Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)–1/TIM4 interaction as a therapeutic strategy in a dendritic cell–induced peanut allergy model

Feng, Bai-Sui; Chen, Xiao; He, Shao-Heng; Zheng, Peng-Yuan; Foster, Jane; Xing, Zhou; Bienenstock, John; Yang, Ping-Chang

doi:10.1016/j.jaci.2008.04.036

« Previous Next »The Journal of Allergy and Clinical Immunology
Volume 122, Issue 1 , Pages 55-61.e7, July 2008

Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)–1/TIM4 interaction as a therapeutic strategy in a dendritic cell–induced peanut allergy model

Bai-Sui Feng, MD, PhD
- Brain-Body Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- Department of Gastroenterology, Zhengzhou University, Zhengzhou, China
Xiao Chen, MD
- Brain-Body Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
Shao-Heng He, MD, PhD
- Clinical Experimental Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Peng-Yuan Zheng, MD, PhD
- Department of Gastroenterology, Zhengzhou University, Zhengzhou, China
Jane Foster, PhD
- Brain-Body Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada
Zhou Xing, MD, PhD
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
John Bienenstock, MD
- Brain-Body Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
Ping-Chang Yang, MD, PhD
- Brain-Body Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- Reprint requests: Ping-Chang Yang, MD, PhD, BBI, Room T3330, St Joseph Hospital, 50 Charlton Ave East, Hamilton, ON, Canada L8N 4A6.

Received 25 November 2007; received in revised form 30 March 2008; accepted 28 April 2008. published online 11 June 2008.

Background

Recent reports indicate that dendritic cell (DC)–derived T-cell immunoglobulin and mucin domain molecule (TIM)–4 plays an important role in the initiation of T_H2 polarization. This study aims to elucidate the mechanisms of peanut allergy mediated by microbial products and DCs and the relationship between peanut allergy and TIM4.

Methods

Mouse bone marrow–derived DCs (BMDCs) were generated and exposed to cholera toxin (CT) or/and peanut extract (PE) for 24 hours and then adoptively transferred to naive mice. After re-exposure to specific antigen PE, the mice were killed; intestinal allergic status was determined.

Results

Increased expression of TIM4 and costimulatory molecules was detected in BMDCs after concurrent exposure to CT and PE. Adoptively transferred CT/PE-conditioned BMDCs resulted in the increases in serum PE-specific IgE and skewed T_H2 polarization in the intestine. Oral challenge with specific antigen PE induced mast cell activation in the intestine. Treating with Toll-like receptor 4 small interfering RNA abolished increased expression of TIM4 and costimulatory molecules by BMDCs. Pretreatment with anti-TIM1 or anti-TIM4 antibody abolished PE-specific T_H2 polarization and allergy in the intestine.

Conclusion

Concurrent exposure to microbial product CT and food antigen PE increases TIM4 expression in DCs and promotes DC maturation, which plays an important role in the initiation of PE-specific T_H2 polarization and allergy in the intestine. Modulation of TIM4 production in DCs represents a novel therapeutic approach for the treatment of peanut allergy.

Key words: Intestine, peanut allergy, T_H cell, dendritic cell, bacteria

Abbreviations used: BMDC, Bone marrow-derived dendritic cell, CFSE, Carboxyfluorescein diacetate succinimidyl ester, C-mice, Mice in which bone marrow-derived dendritic cells were stimulated with cholera toxin alone, CP-mice, Mice in which bone marrow-derived dendritic cells were stimulated with both cholera toxin and peanut extract concurrently, CT, Cholera toxin, DC, Dendritic cell, LPMC, Lamina propria–derived mononuclear cell, PE, Peanut extract, P-mice, Mice in which bone marrow-derived dendritic cells were stimulated with peanut extract alone, RNAi, RNA interference, TIM, T-cell immunoglobulin and mucin domain molecule, TLR, Toll-like receptor