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Infection and Immunity, July 2005, p. 3903-3911, Vol. 73, No. 7
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.7.3903-3911.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antagonizing Deactivating Cytokines To Enhance Host Defense and Chemotherapy in Experimental Visceral Leishmaniasis

Henry W. Murray,1* Kathleen C. Flanders,2 Debra D. Donaldson,3 Joseph P. Sypek,3 Philip J. Gotwals,4 Jianguo Liu,5 and Xiaojing Ma5

Departments of Medicine,1 Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021,5 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892,2 Wyeth Research, Cambridge, Massachusetts 02140,3 Biogen Idec, Cambridge, Massachusetts 021424

Received 13 December 2004/ Returned for modification 16 January 2005/ Accepted 19 February 2005

In experimental visceral leishmaniasis, inhibition of interleukin 10 (IL-10) signaling enhances Th1-cell-associated responses, promoting gamma interferon (IFN-{gamma}) secretion, granuloma assembly, macrophage activation with substantial liver parasite killing, and synergy with pentavalent antimony (Sb) chemotherapy. To determine if inhibiting other suppressive cytokines has similar therapeutic potential, Leishmania donovani-infected BALB/c mice were injected with anti-IL-4 monoclonal antibody or receptor fusion antagonists of IL-13 or transforming growth factor ß (TGF-ß). Targeting IL-13 or TGF-ß enabled inhibition of L. donovani replication but little parasite killing; anti-IL-4 had no effect. None of the three antagonists promoted IFN-{gamma} production, granuloma maturation, or Sb efficacy. Excess IL-13 and TGF-ß exacerbated liver infection; however, effects were transient. Among IL-10, IL-4, IL-13, and TGF-ß, cytokines capable of disabling Th1-cell mechanisms (including those which support chemotherapy), IL-10 appears to be the appropriate target for therapeutic inhibition in visceral L. donovani infection.

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

Editor: W. A. Petri, Jr.

Infection and Immunity, July 2005, p. 3903-3911, Vol. 73, No. 7
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.7.3903-3911.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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