Exploitation of gene knockout mice models to study the pathogenesis of leprosy

Shepard's technique for growth of Mycobacterium leprae in the mouse footpad , described in 1960, and more recent studies in thymectomized-irradiated mi ce and rats, athymic nude mice, nude rats and severe combined immunodeficie ncy (SCID) mice have defined the role of T-cell mediated immunity (CMI) in leprosy. However, the normal mouse and the immunocompromised mouse and rat represent only elements of polar tuberculoid disease and polar lepromatous leprosy, respectively. Transgenic, knockout (KO) mice may be employed to st udy the roles of individual genes in the ability of the host to mount an ef fective immune response to pathogens, and may also allow development of mou se models for the immunologically unstable borderline areas of the spectrum . We are exploiting certain KO mice to improve our understanding of CMI to M. leprae, and to study the role of the microenvironment of the leprosy gra nuloma in pathogenesis. CGD (chronic granulomatous disease) mice and iNOS-K O mice lack the ability to produce reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), respectively, whereas the T cells of GKO mice are unable to produce interferon-gamma (IFN gamma). iNOS-KO mice exhibit an enhanced capacity to form granulomas, and the histopathology of the infected footpad tissues of this strain share many elements of borderli ne tuberculoid disease. The macrophages of CGD mouse kill or inhibit multip lication of M. leprae, although they lack ROI. Multiplication of the organi sms in the footpad is enhanced in GKO mice, although these mice retain some host resistance. In addition, we have been investigating supplementary, co nditional approaches to KO mouse models. For example, the down-regulatory e ffects of local prostaglandin production can be controlled with essential f atty acid deficient diets or indomethacin, RNI can be blocked in CGD and GK O mice by treatment with aminoguanidine, NG monomethyl arginine or N-6-(1-i minoethyl)-L-lysine, and local elaboration of TNF alpha can be neutralized by anti-TNF alpha antibody or excess TNF alpha receptor. Other cytokines ca n be neutralized by antibody as well, broadening the range of conditional k nockout models.