Induction of antigen-specific immunity and tolerance to Mycobacterium leprae in Lewis rats.

Intradermal (i.d.) immunization of Lewis rats with autoclaved Mycobacterium leprae resulted in antigen-specific proliferation responses and interleukin-2 release from spleen and lymph node cells that were detectable as early as 21 days, persisted for at least 9 months, and were dependent on the dose of antigen administered. Immunized animals were also completely resistant to a footpad challenge with viable M. leprae. In contrast, intravenous (i.v.) administration of at least 10(8) irradiated M. leprae isolates induced a state of nonresponsiveness characterized by the absence of proliferation and interleukin-2 release by antigen-stimulated lymphoid cell cultures; however, in vitro responses to mitogenic stimulation and in vivo responses to keyhole limpet hemocyanin and Listeria monocytogenes were normal. Animals that received an i.v. injection of M. leprae remained nonresponsive to M. leprae antigens even after a subsequent i.d. immunization. This state of nonresponsiveness persisted for at least 6 months after induction. Results of footpad challenge experiments showed that the ability of animals rendered nonresponsive by an i.v. injection of M. leprae to control the growth of viable M. leprae in the footpad was not different from that of untreated rats. In addition, animals receiving an initial i.v. injection and a subsequent i.d. immunization with M. leprae were not protected from a viable challenge, as were rats that received only i.d. immunization. These results suggest that i.v. administration of a large dose of M. leprae to rats induces a state of nonresponsiveness to M. leprae antigens that may be similar to that seen in lepromatous leprosy patients.

Superiority of the neonatally thymectomized Lewis rat (NTLR) to monitor a clinical trial in lepromatous leprosy of the two regimens of rifampin and dapsone.

The ability of the neonatally thymectomized Lewis rat (NTLR) and the congenitally athymic (nude) rat systems to detect low numbers of viable Mycobacterium leprae in tissues from lepromatous leprosy patients undergoing short-course chemotherapy was compared with that of the commonly employed mouse foot pad assay. Fifteen previously untreated lepromatous patients were randomly assigned to treatment regimens of either a single initial 1500 mg dose of rifampin plus daily doses of 100 mg of dapsone, or weekly doses of 900 mg of rifampin plus daily doses of 100 mg of dapsone. Four skin biopsies from each patient taken sequentially up to one month after initiation of therapy were used as the source of the M. leprae inocula. Only 2 of 57 skin biopsies (2%) proved positive for viable M. leprae following direct inoculation into mouse foot pads. However, 30 of 58 patient biopsies (52%) provided positive for viable M. leprae following direct passage into NTLR foot pads or in subsequent mouse subpassage. In contrast, the nude rat was observed to be a poor monitor of such trials. Although not statistically significant, the regimen consisting of a single dose of rifampin plus daily dapsone resulted in a lower percentage of biopsies found to contain viable M. leprae at each of the four sampling intervals.

Effects of treatment with muramyl dipeptide on resistance to Mycobacterium leprae and Mycobacterium marinum infection in mice.

Studies were carried out to determine whether treatment of mice with the synthetic adjuvant muramyl dipeptide (MDP) afforded resistance to infection with Mycobacterium leprae or M. marinum in mice. Regardless of the timing, dose, or route of administration, there was no evidence that treatment with MDP or 3 of its analogs (desMDP, abuMDP, valMDP) enhanced resistance to food pad infection with M. leprae or M. marinum. In parallel studies, systemic treatment with Propionibacterium acnes failed to protect against either M. leprae or M. marinum. Administration of P. acnes locally into the foot pad afforded marginal resistance to M. marinum when injected prior to infection. Local treatment with P. acnes afforded marked resistance to growth of M. leprae, even when administered months after infection.

Suppressed natural killer cell activity during episodes of erythema nodosum leprosum in lepromatous leprosy.

Natural killer (NK) cell activity was investigated in peripheral blood mononuclear cells of patients with leprosy. The NK activity of patients with borderline or lepromatous leprosy did not differ significantly from that of normal subjects. However, in a group of patients with lepromatous leprosy undergoing an episode of erythema nodosum leprosum (ENL), NK activity was significantly depressed. In four patients with ENL, NK activity was virtually abolished. Depressed NK activity could not be attributed to the effects of corticosteroid therapy, nor did a serum factor appear to be responsible. Evidence was obtained that depressed NK activity in patients with ENL was not due to dysfunction of the NK cells themselves; they functioned normally when separated from the individual's total mononuclear cell population. Additional cell depletion studies suggested that the patients' monocytes were responsible for the observed depression of NK activity.

Effects of Propionibacterium acnes treatment on the course of Mycobacterium leprae infection in mice.

Studies were carried out to determine the effects of treatment with killed suspensions of Propionibacterium acnes (formerly designated Corynebacterium parvum) on the course of Mycobacterium leprae infection in mice. Systemic (intravenous or intraperitoneal) treatment with P. acnes failed to significantly alter the growth of M. leprae in the mouse footpad. In contrast, injections of P. acnes directly into the infected footpad markedly inhibited the growth of the leprosy bacilli regardless of whether the local treatments were administered before infection or 3 months after infection with M. leprae. The effects of local treatment with P. acnes appeared to be bactericidal and not merely bacteriostatic. Clearance of the organism from the tissues was not enhanced by P. acnes treatment.