Immunological Cytokine Correlates of Protective Immunity and Pathogenesis in Leprosy

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Abstract
The in vitro production of interferon (IFN)-γ, interleukin (IL)-5, tumour necrosis factor (TNF)-α and IL-10 by blood mononuclear cells in response to whole Mycobacterium leprae and polyclonal stimulii of 23 individuals, representing a variety of conditions in relation to exposure/susceptibility to M. leprae, was assayed. In most cases, healthy household contacts of newly diagnosed multibacillary leprosy patients, designated exposed household contacts (EC), showed low-to-undetectable in vitro IFN-γ production in addition to substantial TNF-α production in response to M. leprae. In contrast, peripheral blood mononuclear cells from previously exposed contacts (R) regarded as resistant-to-leprosy released low-to-moderate levels of IFN-γ together with a mixed cytokine profile resembling a T helper (Th)0-type response. TNF-α/IL-10 ratios in response to M. leprae and Concanavalin A were significantly higher in EC than in R contacts suggesting a role for the TNF-α/IL-10 ratio in restraining mycobacteria proliferation and spreading early in infection. The cytokine profiles of leprosy patients were taken as reference points. Post-treatment lepromatous leprosy patients secreted relatively high levels of IL-10 in response to M. leprae, whereas one self-cured tuberculoid leprosy patient produced simultaneously high levels of IFN-γ and TNF-α. In addition, the quantitative changes in the cytokines released by peripheral blood mononuclear cells in EC contacts after Bacille Calmette-Guérin (BCG) vaccination were investigated. Vaccination induced amplification of IFN-γ production with a concomitant decrease in TNF-α/IL-10 ratios that resembled the cytokine pattern observed in R contacts. IFN-γ production was observed in response to both a cross-reactive antigen (Ag 85) and a M. leprae-specific protein (MMP-I), which attests to a BCG nonspecific stimulation of the immune system, thereby casting these antigens as likely candidates for inclusion in a subunit vaccine against leprosy. Finally, a model for protective × pathologic response to mycobacteria is presented.