Drug resistance in patients with leprosy in the United States.

Molecular drug susceptibility testing was performed on 39 US patients with leprosy. Of these, 2 had dapsone-resistant Mycobacterium leprae and 1 of these patients also had rifampin-resistant M. leprae. Even though antileprosy drug resistance occurs in this leprosy population, resistance does not appear to be a major problem.

In vitro thalidomide does not interfere with the activation of complement by M. leprae.

Erythema nodosum leprosum (ENL) is an inflammatory reaction that may occur in multibacillary leprosy patients, and thalidomide is the treatment of choice. Its cause and the mechanism by which thalidomide suppresses ENL are not known. In the skin lesions, im- mune complexes and split products of complement are found. The activation of complement could precipitate ENL, and thalidomide could suppress the inflammation by inhibiting the activation of complement. To determine if thalidomide could suppress the activation of complement, we first incubated normal serum with thalidomide and with M. leprae or zymosan. The amount of residual functional complement was then assessed by determining the dilution of serum required to lyses sheep erythrocytes sensitized by rabbit antibodies (CH50 Assay). M. leprae and zymosan activated complement. The residual complement activity in the serum incubated with M. leprae or with zymosan was equivalent to that incubated with M. leprae or zymosan in the presence of thalidomide, hydrolyzed thalidomide and metabolites of thalidomide. Thalidomide did not inhibit the activation of complement by zymosan, a known initiator of complement activation by the alternative pathway, or by M. leprae.

Activation of complement by Mycobacterium leprae requires disruption of the bacilli.

OBJECTIVE: The immune-mediated events that precipitate erythema nodosum leprosum (ENL) are not well understood. One component may be the complexing of antibody with antigens released from infected macrophages, the activation of complement and the subsequent local inflammation. We assess here the ability of highly-purified, disrupted M. leprae, to activate complement. RESULTS: Intact and sonically-disrupted crude and alkali-purified nu/nu mouse-derived M. leprae suspensions were incubated with normal serum and a hemolytic titer (CH50) was determined as a measure of complement fixation. Crude M. leprae consumed complement, and disrupted preparations more than the intact. Purified M. leprae preparations did not consume complement unless disrupted. CONCLUSION: M. leprae, if disrupted, can activate complement. This supports a hypothesis that links released antigens with ENL, and may explain the increased probability of an occurrence of ENL following chemotherapy.

Thalidomide can costimulate or suppress CD4+ cells' ability to incorporate [H3]-thymidine--dependence on the primary stimulant.

Thalidomide is a drug that can enhance mitogen- and antigen-stimulated cells' ability to synthesize IL-2. To assess if thalidomide could concomitantly enhance the synthesis of IFN-gamma and incorporation of [H3]-thymidine, peripheral blood mononuclear cells (PBMC) were incubated in the presence or absence of thalidomide and staphylococcal enterotoxin A (SEA), anti-CD3, Con-A or PHA. After 18 h, the cultures were sampled for IL-2. At the termination of the 3-day cultures, they were assayed for IFN-gamma and incorporation of [H3]-thymidine. Regardless of the mitogen used to stimulate the PBMC, the thalidomide-treated PBMC produced more IL-2 than controls. Thalidomide enhanced IFN-gamma synthesis in the Con-A and anti-CD3-stimulated PBMC. It suppressed the ability of SEA and PHA-stimulated PBMC to incorporate [H3]-thymidine, whereas it enhanced incorporation of [H3]-thymidine in PBMCs stimulated with anti-CD3. When the PBMC were enriched for CD4+ or CD8+ cells, the SEA- and anti-CD3-stimulated CD4+ cells responded far better than the CD8+ cells in the synthesis of IL-2 and incorporation of [H3]-thymidine. In the thalidomide-treated SEA-stimulated CD4+ and CD8+ cells, thalidomide acted as a costimulant to enhance the synthesis of IL-2. In the anti-CD3-stimulated thalidomide-treated cultures of PBMC enriched for CD4+ cells, thalidomide acted as a costimulant to enhance the incorporation [H3]-thymidine. Thalidomide cooperated with all of the mitogens to enhance T-cell synthesis of IL-2. However, depending on the stimulant, thalidomide could suppress or enhance PBMC incorporation of [H3]-thymidine. The SEA-stimulated cells targeted by thalidomide to suppress incorporation of [H3]-thymidine were CD4+. CD4+ cells stimulated with anti-CD3 were enhanced by thalidomide in their ability to synthesize IL-2 and to incorporate [H3]-thymidine. Increased production of IL-2 by activated T cells may be a mechanism through which thalidomide exerts its immunomodulatory effects.