Experimental autoimmune encephalomyelitis can be prevented and cured by infection with Trypanosoma cruzi Carlos E. Tadokoro a , Adriana L. Vallochi a , Lı´lia S. Rios a , Gislˆaine A. Martins a , David Schlesinger a , Taina´ Mosca a , Vijay K. Kuchroo b , Luiz V. Rizzo a,c,d , Ises A. Abrahamsohn a, ) a Institute of Biomedical Sciences, Department of Immunology, University of Sa ˜o Paulo, Av. Prof. Lineu Prestes, 1730, ICB/USP - Ed. BIO IV, 05508-900 Sa ˜o Paulo, Brazil b Center of Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA c Hospital das Clı´nicas, Division of Allergy and Clinical Immunology, Laboratory of Medical Investigation-60, School of Medicine, University of Sa ˜o Paulo, Sa ˜o Paulo, Brazil d Fundac xa ˜o Zerbini, Sa ˜o Paulo, Brazil Received 18 September 2003; revised 29 April 2004; accepted 12 May 2004 Abstract Trypanosoma cruzi is an intracellular parasite that induces a strong Th1-type response and immunosuppression during the acute phase of infection. To study how the infection with T. cruzi would modulate the development of an autoimmune disease, we immunized C57BL/6 mice and IL-10 or iNOS knock-out mice of the same background with the encephalitogenic MOG 35e55 peptide and infected them with T. cruzi. Our results demonstrate that infection with T. cruzi completely prevents EAE development and furthermore induces complete and lasting remission in mice that were infected with this parasite after they had developed clinical EAE. Nitric oxide and IL-10 participate in triggering the mechanisms associated with EAE suppression by the infection. Decreased lymphoproliferation and increased frequencies of Annexin-positive cells and of T cells bearing CD95, CD95L or CTLA-4 were observed in the spleen from immunized/infected mice, as well as lower IL-2 and increased TGF-beta production in comparison with only immunized mice. Our results indicate that several effector and regulatory mechanisms of the immune response that arise during the acute phase of T. cruzi infection lastingly affect the expansion and/or effector functions of encephalitogenic cells, preventing the onset or inducing complete remission of EAE. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Cytokines; EAE; Nitric oxide; Suppression; Trypanosoma cruzi 1. Introduction Chagas’ Disease is a tropical endemic disease caused by the intracellular protozoa Trypanosoma cruzi [1]. In the course of infection of humans and in resistant mouse strains it is often possible to identify an acute phase during which, for a variable period of time, parasites can be easily detected in the blood. This phase is followed by a chronic phase, when parasites in the blood are scarce [1]. Infection of mice with the Y strain of T. cruzi leads to a progressive increase in the number of parasites in the blood ( parasitemia) until a maximum is reached, followed by its abrupt decrease. During the acute phase, there is marked enlargement of the spleen as a result of the increased number of cells in the organ [2]. At the same time, spleen cells progressively loose their ability to proliferate when stimulated with parasite antigens or mitogens [3], characterizing a state of immunosup- pression. Many factors have been identified as being responsible for this phenomenon: enhanced nitric oxide (NO) production by macrophages stimulated by IFN-g and/or TNF-a [3], decrease in IL-2 synthesis as well as of one of its receptors [3e5], enhanced prostaglandin E 2 synthesis [6], and increased expression of CD95 and ) Corresponding author. Tel.: +55-11-3091-7383; fax: +55-11- 3091-7224. E-mail address: iabraham@usp.br (I.A. Abrahamsohn). Journal of Autoimmunity 23 (2004) 103e115 www.elsevier.com/locate/issn/08968411 0896-8411/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2004.05.003