Regulatory dendritic cell approaches for asthma immunotherapy

International Conference and Exhibition on Lung Disorders & Therapeutics

July 13-15, 2015 Baltimore, Maryland, USA

John R Gordon

Posters-Accepted Abstracts: J Pulm Respir Med

Abstract :

Asthma affects some 300 million people globally and kills â??250,000 annually. While we can manage most asthmatics pharmacologically these therapies are life-long symptom-based approaches and do not address the underlying Th2 immunologic basis of the disease. What we need are therapies that will reverse these Th2 responses such that the treated individual responds to their allergens in the same way as healthy subjects by mounting regulatory T cell (Treg) responses. Tolerogenic dendritic cells (DC) are found in many body compartments but can also be generated in vitro from bone marrow or monocyte precursors by DC differentiation in the presence of mediators like IL-10, dexamethasone or retinoic acid (RA; reviewed in Front Imm 5:7, 2014). For example, treatment of severely asthmatic mice with allergen-presenting IL-10-induced DC (DC10) abrogates airway hyper responsiveness (AHR) within 3 week of treatment in an IL-10-dependent fashion and progressively diminishes all other asthma traits to background for at least 8 mo. DC10 induce Th2 effector T cells to transdifferentiate into CD25+Foxp3+Treg. Human monocyte-derived DC10 similarly suppress autologous Th2 cells converting these into CD25+LAG3+Foxp3+Treg. However, given that some inflammatory environments can suppress Foxp3 expression by such Treg and thereby convert the Treg into highly pathogenic Th17 cells, we have also developed protocols to generate RA-induced DC (DC-RA) which in turn can induce Th2 cells to differentiate into CD25+LAG3+CD49b-Foxp3-Treg in an IL- 27-dependent fashion. Thus, we have the option of inducing distinct kinds to Treg to suit different pathologies.