ACQUIRED-RESISTANCE BUT NOT INNATE RESISTANCE TO MYCOBACTERIUM-BOVIS BACILLUS-CALMETTE-GUERIN IS COMPROMISED BY INTERLEUKIN-12 ABLATION

Interleukin-12 (IL-12) is one of the first cytokines produced by macro phages, key mediators of innate resistance, during the hosts immune re sponse to infections. Therefore, in this study we propose that IL-12 h as an important role in the early phase of the immune response to Myco bacterium bovis BCG, IL-12 has been shown to enhance the maturation of protective Th1 cells and gamma interferon (IFN-gamma) production duri ng mycobacterial infection. Therefore, it may play a crucial role duri ng the immune phase of infection as well. To examine the role of IL-12 in both the innate and the immune phase of infection, me compared BCG -resistant mice, B10.A (Bcg(r)), to the susceptible congenic strain B1 0.A (Bcg(s)) following administration of a blocking monoclonal antibod y to IL-12 (10F6). Anti-IL-12-treated susceptible animals exhibited a two- to threefold increase in spleen CFU by day 21. In contrast, anti- IL-12 treatment had little or no effect on the response of the genetic ally resistant animals to infection. The B10.A (Bcg(r)) but not the B1 0.A (Bcg(s)) mice had an increase in IFN-gamma mRNA relative to baseli ne levels as early as day 1 of infection irrespective of anti-IL-12 tr eatment. By day 14, B10.A (Bcg(r)) mice showed a decrease in IFN-gamma mRNA while the B10.A (Bcg(s)) mice showed a significant increase in I FN-gamma mRNA levels. Thus, during BCG infection, the B10.A (Bcg(r)) m ice mount an early IFN-gamma response against BCG whereas the B10.A (B cg(s)) mice have a delayed IFN-gamma response correlating with their g enetic permissiveness expressed as an increased mycobacterial load by day 21. Overall, our data demonstrate that the inherent resistance of B10.A (Bcg(r)) mice to mycobacteria does not depend on optimal levels of IL-12 to maintain effective control of the bacteria, whereas IL-12 is important for the susceptible animals' response to BCG during the p eak of infection.