Schistosomiasis continues to be a major parasitic disease suffered by millions of people throughout the world. The underlying potentially lethal immunopathology in schistosomiasis is a granulomatous inflammation around parasite eggs, which is mediated by the host s T cells sensitized to parasite egg antigens. The proposed studies are based on the concept that such pathogenic T cell responses are amenable to down-regulation by immunotherapy, thereby resulting in the prevention of amelioration of disease. This approach has been referred to as anti-pathology vaccine. Specific T cell hybridomas will be used as probes to identify and isolate the major sensitizing egg antigens. Antigens will be cloned and their dominant T cell epitope peptide(s) will be synthesized. The type of elicited T cell response will be characterized and the genetic restriction of the T cell response will be determined. The major schistosomal egg antigen Sm-p40 will be the subject of close analysis by investigating the interaction of its dominant epitope 13mer peptide with the MHC class II molecule I-Ak, and by assessing its intrinsic pathogenicity. A broad range of experiments will test selected strategies involving specific homologous or altered peptides for the purpose of down-regulating the pathogenic T cell response. The long-term goal of this project is the achievement of effective and lasting specific T cell tolerance by way of a suitable biological vector capable of delivering the peptides into the host suffering from, or susceptible to, disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018919-18
Application #
6693818
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Wali, Tonu M
Project Start
1995-09-30
Project End
2005-06-14
Budget Start
2004-01-01
Budget End
2005-06-14
Support Year
18
Fiscal Year
2004
Total Cost
$368,566
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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Smith, Patrick M; Sproule, Thomas J; Philip, Vivek M et al. (2015) Minor genomic differences between related B6 and B10 mice affect severity of schistosome infection by governing the mode of dendritic cell activation. Eur J Immunol 45:2312-23
Ponichtera, Holly E; Stadecker, Miguel J (2015) Dendritic cell expression of the C-type lectin receptor CD209a: A novel innate parasite-sensing mechanism inducing Th17 cells that drive severe immunopathology in murine schistosome infection. Exp Parasitol 158:42-7
Ponichtera, Holly E; Shainheit, Mara G; Liu, Beiyun C et al. (2014) CD209a expression on dendritic cells is critical for the development of pathogenic Th17 cell responses in murine schistosomiasis. J Immunol 192:4655-65
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Mbow, Moustapha; Larkin, Bridget M; Meurs, Lynn et al. (2013) T-helper 17 cells are associated with pathology in human schistosomiasis. J Infect Dis 207:186-95
Kosinski, Karen C; Adjei, Michael N; Bosompem, Kwabena M et al. (2012) Effective control of Schistosoma haematobium infection in a Ghanaian community following installation of a water recreation area. PLoS Negl Trop Dis 6:e1709
Larkin, Bridget M; Smith, Patrick M; Ponichtera, Holly E et al. (2012) Induction and regulation of pathogenic Th17 cell responses in schistosomiasis. Semin Immunopathol 34:873-88
Stadecker, Miguel J (2012) The gamut of host immune responses and immunopathology in parasitic diseases caused by protozoa and helminths: human perspective and experimental models. Semin Immunopathol 34:733-4
Smith, Patrick M; Jacque, Berri; Conner, James R et al. (2011) IRAK-2 regulates IL-1-mediated pathogenic Th17 cell development in helminthic infection. PLoS Pathog 7:e1002272

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