Anti-IL-4 antibody therapy causes regression of chronic lesions caused by medium-dose Leishmania major infection in BALB/c mice.
Experimental infection of BALB/c mice with a high number of Leishmania major parasites results in a predominant Th2 response and rapidly progressing, non-healing lesions. Disease can be prevented in such mice by simple therapies, such as administering neutralizing anti-IL-4 or anti-CD4 antibody prior to or around the time of infection, but not once the infection is well established. Established infections can be resolved by combined therapies, such as intralesional administration of massive doses of IL-12 and of anti-leishmanial drugs. We explored the possibility of using simple therapies to cure mice with stable, chronic and large lesions, a state that corresponds more closely to human cutaneous leishmaniasis than does the rapidly progressing model. The anti-parasite immune responses of mice bearing such chronic lesions have a mixed Th1/Th2 phenotype. Administration of either anti-IL-4 or anti-CD4 antibody alone results in the reliable regression of such lesions even when large. Cured mice display a dominant Th1 response with increased L. major-specific IgG2a antibody, increased production of IL-12p40 and of nitric oxide by macrophages, indicating increased parasiticidal activity. Cured mice resist a normally pathogenic L. major challenge. These findings may have implications for treatment of human cutaneous leishmaniasis and other chronic infectious diseases caused by intracellular pathogens.
Uzonna
J E
JE
Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada.
Bretscher
P A
PA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002908:Chronic Disease; D005260:Female; D018664:Interleukin-12 / Q000096:biosynthesis / Q000627:therapeutic use; D015847:Interleukin-4 / Q000037:antagonists & inhibitors*; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000469:parasitology / Q000628:therapy*; D008198:Lymph Nodes / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis; D018417:Th1 Cells / Q000502:physiology; D018418:Th2 Cells / Q000502:physiology
D000911:Antibodies, Monoclonal; D018664:Interleukin-12; D015847:Interleukin-4; D009569:Nitric Oxide