Leishmaniasis is a major public health problem in large parts of the world, due in part to the lack of a vaccine and inadequate chemotherapy. Studies of the immune responses in humans and mice following Leishmania infection have provided an understanding of many of the cells and cytokines that contribute to the control of this disease. Nevertheless, a vaccine for human leishmaniasis does not exist. Understanding how memory T cells develop will be crucial in the development of such vaccines. Two types of memory T cells have been described: T effector memory cells, which produce effector cytokines and migrate through the tissues, and central memory T cells that do not produce effector cytokines and migrate through lymph nodes. C57BL/6 mice infected with Leishmania major are immune to rechallenge after they resolve their infections, but this immunity was thought to be dependent upon residual parasites. Now an attenuated L. major parasite that is eliminated after eight weeks has been shown to stimulate the development of long- lived protective memory T cells. These cells have the characteristics of central memory T cells, and the studies in this proposal will characterize these cells and assess whether we can generate memory T cells with an effector phenotype. The studies will include a comparison of the ability of a Listeria expressing a leishmanial antigen and L. major to stimulate effector memory T cells, assessment of the role that parasite persistence plays in blocking the development of effector memory cells, and how dendritic cells influence memory T cell generation. The experiments utilize state-of-the art tools that will allow qualitative and quantitative assessment of memory T cell development. Overall, the experiments described in this proposal will determine what type of immunologic memory can be induced in leishmaniasis, which will provide direction for the field in establishing what are reasonable goals for a leishmaniasis vaccine.

Public Health Relevance

The development of a vaccine for human leishmaniasis is a major priority, but our understanding of how to stimulate the memory T cells required for vaccine-immunity is limited. This proposal will determine how memory T cells develop, are maintained and are regulated using an experimental model of the disease. The results from these experiments will provide a foundation for the development of a successful leishmaniasis vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI035914-18
Application #
8390503
Study Section
Special Emphasis Panel (ZRG1-IDM-S (02))
Program Officer
Wali, Tonu M
Project Start
1994-09-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
18
Fiscal Year
2013
Total Cost
$362,760
Indirect Cost
$132,436
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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
Krolewiecki, A J; Leon, S; Scott, P A et al. (2001) Effect of chronic ethanol consumption on protective T-helper 1 and T-helper 2 immune responses against the parasites Leishmania major and Strongyloides stercoralis in mice. Alcohol Clin Exp Res 25:571-8