cells. In vitro studies confirmed that M. avium was able to elicit IFN-gamma from SCID spleen in a dose-dependent manner. These data show for the first time that secretion of IFN-gamma from N K cells can mediate a T-cell-independent pathway of granuloma formatio n and cellular infiltration in response to mycobacteria.