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 or 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 l-A k, 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 to 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 #
5R01AI048736-05
Application #
6823201
Study Section
Special Emphasis Panel (ZRG1-BM-1 (01))
Program Officer
Wali, Tonu M
Project Start
2000-12-16
Project End
2005-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
5
Fiscal Year
2005
Total Cost
$167,000
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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
Rutitzky, Laura I; Hernandez, Hector J; Yim, Young-Sun et al. (2005) Enhanced egg-induced immunopathology correlates with high IFN-gamma in murine schistosomiasis: identification of two epistatic genetic intervals. J Immunol 174:435-40
Finger, Eduardo; Brodeur, Peter H; Hernandez, Hector J et al. (2005) Expansion of CD4 T cells expressing a highly restricted TCR structure specific for a single parasite epitope correlates with high pathology in murine schistosomiasis. Eur J Immunol 35:2659-69
Stadecker, Miguel J; Asahi, Hiroko; Finger, Eduardo et al. (2004) The immunobiology of Th1 polarization in high-pathology schistosomiasis. Immunol Rev 201:168-79
Rutitzky, Laura I; Mirkin, Gerardo A; Stadecker, Miguel J (2003) Apoptosis by neglect of CD4+ Th cells in granulomas: a novel effector mechanism involved in the control of egg-induced immunopathology in murine schistosomiasis. J Immunol 171:1859-67
Gause, William C; Urban Jr, Joseph F; Stadecker, Miguel J (2003) The immune response to parasitic helminths: insights from murine models. Trends Immunol 24:269-77
Rutitzky, Laura I; Ozkaynak, Engin; Rottman, James B et al. (2003) Disruption of the ICOS-B7RP-1 costimulatory pathway leads to enhanced hepatic immunopathology and increased gamma interferon production by CD4 T cells in murine schistosomiasis. Infect Immun 71:4040-4