title: Co-administration of CD40 agonistic antibody and antigen fails to overcome the induction of oral tolerance.
abstract: T-cell stimulation in the absence of a second, costimulatory signal can lead to anergy or deletion. There is growing evidence that peripheral tolerance to an exogenous antigen might be caused by the lack of costimulatory molecules on antigen-presenting cells (APCs). In the present study, we examined whether tolerance against orally administered antigen could be reversed by maturation of APCs via CD40 signalling. Monoclonal antibody (mAb) to CD40 efficiently induced costimulatory molecules on APCs. Treatment with anti-CD40 mAb potentiated the division of ovalbumin-specific T cells in response to oral ovalbumin in secondary lymphoid organs. However, such treatment did not prolong the presentation of oral ovalbumin on APCs. Surprisingly, treatment of anti-CD40 mAb at the time of oral administration of ovalbumin did not reverse the induction of tolerance to ovalbumin in either the high- or low-dose regimens. Furthermore, the induction of oral tolerance in our model is not the result of negative signalling by cytotoxic T-lymphocyte antigen-4. These results indicate that tolerance for oral antigen could be established regardless of APC maturation by a CD40-specific mAb, suggesting that there could be a unique mechanism to regulate immunity versus tolerance to encountered antigen in the gut-associated lymphoid tissue.
authors.affiliation: Laboratory of Immunology, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Yeonseok
authors.initials: Y
authors.lastname: Chung
authors.forename: Dong-Hyeon
authors.initials: DH
authors.lastname: Kim
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Chang-Yuil
authors.initials: CY
authors.lastname: Kang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D019013:CD40 Antigens / Q000008:administration & dosage* / Q000276:immunology; D060908:CTLA-4 Antigen; D004334:Drug Administration Schedule; D005260:Female; D007108:Immune Tolerance; D007422:Intestines / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D010047:Ovalbumin