Recovery of IFN-gamma levels in PBMCs from lepromatous leprosy patients through the synergistic actions of the cytokines IL-12 and IL-18.

The shift to the production of a Th1 cytokine profile during an intracellular infection has been shown to depend on antigen presenting cells-derived IL-12 and T-cell-derived IFN-gamma production. IL-18 facilitates Th1 priming in synergy with IL-12 through the stimulation of IFN-gamma production by T cells, B cells, NK cells, macrophages and DCs. A low level of IFN-gamma production in PBMC cultures from lepromatous leprosy patients (LL) has been previously reported by several groups. We evaluated the synthesis of this cytokine after exogenous addition of recombinant IL-12 and IL-18 (IL12/IL18) in order to induce recovery of the IFN-gamma levels with Mycobacterium leprae antigenic stimulation. The aim of this study was to investigate if exogenous addition of IL12/IL18 to PBMC cell cultures in the presence of M. leprae antigens could induce recovery of IFN-gamma levels. We found that IFN-gamma levels in PBMCs cultured from LL patients were reestablished after exogenous addition of exogenous IL12/IL18 and we also observed a diminished IL-18R expression. Although the molecular mechanisms of IL12/IL18 synergy have not been clearly elucidated, we assume that recombinant cytokines can activate several transcription factors that induce IFN-gamma synthesis.

Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement.

Sarcoidosis, a chronic granulomatous disease of unknown etiology, is treated with immune suppressive drugs such as corticosteroids. Sarcoidosis patients have been reported to benefit clinically from treatment with thalidomide. We administered thalidomide for 16 weeks to eight patients with chronic skin sarcoidosis and evaluated the drug's effects before and with treatment. After thalidomide treatment, all skin biopsies showed decreases in granuloma size and reduction in epidermal thickness. We also observed extensive T cell recruitment into the granulomas, the appearance of multinucleated giant cells, and increased numbers of dermal Langerhans cells (CD1a(+)) and mature dendritic cells (CD83(+) or DC-LAMP(+)). Plasma IL-12 levels increased and remained elevated during the treatment period. We noted increased HLA-DR expression on peripheral blood lymphocytes and a corresponding drop in the naive T cell marker CD45RA. Our data suggest that thalidomide treatment of sarcoidosis results in granuloma differentiation to a Th1-type cellular immune response usually associated with protective immunity to tuberculosis and tuberculoid leprosy.

Thalidomide does not perturb CD2, CD4, CD5, CD8, HLA-DR, or HLA-A, B, C molecules in vitro on the membranes of cells with immune potential.

Thalidomide dramatically relieves the signs and symptoms of erythema nodosum leprosum (ENL). ENL is an acute inflammatory complication of lepromatous leprosy. The cause(s) of ENL as well as the mechanism of action of thalidomide in arresting ENL are unknowns. It has been suggested that ENL is the consequence of a transient activation of a cell-mediated-immune (CMI) response to Mycobacterium leprae. To initiate a CMI response, an interaction between adhesion and/or signal transducing molecules on T-cells and molecules on antigen presenting cells would occur. An alteration, induced by thalidomide, of one or more of the molecules on T-cells or antigen presenting cells that are essential to maintaining the reactive state of ENL, could explain Thalidomide's ability to attenuate ENL. Thalidomide did not modify: (a) adhesion and/or signal transducing molecules such as CD2, CD4, CD5 and CD8, or (b) molecules that facilitate antigen presentation such as HLA-DR, HLA-A, HLA-B, or HLA-C.