Cytokine profile and pathology in human leishmaniasis

Abstract

The clinical spectrum of leishmaniasis and control of the infection are influenced by the parasite-host relationship. The role of cellular immune responses of the Th1 type in the protection against disease in experimental and human leishmaniasis is well established. In humans, production of IFN-γ is associated with the control of infection in children infected by Leishmania chagasi. In visceral leishmaniasis, an impairment in IFN-γ production and high IL-4 and IL-10 levels (Th2 cytokines) are observed in antigen-stimulated peripheral blood mononuclear cells (PBMC). Moreover, IL-12 restores IFN-γ production and enhances the cytotoxic response. IL-10 is the cytokine involved in down-regulation of IFN-γ production, since anti-IL-10 monoclonal antibody (mAb) restores in vitro IFN-γ production and lymphoproliferative responses, and IL-10 abrogates the effect of IL-12. In cutaneous and mucosal leishmaniasis, high levels of IFN-γ are found in L. amazonensis-stimulated PBMC. However, low or absent IFN-γ levels were observed in antigen-stimulated PBMC from 50% of subjects with less than 60 days of disease (24 ± 26 pg/ml). This response was restored by IL-12 (308 ± 342 pg/ml) and anti-IL-10 mAb (380 ± 245 pg/ml) (P<0.05). Later during the disease, high levels of IFN-γ and TNF-α are produced both in cutaneous and mucosal leishmaniasis. After treatment there is a decrease in TNF-α levels (366 ± 224 pg/ml before treatment vs 142 ± 107 pg/ml after treatment, P = 0.02). Although production of IFN-γ and TNF-α might be involved in the control of parasite multiplication in the early phases of Leishmania infection, these cytokines might also be involved in the tissue damage seen in tegumentary leishmaniasis.Correspondence

T-Cell-Mediated Immune Responses in Patients with Cutaneous or Mucosal Leishmaniasis: Long-Term Evaluation after Therapy

“…Previous studies have associated the induction of cytokines such as IFN-␥ or tumor necrosis factor alpha, as well as the increased expression of mucosal IL-4 in mucosal lesions with the pathogenesis of the disease (5,6,13,26). Thus, it is likely that the observed exacerbated hypersensitivity to leishmanial antigens in ML associated with high production of both cytokine types may have a detrimental effect, contributing to the severity of the disease (5,6,13,27). Indeed, stronger intradermal leishmanin test and lymphoproliferative responses, as well as higher frequencies of L. braziliensis-reactive T cells and higher specific cytotoxic activity have been observed in patients with ML compared to patients with CL (3,5,6,8,28).…”

“…Thus, most of the knowledge on the immune responses in CL and ML caused by L. braziliensis has originated from studies of patients (5,11,12,17,27,28). Therefore, human tegumentary leishmaniasis does not present a clearly polarized Th1 or Th2 immune response as observed in the mouse-L. major experimental model (11).…”

“…However, the magnitude of the T-cell responses tends to be greater in patients with ML than in patients with CL (5,6,8,28), suggesting that patients with ML present an exacerbated hypersensitivity to parasite antigens, which may have a detrimental effect on aggravation of lesions. On the other hand, well-modulated T-cell-mediated responses as usually observed in CL may have a beneficial effect, leading to mild lesions and susceptibility to therapy (5,6,19,22,27,28).…”

SHORT REPORT: PERSISTENCE OF TUMOR NECROSIS FACTOR-α IN SITU AFTER LESION HEALING IN MUCOSAL LEISHMANIASIS

“…3 Tumor necrosis factor-␣ (TNF-␣), a cytokine involved in the development of lesions in several infections, 4,5 has also been implicated in ML 6 because of high serum levels of TNF-␣ in ML patients during active disease 6,7 and greater production in vitro by stimulated blood mononuclear cells. 8 The production of TNF-␣ in ML patients could be related to regulatory genetic polymorphisms. 9 The local production of this cytokine has been demonstrated in active ML lesions, but no data concerning post-therapy was evaluated.…”

Antihelminthic Therapy and Antimony in Cutaneous Leishmaniasis: A Randomized, Double-Blind, Placebo-Controlled Trial in Patients Co-Infected with Helminths and Leishmania braziliensis

“…2,3 A T H 1-type immune response is crucial in controlling Leishmania infection, with release of interferon-gamma (IFN-γ) leading to activation of macrophages, and killing of the intracellular parasite. However, excessive T H 1 cytokines have also been implicated in the pathogenesis of CL 4,5 and several lines of evidence support this information: 1) parasites are absent or scarce in CL lesions 6 ; 2) ulceration is preceded by a granulomatous vasculitis with lymphocytic infiltration 7 ; 3) use of antimony in the early pre-ulcer phase of CL does not prevent lesion formation 7 ; 4) pre-treatment elevations in IFN-γ and tumor necrosis factor-α (TNF-α) decrease with treatment 8 ; 5) immune modulatory drugs combined with Sb v accelerate healing in cutaneous and mucosal leishmaniasis. 9,10 Chronic infection with helminths is highly prevalent in rural areas in Brazil.…”