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Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis

Elisabeth A. Patton,^, Anne C. La Flamme,^, Joao A. Pedras-Vasoncelos,^, and Edward J. Pearce^*

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853

Received 30 March 2001/ Returned for modification 14 May 2001/ Accepted 11 October 2001

Schistosoma mansoni-infected wild-type (WT) mice develop a Th2 response and chronic disease. In contrast, infected interleukin-4 double-deficient (IL-4^-/-) mice develop a Th1-like response and an acute, lethal syndrome. Disease severity in these animals correlates with excessive and prolonged production of nitric oxide (NO) associated with enhanced antigen-driven gamma interferon (IFN-) production in the absence of IL-4. Strikingly, splenic lymphocytes from infected IL-4^-/- mice failed to proliferate as well as those from infected WT mice following stimulation in vitro with antigen or anti-CD3 antibody. Contrary to antigen-driven IFN- responses, anti-CD3 antibody stimulation of splenocytes resulted in significantly less IFN- being produced by CD8 cells from infected IL-4^-/- mice than by those from infected WT mice or normal mice. NO is largely responsible for the impaired T-cell functions in infected IL-4^-/- mice, as inhibition of iNOS significantly enhanced proliferation and IFN- production.

Editor: J. M. Mansfield

Present address: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wis.

Present address: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.

Present address: NRC-IBS, Ottawa, Ontario K1K-0R6, Canada.

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