Leishmania major infections in (C57BL/6 x BALB/c) Fl mice are either healing or non-healing, depending on the site of parasite inoculation. Thus, lesions in the footpad spontaneously resolve whereas lesions in the dorsal skin at the base of the tail are progressive and ultimately fatal. Based on previous evidence that healing and non-healing infections correlated with the activation of Thl versus Th2 CD4+ cells, site-specific infections in Fl mice will be analyzed to determine mechanisms which may influence the development of divergent patterns of T helper subset activation in the same mouse. Since Fl mice, in contrast to parental strains, develop mixed Thl/Th2 responses during early stages of infection, studies will focus on events which modify Thl vs Th2 induction, as well as events which regulate the divergence of mixed responses toward dominance of a specific subset. Specifically, efforts will be made to determine how host antibody may influence the induction of Thl/Th2 cells as well as regulate established Thl/Th2 responses. A similar role for APC populations in the induction and regulation of Th subsets will be sought. In addition, since macrophage products such as IL-1 and PGE2 have been shown to influence disease progression, studies will determine whether these factors simply promote inflammation, or also influence Th subset activation or expansion. Finally, infections in Fl mice will be utilized to determine whether CD8+ cells are important in the development of acquired resistance to L. major and whether these cells are a significant source of IFN-gamma production during infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI027828-03
Application #
3142102
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1991-04-01
Project End
1996-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Padigel, Udaikumar M; Farrell, Jay P (2005) Control of infection with Leishmania major in susceptible BALB/c mice lacking the common gamma-chain for FcR is associated with reduced production of IL-10 and TGF-beta by parasitized cells. J Immunol 174:6340-5
Padigel, Udaikumar M; Alexander, James; Farrell, Jay P (2003) The role of interleukin-10 in susceptibility of BALB/c mice to infection with Leishmania mexicana and Leishmania amazonensis. J Immunol 171:3705-10
Padigel, Udaikumar M; Farrell, Jay P (2003) CD40-CD40 ligand costimulation is not required for initiation and maintenance of a Th1-type response to Leishmania major infection. Infect Immun 71:1389-95
Padigel, Udaikumar M; Kim, Nacksung; Choi, Yongwon et al. (2003) TRANCE-RANK costimulation is required for IL-12 production and the initiation of a Th1-type response to Leishmania major infection in CD40L-deficient mice. J Immunol 171:5437-41
Compton, Helen L; Farrell, Jay P (2002) CD28 costimulation and parasite dose combine to influence the susceptibility of BALB/c mice to infection with Leishmania major. J Immunol 168:1302-8
Li, Jian; Padigel, Udaikumar M; Scott, Phillip et al. (2002) Combined treatment with interleukin-12 and indomethacin promotes increased resistance in BALB/c mice with established Leishmania major infections. Infect Immun 70:5715-20
Murphy, M L; Wille, U; Villegas, E N et al. (2001) IL-10 mediates susceptibility to Leishmania donovani infection. Eur J Immunol 31:2848-56
Padigel, U M; Perrin, P J; Farrell, J P (2001) The development of a Th1-type response and resistance to Leishmania major infection in the absence of CD40-CD40L costimulation. J Immunol 167:5874-9
Fields, P A; Armstrong, E; Hagstrom, J N et al. (2001) Intravenous administration of an E1/E3-deleted adenoviral vector induces tolerance to factor IX in C57BL/6 mice. Gene Ther 8:354-61
Li, J; Hunter, C A; Farrell, J P (1999) Anti-TGF-beta treatment promotes rapid healing of Leishmania major infection in mice by enhancing in vivo nitric oxide production. J Immunol 162:974-9

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