GENERATION OF IMMUNE RESPONSES IN EXPERIMENTAL ALLERGIC AIRWAY INFLAMMATION

Abstract

<p>Allergic diseases, including asthma, result from airway inflammatory responses directed against ubiquitous antigens-allergens. The detailed immunological mechanisms underlying the development of allergy (allergic sensitization) have not been fully elucidated. Our understanding of the complexity of cellular interactions underlying allergic inflammation originates mainly, but not exclusively, from studies in experimental animal models. The studies presented in this thesis utilize experimental mouse models of anti-geninduced allergic airways inflammation in order to investigate 1) the events occurring during sensitization (primary immune responses) and following re-challenge (secondary immune responses) in two immunologically important sites: lungs and lymph nodes following experimental allergen (ovalbumin; OVA) exposure; 2) the role of the secondary lymphoid organs vs. lungs in elicitation of immune responses to allergen; 3) the importance of two major costimulatory pathways - CD28/B7 and ICOS/B7RP-1 - in the generation of allergic airways inflammation. Findings presented here indicate that introduction of antigen leads to vigorous T and B cell activation in the draining lymph nodes. Such activation translates into the acquisition of a Th2 phenotype, an important step in the generation of allergic sensitization. Considering the multitude of changes occurring in the draining lymph nodes, the importance of lymph nodes during sensitization was investigated in mice devoid of lymph nodes - Iymphotoxin (l deficient mice. The study demonstrated the absolute requirement of lymphoid organs, either lymph nodes or spleen in generating of Th2-type inflammatory responses. Finally, studies on CD28 and B7RP-1 deficient mice indicated that, whereas the CD28/B7 pathway is necessary for the establishment of allergic airway inflammation, the ICOSIB7RP-1 pathway is redundant. The data presented in this thesis identifies several important aspects by which the immune system generates efficient allergic airway inflammation. As we suspect that new-sensitization occurs after each exposure to allergens. information in this thesis may provide insights into novel therapeutic strategies.</p>