The long-term goals of this project are to develop novel immune response-modifying vaccines for the treatment of asthma. Asthma is a major public health problem, and affects 15 million Americans, roughly 5-8 percent of the population. It has increased substantially in prevalence and in terms of mortality and morbidity over the past two decades, and this increase has occurred despite a substantial improvement in our understanding of asthma pathophysiology and the availability of improved medications for asthma. We propose to generate therapeutic fusion proteins and constructs for asthma by molecularly linking a prototypic allergen, ovalbumin (OVA), to an immune response polarizing cytokine, IL-18, and to a tolerogenic agent, cholera toxin, subunit B. We will use these immunotherapeutic agents in a murine model for asthma, and convert established, pathogenic Th2-dominated, allergic inflammatory responses into protective responses. The proposed studies are based on our previous results, which demonstrated that allergen immunotherapy improves allergic disease by correcting the underlying immune dysregulation, and that the efficacy of immunotherapy can be greatly improved by the use of antigen-cytokine fusion constructs. These constructs, by directing the activity of potent cytokines and other agents towards antigen-specific T cells, rectify the cytokine profile and activity of such pathogenic allergen-specific Th2 cells. Here we propose to produce and study more potent allergen-fusion proteins as well as cDNA plasmid vaccines containing OVA and IL-18 in established models of allergic inflammation and airway hyperreactivity. In addition, we will determine the role of allergen specific Th1 cells, other regulatory T cells (Th3, CD8, or gammadelta T cells), and of peripheral tolerance in down regulating allergic inflammation and asthma. These innovative studies will provide the basis for development of new disease-modifying strategies to treat and potentially cure patients with allergy and asthma. In addition, these studies will expand our understanding of the role of T cells that protect against these common disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045900-04
Application #
6510891
Study Section
Special Emphasis Panel (ZRG1-IMB (02))
Program Officer
Adams, Ken
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$284,903
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Silvie, Olivier; Greco, Celine; Franetich, Jean-Francois et al. (2006) Expression of human CD81 differently affects host cell susceptibility to malaria sporozoites depending on the Plasmodium species. Cell Microbiol 8:1134-46
Levy, Shoshana; Shoham, Tsipi (2005) Protein-protein interactions in the tetraspanin web. Physiology (Bethesda) 20:218-24
Cariappa, Annaiah; Shoham, Tsipi; Liu, Haoyuan et al. (2005) The CD9 tetraspanin is not required for the development of peripheral B cells or for humoral immunity. J Immunol 175:2925-30
Song, Bong K; Levy, Shoshana; Geisert Jr, Eldon E (2004) Increased density of retinal pigment epithelium in cd81-/- mice. J Cell Biochem 92:1160-70
Cherukuri, Anu; Shoham, Tsipi; Sohn, Hae Won et al. (2004) The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts. J Immunol 172:370-80
Shoham, Tsipi; Rajapaksa, Ranjani; Boucheix, Claude et al. (2003) The tetraspanin CD81 regulates the expression of CD19 during B cell development in a postendoplasmic reticulum compartment. J Immunol 171:4062-72
Silvie, Olivier; Rubinstein, Eric; Franetich, Jean-Francois et al. (2003) Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity. Nat Med 9:93-6
Geisert Jr, Eldon E; Williams, Robert W; Geisert, Grace R et al. (2002) Increased brain size and glial cell number in CD81-null mice. J Comp Neurol 453:22-32
Deng, Jun; Dekruyff, Rosemarie H; Freeman, Gordon J et al. (2002) Critical role of CD81 in cognate T-B cell interactions leading to Th2 responses. Int Immunol 14:513-23
Maecker, H T; Hansen, G; Walter, D M et al. (2001) Vaccination with allergen-IL-18 fusion DNA protects against, and reverses established, airway hyperreactivity in a murine asthma model. J Immunol 166:959-65

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