Leishmania donovani-reactive Th1- and Th2-like T-cell clones from individuals who have recovered from visceral leishmaniasis

Abstract

Infections in humans by Leishmania donovani parasites can result in a fatal disease, visceral leishmaniasis (VL), or in a self-limiting asymptomatic infection. In murine models of the infection employing Leishmania major, the course of the disease can be directed into a VL-like syndrome by interleukin4 (IL-4)-producing Th2 cells, or cure may result by Thl cells secreting gamma interferon (IFN-y). The present study examined the potential of human T cells to generate Thl or Th2 responses to L. donovani. The profiles of IFN-y, ILA4, and lymphotoxin secretion after antigen stimulation were analyzed in a panel ofL. donovani-reactive CD4+ human T-celi clones generated from individuals who had recovered from VL after antimonial treatment. Two of the T-cell clones produced large amounts of IL-4 without production of IFN-y, seven clones produced both IFN-y and IL-4, and eight produced only IFN'y. This is the first report of a Thland Th2-type response in human leishmaniasis. These results suggest that in analogy with murine models, there is a dichotomy in the human T-cell response to L. donovani infections. Preferential activation of ILH4-producing Th2-like cells may be involved in the exacerbation of human VL, whereas activation of IFN-'y-producing Thl cells may protect the host from severe disease. Identification of leishmanial antigens activating one or the other type of T cells will be important in the development of vaccines against leishmaniasis.

Dichotomy of the human T cell response to Leishmania antigens. II. Absent or Th2-like response to gp63 and Thl-like response to lipophosphoglycan- associated protein in cells from cured visceral leishmaniasis patients

“…The mixed produclion of IFN-7 and IL-4 is in line wilh the recenl finding by our group that Lt=(.v/)»ifl/iio-reactive CD4' T cell clones isolated from cured visceral leishmaniasis patients can be either Th2. Thl, or ThO [19]. Similar findings have been reported in BALB/c mice infected with L. major.…”

The Leishmania promastigote surface antigen-2 (PSA-2) is specifically recognised by Th1 cells in humans with naturally acquired immunity to L. major

“…As for IFN-Q, TNF-L was produced in relatively large amounts by cells incubated with PSA-2 compared to tetanus toxoid-stimulated cells. The association between TNF-L and IFN-Q is in accordance with our previous observations of co-expression of these two cytokines in Leishmania-reactive CD4 T-cell clones [17].…”

Isobenzofuranone derivatives exhibit antileishmanial effect by inhibiting type II DNA topoisomerase and inducing host response

“…Leishmania donovani infection causes strong immunosuppressive effect in the host (Awasthi et al 2004) by downregulating the production of reactive oxygen species (ROS) and nitric oxide (NO) within the host macrophages (Lima-Junior et al 2013). Leishmania infection impairs the production of host protective (Th1) cytokines, for example, interferon-c (IFN-c), interleukin-12, and interleukin-2 and induces the production of the diseasepromoting (Th2) cytokines, for example, transforming growth factor b (TGF-b), interleukin-10, and interleukin-4 (Kemp et al 1993). Consequently, a potential therapy for leishmaniasis would not only be limited to the antileishmanial property of the molecule but also be to modulate immune responses mediated by the parasite-infected immune cells (Walker et al 1999).…”