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Progressive infection with Leishmania major in susceptible BALB/c mice is mediated by interleukin (IL)-4–producing T helper cell type 2 (Th2) CD4+ T cells that, once established, become resistant to Th1-deviating therapies with recombinant (r)IL-12 and/or neutralizing anti–IL-4 antibodies. We sought to restore protective immunity in advanced leishmaniasis by depletion of Th2-biased CD4+ populations and by cytokine-directed reconstitution of Th1 cellular responses during lymphocyte recovery. Treatment with cytolytic GK1.5 anti-CD4 mAb alone did not reverse disease in 3 wk–infected BALB/c mice, but GK1.5 combined with anti–IL-4 antibody and intralesional rIL-12 cured cutaneous lesions in 80% of mice and established a Th1-polarized cytokine response to L. major antigen protective against reinfection. The curative effects of GK1.5 were not replaced by cytotoxic anti-CD8 monoclonal antibody 2.43 or nondepleting anti-CD4 mAb YTS177, confirming that depletion of CD4+ cells was specific and essential for therapeutic effect. Finally, combined CD4+ depletion and IL-4 neutralization were curative, indicating that neither increased parasite burden nor altered accessory cell function independently biased towards Th2 reconstitution in advanced leishmaniasis. Advanced leishmaniasis can be cured by T cell depletion and cytokine-directed recovery of Th1 cellular responses, suggesting novel interventions for other immune-mediated diseases and identifying distinct roles for CD4+ T cell and non-T cell in the maintenance of Th2 and Th1 phenotypes.
Key Words: T helper cells type 2/immunology interferon type II interleukin 12 T helper cells type 1/immunology immunity/cellular
We are thankful to Andrea Hujer for providing superb technical assistance in these studies. We gratefully acknowledge the gift of anti-CD4 mAb YTS177 from Dr. Shixin Qin and thank Drs. Eric Pearlman, Paul Lehmann, and Peter Heeger for their critical review of the manuscript.
F.P. Heinzel is supported by the Veteran's Affairs Medical Research Service and by grants RO1 AI35979 and K04 AI01229 from the National Institute of Allergy and Infectious Disease.
Abbreviations used: FBS, fetal bovine serum; iNOS, inducible nitric oxide synthase.
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