Leishmaniasis is a chronic infection that can cause severe disfiguring cutaneous lesions or fatal visceral disease. Chemotherapy is the only commonly practiced therapeutic intervention in this disease. The potential for such therapy is excellent, since major advances have been made in our understanding of the factors that regulate the immune system. The most notable advance has been the description of the major T helper cell subsets that control the immune system, namely CD4+ Th1 and Th2 cells. The understanding of how these T cell subsets are regulated has provided the potential to intervene in the disease state and potentiate appropriate immune responses. In leishmaniasis it is well established that disease progression in many cases is related to either the inappropriate expansion of the CD4+ Th2 cell subset, or a deficit in the development of CD4+ Th1 cells, which mediate protection. One of the principle cytokines that influences Th1 cell expansion and function is IL-12. This cytokine induces IFN-y, enhances Th1 cell differentiation, and preferentially expands the Th1 subset. In the proposed studies, a murine model of cutaneous leishmaniasis will be employed to develop an immunologically based therapy that incorporates IL-12 as an immunopotentiator. These studies are designed to evaluate basic questions of IL-12 biology, and apply that information towards the development of a prophylactic and therapeutic vaccine. To achieve this goal the first series of studies proposed is to define the mechanism(s) by which IL-12 functions. These experiments include characterization of the role of endogenous IL-12 in resistance to Leishmania major by comparative studies in resistant and susceptible mice, and an evaluation of the cells and cytokines associated with the response to IL-12 when it is used as an immunopotentiator. We will then assess the ability of IL- 12 administered in a therapeutic vaccine to induce resolution of disease. The first series of studies will determine if IL-12 can inhibit TH2 cells in vitro, and what inhibitors (such as monoclonal anti-cytokine antibodies) are required for expansion of Th1 cells. Studies will then directly address the potential to reverse disease development using IL-12 in a therapeutic vaccine. Parallel studies are also proposed to determine if IL-12 can augment the efficacy of chemotherapy. In a related series of experiments we will further define the optimal conditions for induction of protection using IL-12 as an immunopotentiator in a prophylactic vaccine. These experiments will delineate the optimal conditions for induction and expansion of protective CD4+ Th1 cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI035914-04
Application #
2429418
Study Section
Special Emphasis Panel (SRC (40))
Project Start
1994-09-01
Project End
1998-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
4
Fiscal Year
1997
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
Crosby, Erika J; Goldschmidt, Michael H; Wherry, E John et al. (2014) Engagement of NKG2D on bystander memory CD8 T cells promotes increased immunopathology following Leishmania major infection. PLoS Pathog 10:e1003970
Carvalho, Lucas P; Petritus, Patricia M; Trochtenberg, Alyssa L et al. (2012) Lymph node hypertrophy following Leishmania major infection is dependent on TLR9. J Immunol 188:1394-401
Colpitts, Sara; Scott, Phillip (2010) Memory T-cell subsets in parasitic infections. Adv Exp Med Biol 684:145-54
Colpitts, Sara L; Scott, Phillip (2010) The early generation of a heterogeneous CD4+ T cell response to Leishmania major. J Immunol 185:2416-23
Colpitts, Sara L; Dalton, Nicole M; Scott, Phillip (2009) IL-7 receptor expression provides the potential for long-term survival of both CD62Lhigh central memory T cells and Th1 effector cells during Leishmania major infection. J Immunol 182:5702-11
Pakpour, Nazzy; Zaph, Colby; Scott, Phillip (2008) The central memory CD4+ T cell population generated during Leishmania major infection requires IL-12 to produce IFN-gamma. J Immunol 180:8299-305
Gray, Peter M; Reiner, Steven L; Smith, Deborah F et al. (2006) Antigen-experienced T cells limit the priming of naive T cells during infection with Leishmania major. J Immunol 177:925-33
Buxbaum, Laurence U; Scott, Phillip (2005) Interleukin 10- and Fcgamma receptor-deficient mice resolve Leishmania mexicana lesions. Infect Immun 73:2101-8
Buxbaum, Laurence U; Denise, Hubert; Coombs, Graham H et al. (2003) Cysteine protease B of Leishmania mexicana inhibits host Th1 responses and protective immunity. J Immunol 171:3711-7
Buxbaum, Laurence U; Uzonna, Jude E; Goldschmidt, Michael H et al. (2002) Control of New World cutaneous leishmaniasis is IL-12 independent but STAT4 dependent. Eur J Immunol 32:3206-15

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