Leishmaniasis is a widespread and debilitating protozoal disease of man and animals. An improved understanding of the immunologic aspects of this infection should provide the basis for new therapies. We propose to study how IL-12 can be used to promote the development of a protective immune response, specifically focusing on the development of a therapeutic vaccine for chronic cutaneous leishmaniasis. Experimental infections in mice mimic to a large extent the spectrum of clinical presentations associated with human disease, and have been used extensively to study immunologic responses in leishmaniasis. From such studies we have learned a great deal about the factors involved in the differentiation and regulation of T cell subsets. Our hypothesis is that during chronic leishmanial infections mice are non-responsive to IL-12, leading to the inability to promote the development of a Th1-type immune response. We will define the factors that regulate IL-12 responsiveness, by identifying the cells that need to respond to IL-12 in order to shift a T cell population from a Th2 to a Th1 phenotype, defining the requirements for CD28-B7 interactions for effective IL-12 function, and determining what regulates the IL-12 receptor during Leishmania infection. Our approach will be to manipulate in vitro and in vivo levels of cytokines and costimulatory interactions to promote a shift in the Th2 population from L. major infected BALB/c mice towards a protective Th1 phenotype. We will use an in vitro system to define the cells and cytokines involved in switching, and we will then validate our in vitro findings with in vivo studies. Because antigen-reactive cells are difficult to track, due to their low frequency in a normal (or even infected) animal and the lack of reagents that specifically identify them, for some studies we will use cells from an OVA T cell receptor (TCR) transgenic mouse (DO11.10) in combination with an OVA expressing L. major parasite. The expression of OVA by L. major establishes this antigen as a model parasite antigen, that will be exposed to the same environment that shapes the T cell response to other antigens produced by L. major. An additional advantage to using DO11.10 TCR transgenic mice is that regulation of the IL-12 receptor by these T cells has been well studied. We will apply the information gained from these in vitro studies to design the best approach for promoting a Th1 response in infected L. major infected mice using a therapeutic vaccine.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG5-BM-2 (01))
Program Officer
Hall, B Fenton
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Veterinary Medicine
United States
Zip Code
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

Showing the most recent 10 out of 11 publications