Schistosomiasis continues to be a major helminthic disease suffered by millions of people throughout the world. This proposal describes the continuation of studies to investigate basic immunologic and immunopathologic mechanisms in the experimental murine model of schistosomiasis. The analysis and understanding of the specific T cell response and of non-specific immunoregulatory mechanisms will facilitate the design of strategies to down-regulate the T cell-mediated granulomatous hypersensitivity responsible for the schistosomal disease. Known and newly identified parasite egg antigens will be investigated with the use of specific T cell clones/hybridomas and their epitopes will be mapped. The recognition of specifiC antigens/epitopes, as well as of the corresponding T cell receptor repertoire, will be compared in large and small granuloma-forming strains of mice possibly representing polar forms of human disease. The hypothesis that the down-modulation of schistosomal disease is due to the induction of specific T cell anergy by granuloma macrophages will be further tested. Specific experiments will investigate the role of IL-10 in the inhibition of macrophage-derived """"""""costimulatory"""""""" signals necessary for the stimulation of T cells. IL-10 and costimulation-blocking reagents will be directly tested for their ability to down-regulate the magnitude of granulomatous inflammation in vivo. The long-term goals of this project are the design and administration of appropriate egg antigens/peptides, in possible conjunction with anti- costimulation agents, for induction of lasting specific T cell anergy and amelioration of granulomatous disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018919-13
Application #
2671741
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1995-09-30
Project End
2000-01-14
Budget Start
1998-08-01
Budget End
2000-01-14
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Kalantari, Parisa; Morales, Yoelkys; Miller, Emily A et al. (2018) CD209a Synergizes with Dectin-2 and Mincle to Drive Severe Th17 Cell-Mediated Schistosome Egg-Induced Immunopathology. Cell Rep 22:1288-1300
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
Liberman, Rachel; Bond, Sarah; Shainheit, Mara G et al. (2014) Regulated assembly of vacuolar ATPase is increased during cluster disruption-induced maturation of dendritic cells through a phosphatidylinositol 3-kinase/mTOR-dependent pathway. J Biol Chem 289:1355-63
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
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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