Th1/Th2 immune responses are associated with active cutaneous leishmaniasis and clinical cure is associated with strong interferon- production LÛcio Roberto Castellano a , Dalmo Correia Filho a , Laurent Argiro b , Helia Dessein b , AluÎzio Prata a , Alain Dessein b , Virmondes Rodrigues a, * a Laboratory of Immunology, Universidade Federal do Triángulo Mineiro, Minas Gerais, Brazil b Laboratory of Parasitology Mycology, Faculty of Medicine, U399 INSERM, Marseille, France ARTICLE INFO Article history: Received 4 October 2008 Accepted 15 January 2009 Available online 20 January 2009 Keywords: Cutaneous leishmaniasis Cytokines Antibodies IFN-gamma IL-10 ABSTRACT In leishmaniasis, Th1-related cytokines production seems to be crucial for host control of parasite burden and clinical cure. Visceral and diffuse cutaneous leishmaniasis are characterized by negative skin test for parasite antigens and failure to produce Th1 cytokines, whereas tegumentary leishmaniasis is characterized by positive skin test and the ability of peripheral blood mononuclear cells (PBMCs) to produce Th1 cytokines. In this study, specific antibody plasma levels and cytokine production in PBMC culture supernatants were evaluated by enzyme-linked immunoabsorbent assay in patients with active or cured cutaneous leishmanial lesions and in subjects without disease history living in the same endemic area. Higher tumor necrosis factor–, interferon (IFN)–, interleukin (IL)–12, IL-4, and IL-10 levels were observed in patients with active lesions, whereas cured subjects produced only IFN- at elevated levels. Analysis of specific antibody isotypes correlate with cellular immune response observed in vitro, as the production of IgG1 and IgG3 was higher in patients with active lesions. Our results suggest the presence of a mixed Th1/Th2 response during active disease and that clinical cure is associated with a sustained Th1 response characterized by elevated IFN- levels and down-modulation of IL-4 and IL-10 production.  2009 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. Introduction Leishmaniasis is a complex of diseases caused by the intracellu- lar protozoan parasite Leishmania that affects more than 12 million persons worldwide. Clinical manifestation is broad, ranging from single cutaneous lesions to lethal visceral infection. Development into different clinical forms is associated with both the immuno- logic status of the host and the parasite species. Both Leishmania (L.) amazonensis and L. (Viannia) braziliensis cause localized cutaneous leishmaniasis (LCL), although subsequent progression to diffuse cutaneous leishmaniasis in more susceptible individuals is nor- mally attributed to L. amazonensis. Mucosal leishmaniasis is usually associated with L. (V.) braziliensis. Whereas diffuse cutaneous leish- maniasis is characterized by large numbers of parasites and a lack of cell-mediated immunity to Leishmania antigens, cutaneous and mucosal leishmaniasis are generally accompanied by strong cellu- lar responses and sparse numbers of parasites in the lesions [1]. In experimental models, it is widely accepted that susceptibility of BALB/c mice to L. major infection is associated with interleukin (IL)– 4 and IL-10 –producing Th2-type T cells, whereas resistance is related to early and persistent interferon (IFN)– production (Th1) [2]. However, this dichotomy is not so clear in human infection. High IFN- production was found to be associated with spontane- ous healing [3]. Simultaneous production of IFN-, tumor necrosis factor (TNF)–, and IL-10 by antigen-stimulated peripheral blood mononucleaer cells (PBMCs) from patients with active lesions [4] and IL-2, IL-4, IL-5, IL-10, and IFN- mRNAs were demonstrated in biopsy samples taken from active lesions [5– 8]. IL-10 expression was also significantly higher in patients who responded poorly to pentamidine treatment [5]. In a previous study, our group showed a major role of IL-10 in the development of skin lesions in human beings infected with L. (V.) braziliensis [9]. Analysis of the antibody response in LCL patients revealed ele- vated anti-Leishmania IgG antibodies plasma levels, mainly IgG1 and IgG3 isotypes [10 –12]. Although the protective role of antibod- ies in leishmaniasis is questionable, it is useful for diagnosis and for predicting in vivo cellular immune responses. In the present study, we analyzed cytokines involved in T– helper cell balance and specific antibody isotypes in patients with active cutaneous leishmaniasis, individuals with cured leishmaniasis, and individuals without lesions living in the same endemic area. 2. Subjects and methods 2.1. Subjects The study population included 20 patients with active infection characterized by typical lesions and positive Montenegro skin test * Corresponding author. E-mail address: vrodrigues@mednet.com.br (V. Rodrigues, Jr.). Human Immunology 70 (2009) 383-390 Contents lists available at ScienceDirect 0198-8859/09/$32.00 - see front matter  2009 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.humimm.2009.01.007