SummaryThalidomide selectively inhibits the production of human monocyte tumor necrosis factor a (TNF-a) when these cells are triggered with lipopolysaccharide and other agonists in culture. 40% inhibition occurs at the clinically achievable dose of the drug of 1 Ag/ml . In contrast, the amount of total protein and individual proteins labeled with [31 S]methionine and expressed on SDS-PAGE are not influenced . The amounts of interleukin 10 (11,1(3), Ilr6, and granulocyte/ macrophage colony-stimulating factor produced by monorytes remain unaltered . The selectivity of this drug may be useful in determining the role of TNF-a in vivo and modulating its toxic effects in a clinical setting.

SummaryWe have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor ot (TNF<~) production and found that the drug enhances the degradation of TNF-oe mRNA. Thus, the half-life of the molecule was reduced from "o30 to ~o17 rain in the presence of 50/zg/ml of thalidomide. Inhibition of TNF-ot production was selective, as other LPS-induced monocyte cytokines were unaffected. PentoxifyUine and dexamethasone, two other inhibitors of TNF-c~ production, are known to exert their effects by means of different mechanisms, suggesting that the three agents inhibit TNF-c~ synthesis at distinct points of the cytokine biosynthetic pathway. These observations provide an explanation for the synergistic effects of these drugs. The selective inhibition of TNF-cr production makes thalidomide an ideal candidate for the treatment of inflammatory conditions where TNF-c~-induced toxicities are observed and where immunity must remain intact.

Diagnosis of leprosy is a major obstacle to disease control and has been compromised in the past due to the lack of specific reagents. We have used comparative genome analysis to identify genes that are specific to Mycobacterium leprae and tested both recombinant proteins and synthetic peptides from a subset of these for immunological reactivity. Four unique recombinant proteins (ML0008, ML0126, ML1057, and ML2567) and a panel of 58 peptides (15 and 9 mer) were tested for IFN-γ responses in PBMC from leprosy patients and contacts, tuberculosis patients, and endemic and nonendemic controls. The responses to the four recombinant proteins gave higher levels of IFN-γ production, but less specificity, than the peptides. Thirty-five peptides showed IFN-γ responses only in the paucibacillary leprosy and household contact groups, with no responses in the tuberculosis or endemic control groups. High frequencies of IFN-γ-producing CD4+ and CD8+ T cells specific for the 15- and 9-mer peptides were observed in the blood of a paucibacillary leprosy patient. 9-mer peptides preferentially activated CD8+ T cells, while the 15-mer peptides were efficient in inducing responses in both the CD4+ and CD8+ T cell subsets. Four of the six 9-mer peptides tested showed promising specificity, indicating that CD8+ T cell epitopes may also have diagnostic potential. Those peptides that provide specific responses in leprosy patients from an endemic setting could potentially be developed into a rapid diagnostic test for the early detection of M. leprae infection and epidemiological surveys of the incidence of leprosy, of which little is known.

SummaryTo elucidate further the possible role of the tryptophan, rate-limiting enzyme indoleamine 2, 3-dioxygenase (IDO) in leprosy, the distribution of IDOpositive cells and IDO activity in the skin biopsies and sera of these patients representing the entire spectrum of the disease were studied.

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