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Infection and Immunity, November 2003, p. 6453-6462, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6453-6462.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Modulation of T-Cell Costimulation as Immunotherapy or Immunochemotherapy in Experimental Visceral Leishmaniasis

Henry W. Murray,1* Cristina M. Lu,1 Elaine B. Brooks,1 Richard E. Fichtl,2 Jennifer L. DeVecchio,3 and Frederick P. Heinzel3

Department of Medicine, Weill Medical College of Cornell University,1 Department of Pharmacy, New York Presbyterian Hospital, New York, New York 10021,2 Center for Global Health and Disease, Case Western Reserve University School of Medicine, Cleveland, Ohio 441063

Received 23 December 2002/ Returned for modification 7 March 2003/ Accepted 4 August 2003

CD40 ligand (CD40L)-deficient C57BL/6 mice failed to control intracellular Leishmania donovani visceral infection, indicating that acquired resistance involves CD40-CD40L signaling and costimulation. Conversely, in wild-type C57BL/6 and BALB/c mice with established visceral infection, injection of agonist anti-CD40 monoclonal antibody (MAb) induced killing of ~60% of parasites within liver macrophages, stimulated gamma interferon (IFN-{gamma}) secretion, and enhanced mononuclear cell recruitment and tissue granuloma formation. Comparable parasite killing was also induced by MAb blockade (inhibition) of cytotoxic T lymphocyte antigen-4 (CTLA-4) which downregulates separate CD28-B7 T-cell costimulation. Optimal killing triggered by both anti-CD40 and anti-CTLA-4 required endogenous IFN-{gamma} and involved interleukin 12. CD40L-/- mice also failed to respond to antileishmanial chemotherapy (antimony), while in normal animals, anti-CD40 and anti-CTLA-4 synergistically enhanced antimony-associated killing. CD40L-CD40 signaling regulates outcome and response to treatment of experimental visceral leishmaniasis, and MAb targeting of T-cell costimulatory pathways (CD40L-CD40 and CD28-B7) yields macrophage activation and immunotherapeutic and immunochemotherapeutic activity.

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

Editor: J. M. Mansfield

Infection and Immunity, November 2003, p. 6453-6462, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6453-6462.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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