INDOLEAMINE 2,3-DIOXYGENASE IN OPPORTUNISTIC INFECTIONS

CENTRAL NERVOUS SYSTEM TOXOPLASMOSIS HAS CAUSED DISABILITY AND DEATH IN UP TO 30% OF PATIENTS WITH AIDS. CURRENT CLINICAL TREATMENT FOR TOXOPLASMA INFECTION IS MAINLY CHEMOTHERAPEUTICAL, WHICH IS OFTEN ASSOCIATED WITH DOSE-RELATED BONE MARROW SUPPRESSION. COMPLETE REMISSION OF THE INFECTION DEPENDS LARGELY ON THE ADEQUATE RESTORATION OF THE CELL-MEDIATED IMMUNE SYSTEM OF THE PATIENTS AND THUS, IT POSES A CONTINUOUS THREAT TO AIDS PATIENTS. AN ALTERNATIVE TREATMENT USING RECOMBINANT INTERFERON-GAMMA (IFN-GAMMA) HAS BEEN PROPOSED SINCE IFN-GAMMA, A CD4+T CELL PRODUCT, BLOCKS THE GROWTH OF T GONDII IN A VARIETY OF TISSUES AND CELLS. THIS IFN-GAMMA-MEDIATE ANTI-TOXOPLASMIC ACTIVITY IS STRONGLY CORRELATED WITH THE DEGRADATION OF THE ESSENTIAL AMINO ACID L-TRYPTOPHAN IN VITRO. DESTRUCTION L-TRYPTOPHAN IS DUE TO THE INCREASED ACTIVITY OF INDOLEAMINE 2,3 DIOXYGENASE (ISO) WHICH IS IN TURN TRANSCRIPTIONALLY ACTIVATED BY IFN-GAMMA. IT HAS BEEN SUGGESTED THAT T GONDII INFECTION IS PRIMARILY CONTROLLED BY IDO ACTIVITY INDUCED BY IFN-GAMMA DERIVED FROM CD4+ T LYMPHOCYTES. THEREFORE, WE WILL INVESTIGATE THE ROLE OF IDO IN HOST DEFENSE AGAINST T GONDII INFECTION, AND SPECIFICALLY TO DETERMINE WHETHER IDO ACTIVITY ALONE, EXPRESSED VIA STABLE TRANSFECTION OF IDO CDNA CONTROLLED BY A METALLOTHIONEIN INDUCIBLE PROMOTER, BLOCKS THE GROWTH OF T GONDII IN CULTURED HUMAN FIBROBLASTS AND MACROPHAGE CELL LINE. ELUCIDATION OF THE ROLE OF IDO IN BLOCKING T GONDII REPLICATION WILL PROVIDE NOT ONLY HOST DEFENSE MECHANISM BUT ALO NEW CONCEPT FOR DEVELOPING EFFECTIVE DRUGS FOR PREVENTION AND TREATMENT OF TOXOPLASMOSIS IN AIDS PATIENTS.