Anti-TGF-beta treatment promotes rapid healing of Leishmania major infection in mice by enhancing in vivo nitric oxide production.

Abstract

CB6F1 mice display intermediate susceptibility to Leishmania major infection compared with the highly susceptible BALB/c and resistant C57BL/6 parental strains. During early weeks of infection, these mice develop dominant Th2 type responses to L. major, although they eventually exhibit a Th2 to Th1 switch and spontaneously resolve their infections. In this study, we have examined the effects of either IL-12 or anti-TGF-beta therapy on the immune response and course of disease in chronically infected CB6F1 mice. Local treatment with IL-12 inoculated into the parasitized lesion at 4 wk of infection induced a marked increase in IFN-gamma production but did not result in a significant reduction in numbers of parasite or promote more rapid healing. However, local treatment with an Ab to TGF-beta led to both a decrease in parasite numbers and more rapid healing, despite the fact that such treatment did not significantly alter the pattern of IL-4 and IFN-gamma production. Immunohistochemical studies showed that anti-TGF-beta treatment resulted in increased nitric oxide production within parasitized lesions. Our results suggest that TGF-beta may play an important regulatory role during chronic stages of a L. major infection by suppressing macrophage production of nitric oxide and that, in the absence of TGF-beta, even the relatively low levels of IFN-gamma observed in mice with dominant Th2-type responses are sufficient to activate macrophages to destroy amastigotes within parasitized lesions.

• Authors: J Li, C A Hunter, J P Farrell
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 162 Issue 2 Pg. 974-9 (Jan 15 1999) ISSN: 0022-1767 [Print] United States
• PMID: 9916722 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adjuvants, Immunologic
• Antibodies, Monoclonal
• Drug Combinations
• Transforming Growth Factor beta
• Interleukin-12
• Nitric Oxide
• Interferon-gamma

Topics

• Adjuvants, Immunologic (therapeutic use)
• Animals
• Antibodies, Monoclonal (administration & dosage, therapeutic use)
• Chronic Disease
• Crosses, Genetic
• Drug Combinations
• Female
• Injections, Intralesional
• Injections, Subcutaneous
• Interferon-gamma (biosynthesis)
• Interleukin-12 (administration & dosage, therapeutic use)
• Leishmania major (growth & development, immunology)
• Leishmaniasis, Cutaneous (immunology, metabolism, parasitology, therapy)
• Lymphocytes (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Nitric Oxide (biosynthesis)
• Transforming Growth Factor beta (administration & dosage, antagonists & inhibitors, immunology)