Cure of progressive murine leishmaniasis: interleukin 4 dominance is abolished by transient CD4(+) T cell depletion and T helper cell type 1-selective cytokine therapy.
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.
Heinzel
F P
FP
Division of Geographic Medicine, Case Western Reserve University School of Medicine and the Research Service, Veteran's Affairs Medical Center, Cleveland, Ohio 44106-4983, USA. fxh10@po.cwru.edu
Rerko
R M
RM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D016827:CD8 Antigens / Q000276:immunology; D016207:Cytokines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018664:Interleukin-12 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology; D007896:Leishmaniasis / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D018664:Interleukin-12; D015847:Interleukin-4