CD4+CD25+ T regs with acetylated FoxP3 are associated with immune suppression in human leprosy.

Leprosy is a chronic human disease that results from infection of Mycobacterium leprae. T reg cells have been shown to have important implications in various diseases. However, in leprosy, it is still unclear whether T regs can mediate immune suppression during progression of the disease. In the present study, we have proposed the putative mechanism leading to high proportion of T reg cells and investigated its significance in human leprosy. High levels of TGF-ß followed by adaptation of FoxP3(+) naive and memory (CD4(+)CD45RA(+)/RO(+)) T cells were observed as the principal underlying factors leading to higher generation of T reg cells during disease progression. Furthermore, TGF-ß was found to be associated with increased phosphorylation-mediated-nuclear-import of SMAD3 and NFAT towards BL/LL pole to facilitate FoxP3 expression in these cells, the same as justified after using nuclear inhibitors of SMAD3 (SIS3) and NFAT (cyclosporin A) in CD4(+)CD25(+) cells in the presence of TGF-ß and IL-2. Interestingly, low ubiquitination of FoxP3 in T reg cells of BL/LL patients was revealed to be a major driving force in conferring stability to FoxP3 which in turn is linked to suppressive potential of T regs. The present study has also pinpointed the presence of CD4(+)CD25(+)IL-10(+) sub class of T regs (Tr1) in leprosy.

Administration of Ag85B showed therapeutic effects to Th2-type cytokine-mediated acute phase atopic dermatitis by inducing regulatory T cells.

Increase in the number of patients with atopic dermatitis (AD) has been recently reported. T helper (Th) cells that infiltrate AD skin lesions are Th2-type dominant; reduced exposure to environmental Th1-cytokine-inducing microbes is believed to contribute to the increased number of AD patients. Regulatory type immune responses have been also associated with the occurrence of AD. It has been reported that antigen 85B (Ag85B) purified from mycobacteria is a potent inducer of Th1-type immune response in mice as well as in humans. In this study, we have examined the effect of plasmid DNA encoding Ag85B derived from Mycobacterium kansasii on AD skin lesions induced by oxazolone (OX) application. Th2-cytokine mediated mouse AD model with immediate type response followed by a late phase reaction was developed by repeated applications of low-dose OX to sensitized mice. Mice were immunized with plasmid DNA encoding cDNA of Ag85B before OX sensitization or during repeated elicitation phase. Both therapies were associated with significant suppression of immediate type response, clinical appearance, dermal cell infiltration, reduced IL-4 production, and augmented IFN-gamma mRNA expression compared to placebo-treated mice. Additionally, increased number of Foxp3(+) regulatory T cells were observed in the skin sections in Ag85B treated mice. The results of this study suggest that Ag85B DNA vaccine is a potential therapy for Th2 type dermatitis.

[Immunologic indices in a varying course of lepromatous leprosy]. / Immunologicheskie pokazateli pri razlichnom techenii lepromatoznoi lepry.

The study of the proliferative and regulatory functions of lymphocytes in patients with lepra of the lepromatous type has shown that at the active stage of the disease both the response of lymphocytes to mitogens and their suppressor functions are decreased. During the regression of the disease these characteristics are restored to the normal level only in patients with the relapse-free course of the disease, while patients with relapses in their medical history retain the low level of such characteristics. It is expedient to use these cell-mediated immunity characteristics as signs permitting the formation of risk groups of patients who may expect the relapse of the disease.

Effect of suppressor cells on antibody producing cells in mice infected with Mycobacterium leprae.

Swiss albino mice were transfused with suppressor cells obtained after in vivo stimulation of mice with Con A (NS group). Some of the animals were infected with Mycobacterium leprae (NSI-group). Half of these animals were treated with dapsone (NSIT group). Adequate normal (NC) and infected (NI) controls were included. A plaque assay was carried out at different time periods to elucidate the effect of suppressor cells on antibody producing cells. No significant difference was seen in the number of plaque forming cells (PFC) in infected and dapsone treated animals (NSIT) when these were compared with controls. However significant increase seen in the number of IgM plaque forming cells at 6 months in NI and NSI groups and IgG PFC in NI group could be due to the peak footpad infection during this period. The significant decrease in the number of IgG PFC in NS and NSIT group compared to NC at 0 month is probably due to the suppressor cell activity in these groups.

Effect of cyclosporine A in erythema nodosum leprosum.

Erythema nodosum leprosum (ENL) is a reactional state of lepromatous leprosy in which the loss of suppressor cell function, decrease in suppressor cell numbers, and increase of interleukin 2 production are observed. We reasoned that cyclosporine A (CsA), by opposing these immune responses, could suppress the ENL reaction and restore patients to the quiescent lepromatous state. We tested this hypothesis in vitro by measuring the effect of CsA on M. leprae-triggered suppressor cells. In 24 of 25 patients with ENL, suppressor cell activity was restored by CsA. The target of CsA appeared to be macrophages. These findings are significant in that they provide the first evidence for the potential efficacy of CsA in the treatment of ENL. Preliminary clinical trials indicate a beneficial therapeutic effect associated with increased T suppressor cells in lesions.

ConA-induced suppressor cells in lepromatous leprosy patients during and after erythema nodosum leprosum.

ConA-induced suppressor activity in patients with lepromatous leprosy (LL) was studied. Patients were studied during and after erythema nodosum leprosum (ENL) reactions. The study included 16 patients with ENL, nine of whom returned once the ENL episode was over. Patients were compared to 12 normal controls. Suppressor activity was evaluated in vitro by cultivating peripheral blood lymphocytes (PBL) with an inducer of T suppressor cells, concanavalin A (ConA), and with two different mitogens, phytohemagglutinin (PHA) and ConA, in order to measure the inhibition of the proliferative responses in all cases. In contrast, in LL patients during ENL the ConA-induced suppressor response was markedly reduced. The reduction in suppressor responses was even more marked in the LL patients after the ENL episode. Reduced levels of suppressor activity in LL patients reveal a defect in central mechanisms of control in the immune response.