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J. Exp. Med.,
Volume 189, Number 12, June 21, 1999 1895-1906
By
From the Division of Geographic Medicine, Case Western Reserve University School of Medicine and
the Research Service, Veteran's Affairs Medical Center, Cleveland, Ohio 44106-4983
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.
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