The long-term goals of this project are to understand immune regulation of asthma, a serious public health problem that has doubled in prevalence in industrialized countries over the last two decades. We have examined different cell types that are involved in the pathogenesis of and in the protection against asthma, and we now propose to study the role of subsets of NK T cells in these processes. Our focus on NK T cells in asthma is based on striking and novel preliminary data demonstrating that mice deficient in NK T cells do not develop allergen-induced airway hyperresponsiveness (AHR), a cardinal feature of asthma. Thus, neither CD1d knockout nor Ja281 knockout mice sensitized and challenged with ovalbumin, develop AHR. Since NK T cells produce large quantities of cytokines on activation, NK T cells are thought to have a profound influence on the development of immune responses, and therefore we hypothesize that NK T cells in the lungs play a major role in regulating the development of asthma. We will examine the mechanisms by which NK T cells enhance the development of AHR by further examination of Ja281 knockout mice. We will use a model in which BALB/c Jaa281 knockout mice are reconstituted with NK T cells from histocompatible wild type mice or from mice deficient in IL-4, IL-13, IL-10 or costimulatory molecules, isolated with CD1d tetramers and NK T cell specific monoclonal antibodies. These studies will determine the specific cytokines and molecules that NK T cells require for inducing the development of AHR and asthma. In addition, we will determine if subsets of NK T cells, activated to enhance cytolytic activity and IFN-gamma but not IL-4 production, will protect against, rather than enhance, the development of AHR. Finally, we will determine whether NK T cells play a significant role in regulating the development of human asthma by examining the number, distribution and cytokine profiles of NK T cells in the blood and lungs of asthmatic patients and matched control subjects. These studies will ascertain the precise role of NK T cells in the development of asthma, and greatly enhance our understanding of pathogenic and protective mechanisms in asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL062348-05
Application #
6610108
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Noel, Patricia
Project Start
1999-04-01
Project End
2008-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$357,639
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Kim, Hye Young; Lee, Hyun Jun; Chang, Ya-Jen et al. (2014) Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med 20:54-61
Kim, Hye Young; Chang, Ya-Jen; Subramanian, Srividya et al. (2012) Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity. J Allergy Clin Immunol 129:216-27.e1-6
Chang, Ya-Jen; Kim, Hye Young; Albacker, Lee A et al. (2011) Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12:631-8
Chang, Ya-Jen; Kim, Hye Young; Albacker, Lee A et al. (2011) Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity. J Clin Invest 121:57-69
Umetsu, Dale T; Dekruyff, Rosemarie H (2010) Natural killer T cells are important in the pathogenesis of asthma: the many pathways to asthma. J Allergy Clin Immunol 125:975-9
Kim, Hye Young; DeKruyff, Rosemarie H; Umetsu, Dale T (2010) The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol 11:577-84
Akbari, O; Stock, P; Singh, A K et al. (2010) PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunol 3:81-91
Lee, Hyun-Hee; Meyer, Everett H; Goya, Sho et al. (2010) Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity. J Immunol 185:5225-35
Matangkasombut, Ponpan; Marigowda, Gautham; Ervine, Aaron et al. (2009) Natural killer T cells in the lungs of patients with asthma. J Allergy Clin Immunol 123:1181-5
Kim, Hye Young; Pichavant, Muriel; Matangkasombut, Ponpan et al. (2009) The development of airway hyperreactivity in T-bet-deficient mice requires CD1d-restricted NKT cells. J Immunol 182:3252-61

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