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      Immunosuppression with cyclophosphamide favors reinfection with recombinant Toxoplasma gondii strains Translated title: L’immunosuppression par la cyclophosphamide favorise la réinfection par différentes souches recombinantes de Toxoplasma gondii

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          The aim of this study was to verify the effect of immunosuppression by cyclophosphamide (Cy) on susceptibility of BALB/c mice subjected to challenge with recombinant strains of Toxoplasma gondii. Animals were prime infected with the D8 (recombinant I/III) or the ME49 (type II) non-virulent strains, weekly immunosuppressed with Cy and challenged with the CH3 or EGS virulent strains (I/III). Parasites recovered from surviving mice were submitted to PCR-RFLP analysis to confirm co-infection. Prime-infection with the D8 strain conferred more protection against challenge with the CH3 and EGS strains when compared with ME49 prime infection. Cy treatment caused significant leukopenia in the infected mice, what probably favors reinfection after challenge. Reinfection was associated with increased levels of IgA. Otherwise, Cy-treated mice presented significantly lower IgA levels after challenge, suggesting involvement of this immunoglobulin on protection against reinfection. In conclusion, BALB/c mice susceptibility to reinfection by T. gondii is related to genetic differences among the strains used for primary and challenge infections. Alteration of the host’s immune integrity by Cy probably compromises the protection previously established by primary infection.

          Translated abstract

          L’objectif de cette étude était de vérifier l’effet de l’immunosuppression par la cyclophosphamide (Cy) sur la susceptibilité de souris BALB/c soumises à la réinfection par des souches recombinantes de Toxoplasma gondii. Les souris ont été infectées par des souches non virulentes de T. gondii : D8 (recombinant I/III) ou la souche ME49 (type II), et immunosupprimées avec Cy une fois par semaine pendant un mois et après infection d’épreuve par les souches virulentes CH3 ou EGS (I/III). Les parasites récupérés sur les souris survivantes ont été soumis à l’analyse par PCR-RFLP pour confirmer la co-infection. Des anticorps spécifiques à T. gondii ont été analysés par ELISA. La primo infection par la souche D8 a conféré une protection contre l’infection par les souches CH3 et EGS en comparaison avec la primo infection par ME49. Le traitement Cy a causé une leucopénie significative chez les souris infectées, ce qui a favorisé probablement la réinfection après infection d’épreuve. La réinfection était associée à une augmentation du niveau d’IgA. Les souris traitées par Cy ont présenté des niveaux d’IgA significativement plus faibles après infection d’épreuve, suggérant l’implication de cet isotype sur la protection contre la réinfection. En conclusion, la sensibilité des souris BALB/c à la réinfection par T. gondii est liée à des différences génétiques entre les souches de parasites utilisées pour les primo infections et pour les infections d’épreuve. L’altération de l’intégrité immunitaire de l’hôte par le traitment avec la Cy a probablement compromis la protection établie préalablement par la primo infection.

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          Most cited references 19

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          Congenital toxoplasmosis and reinfection during pregnancy: case report, strain characterization, experimental model of reinfection, and review.

          We present a case of disseminated congenital toxoplasmosis in a newborn born to a mother who had been immunized against toxoplasmosis before conception. The mother was reinfected, likely by ingestion of imported raw horse meat during pregnancy. This clinical presentation is exceptional in France and raised the possibility of infection by a highly virulent Toxoplasma strain. The strain responsible was isolated from the peripheral blood of the newborn, and when genotyped with microsatellite markers, it exhibited an atypical genotype, one which is very uncommon in Europe but had been described in South America. We tested the hypothesis of a reinfection with a different genotype by using an experimental mouse model, which confirmed that acquired immunity against European Toxoplasma strains may not protect against reinfection by atypical strains acquired during travel outside Europe or by eating imported meat.
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            Immunosuppressive drugs: the first 50 years and a glance forward.

            During the past 50 years, many immunosuppressive drugs have been described. Often their mechanisms of action were established long after their discovery. Eventually these mechanisms were found to fall into five groups: (i) regulators of gene expression; (ii) alkylating agents; (iii) inhibitors of de novo purine synthesis; (iv) inhibitors of de novo pyrimidine synthesis; and (v) inhibitors of kinases and phosphatases. Glucocorticoids exert immunosuppressive and anti-inflammatory activity mainly by inhibiting the expression of genes for interleukin-2 and other mediators. Cyclophosphamide metabolites alkylate DNA bases and preferentially suppress immune responses mediated by B-lymphocytes. Methotrexate and its polyglutamate derivatives suppress inflammatory responses through release of adenosine; they suppress immune responses by inducing the apoptosis of activated T-lymphocytes and inhibiting the synthesis of both purines and pyrimidines. Azathioprine metabolites inhibit several enzymes of purine synthesis. Mycophenolic acid and mizoribine inhibit inosine monophosphate dehydrogenase, thereby depleting guanosine nucleotides. Mycophenolic acid induces apoptosis of activated T-lymphocytes. A leflunomide metabolite and Brequinar inhibit dihydroorotate dehydrogenase, thereby suppressing pyrimidine nucleotide synthesis. Cyclosporine and FK-506 (Tacrolimus) inhibit the phosphatase activity of calcineurin, thereby suppressing the production of IL-2 and other cytokines. In addition, these compounds have recently been found to block the JNK and p38 signaling pathways triggered by antigen recognition in T-cells. In contrast, rapamycin inhibits kinases required for cell cycling and responses to IL-2. Rapamycin also induces apoptosis of activated T-lymphocytes. Immunosuppressive and anti-inflammatory compounds in development include inhibitors of p38 kinase and of the type IV isoform of cyclic AMP phosphodiesterase which is expressed in lymphocytes and monocytes.A promising future application of immunosuppressive drugs is their use in a regime to induce tolerance to allografts. The role of leukocytes in grafts, and the induction of apoptosis of clones of responding T-lymphocytes, is discussed.
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              Congenital and acquired toxoplasmosis: diversity and role of antibodies in different compartments of the host.

              The apicomplexan parasite Toxoplasma gondii is remarkable in several aspects, since it is a protozoan that infects most nucleated cells in many warm-blooded animals, worldwide. Although the cellular immune response against T. gondii is critical for infection control, antibodies may either enhance or block protective mechanisms, and even mediate immunological damage, directly or indirectly. Since cytokines regulate the class/subclass switch, antibodies may also be the biomarkers of protective or pathological cellular immune events. There is a scientific and clinical interest in the presence of natural and autoreactive antibodies, as well as in the 'chronic' immunoglobulin M (IgM) response and the post-treatment 'rebound'. Another interesting aspect is compartmentalization; certain immunoglobulins may uniquely be found in specific host fluids. Local synthesis has been demonstrated, but antibodies may also traverse several cell layers, like the blood-brain and haemato-ocular barriers, and the placenta. In some instances, Fc receptors (FcRs) facilitate transport and may even have a concentrator effect, which can be related to resistance or pathology. These aspects of the humoral response against T. gondii are reviewed in the present paper.

                Author and article information

                Parasite : journal de la Société Française de Parasitologie
                EDP Sciences
                August 2012
                15 August 2012
                : 19
                : 3 ( publisher-idID: parasite/2012/03 )
                : 249-257
                [1 ] Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG) Av. Antonio Carlos 6627 31270-901 Belo Horizonte, MG Brazil
                Author notes
                [* ]Correspondence: Ricardo Wagner de Almeida Vitor. Tel.: 55 31 34092875 – Fax: 55 31 34092970. E-mail: ricardovitor@ 123456icb.ufmg.br
                parasite2012193p249 10.1051/parasite/2012193249
                © PRINCEPS Editions, Paris, 2012

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 24, Pages: 9
                Original Contribution


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