Different inbred strains of mice develop either of two divergent patterns of infection with Leishmania major. Most strains develop healing infections whereas certain strains, such as the BALB/c, develop progressive non-healing disease. The development of resistance to infection occurs when the Th1 subset of CD4plus T cells is activated, while progressive disease occurs in mice in which the Th2 subset of CD4plus is preferentially induced. Although patterns of Th1 or Th2 cell predominance become well established early during infection in specific strains of mice, these patterns are not irreversible since a variety of immunological interventions, including treatment with IL-12 or antibodies to IL-2 and IL-4, will reverse the expected course of disease and immunological phenotype, especially if they are administered at or near the time of infection. These immunological interventions function to influence the initial stages of T cell activation from naive CD4plus cells into full differentiated Th1 or Th2 cells, rather than alter the phenotype of an established response. However, neither IL-12 nor anti-IL-4 treatment, alone, will induce healing in mice with established Th2 type responses. Our laboratory has examined ways to reverse established patterns of Th2 cell predominance in mice with non- healing infections and has shown that immunological interventions designed to either suppress Th2 type responses (anti-IL-4 therapy) or enhance Th1 type responses (IL-12 therapy) will promote healing and resistance in susceptible strains of mice if combined with anti- parasite drug therapy to reduce in vivo levels or parasitization. This proposal will examine how differing levels of infection influence the perpetuation of established populations of Th2 cells or the activation of protective Th1 cells and how drug treatment functions to promote successful immunotherapy. In addition, the source of newly derived populations of Th1 cells and the fate of Th2 type populations will e investigated in mice induced to switch from a Th2 to Th1 type response. Finally, the cellular and biochemical events induced by differing immunotherapeutic protocols will be examined in mice exhibiting varying degrees of polarization toward a Th1 or Th2 type response. These studies should provide a better understanding of how mice with chronic infections respond to therapeutic intervention and provide valuable insight into the development of more innovative treatment regimes for leishmaniasis and other infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI027828-08
Application #
2886600
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
James, Stephanie
Project Start
1991-04-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
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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