This proposal describes the continuation of studies to investigate basic immunologic and immunopathologic mechanisms in experimental murine schistosomiasis mansoni. They involve the identification of the major stimulatory egg antigens responsible for eliciting T cell-mediated granulomatous hypersensitivity and immunopathologic damage, as well as the elucidation of the basic mechanisms that underlie the phenomenon of immunological down-regulation (immunomodulation), characteristic of this disease. T cell clones will be produced to analyze the basis of the cell-mediated antischistosomal immune response. Clone phenotypes will be established. Clonality will be verified by Southern blot analysis. Fine specificities recognized by the clones will be ascertained by stimulation with, individual antigenic egg components following fractionation by agarose-isoelectric focusing and high pressure liquid chromatography, and/or identification by monoclonal antibody analysis. The genetic restrictions of the response will be determined. Functional capabilities of SEA-specific T cell clones will be ascertained in vivo. The hypothesis that granuloma macrophages induce a state of unresponsiveness to antigen in specific T cell clones will be tested. This may offer a novel explanation for the phenomenon of immunomodulation, which has, so far, defied satisfactory understanding. This hypothesis will also be implemented by assessing the effect of specific T cell clone unresponsiveness-inducing regimens on the development and course of a challenge schistosomal infection in vivo. These experiments will contribute to the understanding of the basic immunological mechanisms in schistosomiasis, and are expected to have a direct impact in the development of preventive and therapeutic approaches against the pathology resulting from this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018919-08
Application #
3128305
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1983-01-01
Project End
1994-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Tufts University
Department
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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