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Infection and Immunity, November 2002, p. 6284-6293, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6284-6293.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Interleukin-10 (IL-10) in Experimental Visceral Leishmaniasis and IL-10 Receptor Blockade as Immunotherapy

Henry W. Murray,1* Christina M. Lu,1 Smita Mauze,2 Sherry Freeman,3 Andre L. Moreira,4 Gilla Kaplan,3 and Robert L. Coffman2,{dagger}

Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021,1 Department of Immunology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California 94304,2 Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021,3 Department of Pathology, New York University School of Medicine, New York, New York 100164

Received 11 March 2002/ Returned for modification 22 May 2002/ Accepted 11 June 2002

Interleukin-10 (IL-10) is thought to promote intracellular infection, including human visceral leishmaniasis, by disabling Th1 cell-type responses and/or deactivating parasitized tissue macrophages. To develop a rationale for IL-10 inhibition as treatment in visceral infection, Th1 cytokine-driven responses were characterized in Leishmania donovani-infected BALB/c mice in which IL-10 was absent or overexpressed or its receptor (IL-10R) was blockaded. IL-10 knockout and normal mice treated prophylactically with anti-IL-10R demonstrated accelerated granuloma assembly and rapid parasite killing without untoward tissue inflammation; IL-12 and gamma interferon mRNA expression, inducible nitric oxide synthase reactivity, and responsiveness to antimony chemotherapy were also enhanced in knockout mice. In IL-10 transgenic mice, parasite replication was unrestrained, and except for antimony responsiveness, measured Th1 cell-dependent events were all initially impaired. Despite subsequent granuloma assembly, high-level infection persisted, and antimony-treated transgenic mice also relapsed. In normal mice with established infection, anti-IL-10R treatment was remarkably active, inducing near-cure by itself and synergism with antimony. IL-10's deactivating effects regulate outcome in experimental visceral leishmaniasis, and IL-10R blockade represents a potential immuno- and/or immunochemotherapeutic approach in this infection.

* Corresponding author. Mailing address: Box 136, 1300 York Avenue, New York, NY 10021. Phone: (212) 746-6330. Fax: (212) 746-6332. E-mail: hwmurray{at}med.cornell.edu.

Editor: J. M. Mansfield

{dagger} Present address: Dynavax Technologies, Berkeley, CA 94710.

Infection and Immunity, November 2002, p. 6284-6293, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6284-6293.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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