면역계 내 보조 T세포의 분화 조절 과정에 대한 수학적 모델링과 분석

Abstract

Airway exposure levels of lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid(poly I:C) are known to promote different types of T helper cell induced experimental asthma. While low doses of LPS or poly I:C derive Th2 inflammatory responses, high (or intermediate) levels induce Th1- or Th17-dominant responses. The present thesis develops mathematical models of the phenotypic switches among three Th phenotypes (Th1, Th2, and Th17) in response to various LPS or poly I:C levels. In the present work we simplify the complex network of the interactions between cells and regulatory molecules. The first model describes the nonlinear cross-talks between the IL-4/Th2 activities and a key regulatory molecule, transforming growth factor β (TGF-β), in response to high, intermediate, and low levels of LPS. The model characterizes development of three phenotypes (Th1, Th2, and Th17) and predicts the onset of a new phenotype, Th17, under the tight control of TGF-β. The second model describes the interactions between IL-12/Th1, IL-6/Th17, and IL-4/Th2 activities, in respose to various levels of poly I:C. Analysis of the models illustrates the mono-, bi-, and oneway-switches in the key regulatory parameter sets in the absence or presence of time delays. The models predicts coexistence of those phenotypes and Th1- or Th2-dominant immune responses in a spatial domain under various biochemical and bio-mechanical conditions in the microenvironment. Stochasticity also enables immune responses to move into another phenotypes without time delays or spatial effects.