A number of studies suggest that early exposure to endotoxin is associated with a lower risk of asthma and allergies. The overall objective of this research is to understand the mechanism of that effect. This includes 1) clarifying whether endotoxin mediates its effect through the binding and activation of Toll-like receptors (TLRs), and 2) determining endotoxin's role in T-cell differentiation. Toll-like receptor (TLR)-2, TLR-4, and CD 14 are known to bind endotoxin and to mediate its stimulation of the innate immune system. What is not known is whether this pathway also mediates endotoxin's effect on allergy. As type-2 helper T-cells (Th2) appear to be responsible for allergic expression, endotoxin's probable downstream effect is suppression of this T-cell phenotype. Since the TLR family recognizes a broad range of infectious organisms, clarifying this mechanism has obvious implications for long-standing, but unproven, """"""""Hygiene Hypothesis,"""""""" which posits a protective association between early infections and allergic development. The research proposed here will take advantage of a large, prospective, multi-ethnic, birth cohort which began in the Detroit area in September 2003. To achieve the first objective, endotoxin levels will be measured in the home in the first year of life and related to subsequent serologic and skin prick measures of atopy. Single nucleotide polymorphisms (SNPs) known to cause alterations in either the expression or the function of CD14, TLR-2, and TLR-4 will be studied. If the TLR pathway mediates endotoxin's effect on allergy, children with these polymorphisms should display an altered or diminished response to endotoxin. The second objective will determine whether endotoxin exposure results in skewing of the helper T-cell phenotype (i.e., Thl vs. Th2) or whether it results in T-cell anergy. To achieve this objective, intracellular cytokine production in CD4+ lymphocytes will be prospectively measured. Interleukin (IL)-4, IL-10, and interferon-3, will be measured in cord blood, at 6 months, 1 year, and 2 years of age. As CD4+/CD25+ regulatory T-cells appear to be responsible for anergy, changes in this group of cells over time will be related to the level of endotoxin exposure. It is the hoped that understanding the mechanism of endotoxin's effect will establish new targets for the prevention of allergies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061774-04
Application #
7178466
Study Section
Special Emphasis Panel (ZAI1-KLW-I (M6))
Program Officer
Togias, Alkis
Project Start
2004-08-15
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2007
Total Cost
$652,896
Indirect Cost
Name
Henry Ford Health System
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Levin, Albert M; Gui, Hongsheng; Hernandez-Pacheco, Natalia et al. (2018) Integrative approach identifies corticosteroid response variant in diverse populations with asthma. J Allergy Clin Immunol :
Oh, Sam S; Du, Randal; Zeiger, Andrew M et al. (2017) Breastfeeding associated with higher lung function in African American youths with asthma. J Asthma 54:856-865
Wells, Karen E; Cajigal, Sonia; Peterson, Edward L et al. (2016) Assessing differences in inhaled corticosteroid response by self-reported race-ethnicity and genetic ancestry among asthmatic subjects. J Allergy Clin Immunol 137:1364-1369.e2
Pino-Yanes, Maria; Gignoux, Christopher R; Galanter, Joshua M et al. (2015) Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos. J Allergy Clin Immunol 135:1502-10
Pino-Yanes, Maria; Thakur, Neeta; Gignoux, Christopher R et al. (2015) Genetic ancestry influences asthma susceptibility and lung function among Latinos. J Allergy Clin Immunol 135:228-35
Yessayan, L; Shafiq, A; Peterson, E et al. (2015) Race, Calcineurin Inhibitor Exposure, and Renal Function After Solid Organ Transplantation. Transplant Proc 47:2968-72
El-Refai, Mostafa; Hrobowski, Tara; Peterson, Edward L et al. (2015) Race and association of angiotensin converting enzyme/angiotensin receptor blocker exposure with outcome in heart failure. J Cardiovasc Med (Hagerstown) 16:591-6
Velez, Mauricio; Peterson, Edward L; Wells, Karen et al. (2015) Association of antidiabetic medications targeting the glucagon-like peptide 1 pathway and heart failure events in patients with diabetes. J Card Fail 21:2-8
Padhukasahasram, Badri; Reddy, Chandan K; Levin, Albert M et al. (2015) Powerful Tests for Multi-Marker Association Analysis Using Ensemble Learning. PLoS One 10:e0143489
Lanfear, David E; Li, Jia; Abbas, Raza et al. (2015) Genetic Factors Influencing B-type Natriuretic Peptide-Mediated Production of Cyclic Guanosine Monophosphate and Blood Pressure Effects in Heart Failure Patients. J Cardiovasc Transl Res 8:545-53

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