MANIPULATION AND POTENTIATION OF ANTIMYCOBACTERIAL IMMUNITY USING RECOMBINANT BACILLE CALMETTE-GUERIN STRAINS THAT SECRETE CYTOKINES

Bacille Calmette-Guerin (BCG) is a live, attenuated strain of Mycobact erium bovis used widely for tuberculosis prophylaxis and bladder cance r immunotherapy, although it has limitations in both contexts. To inve stigate whether BCG's immunostimulatory properties could be modified, and to gain insight into the interaction between mycobacteria and thei r hosts, we constructed recombinant BCG strains that secrete functiona l murine cytokines and studied their properties in mouse models of exp erimental infection. Cell-mediated immune responses to mycobacterial a ntigen (purified protein derivative) were assayed using splenocytes fr om mice inoculated with various BCG recombinants. Antigen-specific pro liferation and cytokine release were found to be substantially greater with splenocytes derived from mice injected with cytokine-secreting B CG than with splenocytes from mice injected with BCG lacking cytokines . The most profound effects were induced by BCG secreting interleukin 2, interferon gamma, or granulocyte-macrophage colony-stimulating fact or. Thus, cytokine-secreting BCG can enhance immune responses to mycob acterial antigens and may be improved reagents for tuberculosis prophy laxis and cancer immunotherapy.