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Recombinant Human IFN- Inhibits Cerebral Malaria and Reduces Parasite Burden in Mice¹

Ana Margarida Vigário^*,,,,¶, Elodie Belnoue^2,*,,,, Anne Charlotte Grüner^*,,,, Marjorie Mauduit^*,,,, Michèle Kayibanda^*,,,, Jean-Christophe Deschemin^*,,,, Myriam Marussig^||, Georges Snounou, Dominique Mazier^||, Ion Gresser^* and Laurent Rénia^3,*,,,

^* Institut Cochin, Département d’Immunologie, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 567, Paris, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France; Université René Descartes, Hôpital Cochin, Paris, France; ^¶ Instituto Gulbenkian de Ciências, Oeiras, Portugal; ^|| Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S511, Paris, France; ^# Assistance Publique-Hopitaux de Paris, Groupe hospitalier Pitié-Salpétrière, Service Parasitologie Mycologie, Paris, France; ^** INSERM Unité 511, Paris, France; Equipe Parasitologie Comparée et Modèles Expérimentaux Unite Scientifique de Museum 0307, Centre National de la Recherche Scientifique Institut Federatif de Recherche 101, Muséum National d’Histoire Naturelle, Paris, France; and ^* INSERM Unité 255, Institut des Cordeliers, Paris, France

Most C57BL/6 mice infected i.p. with Plasmodium berghei ANKA (PbA) die between 7 and 14 days with neurologic signs, and the remainder die later (>15 days) with severe anemia. Daily i.p. injections of a recombinant human IFN- (active on mouse cells) prevented death by cerebral malaria (87% deaths in the control mice vs 6% in IFN--treated mice). The mechanisms of this IFN- protective effect were multiple. IFN--treated, PbA-infected mice showed 1) a marked decrease in the number of PbA parasites in the blood mediated by IFN-, 2) less sequestered parasites in cerebral vessels, 3) reduced up-regulation of ICAM-1 expression in brain endothelial cells, 4) milder rise of blood levels of TNF, 5) increased levels of IFN- in the blood resulting from an increased production by splenic CD8⁺ T cells, and 6) fewer leukocytes (especially CD8⁺ T cells) sequestered in cerebral vessels. On the other hand, IFN- treatment did not affect the marked anemia observed in PbA-infected mice. Survival time in IFN--treated mice was further increased by performing three blood transfusions over consecutive days.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported in part by grants from INSERM, Fundação para Ciencias e Technologia, Fondation de La Recherche Médicale (10000017), Association Française du Sang (96007), and Fondation Electricité et Santé (to L.R.). A.M.V. held a fellowship from Fundação para a Ciência e a Tecnologia (BD9255/96). E.B. held a fellowship from Ministere de L’Education Nationale, de la Recherche et de la Technologie. A.C.G. was supported by a grant from the Carlsberg Foundation.

² Current address: Center for Vaccinology and Neonatal Immunology, University of Geneva, Centre Medical Universitaire, Geneva, Switzerland.

³ Address correspondence and reprint requests to Dr. Laurent Rénia, Département d’Immunologie, Institut Cochin, Hôpital Cochin, Bâtiment Gustave Roussy, 27 rue du Fb St. Jacques, 75014 Paris, France. E-mail address: renia{at}cochin.inserm.fr

⁴ Abbreviations used in this paper: CM, cerebral malaria; BSL, brain-sequestered leukocyte; Hb, hemoglobin; iRBC, infected RBC; PbA, Plasmodium berghei ANKA.

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