Experimental approaches to analysis of immune dysregulation in human allergic disease

Over the last 40 years, much attention has been directed towards identifica tion of the immunologic, genetic and environmental factors that predispose towards development of allergic disease. An implicit assumption in many suc h studies is that clinical tolerance reflects from immunologic tolerance. H ere we critically review the conceptual background and experimental data ar guing for the alternative hypothesis that failure to develop atopic disease reflects the success of type 1 dominated immunity that constitutively impe des development of type 2 responses to environmental antigens, hence, clini cal immediate hypersensitivity. We report that endogenous production of typ e 1 chemokines such as IP-10 by non-atopic individuals may play a substanti ve role in maintaining this putatively protective type 1 bias in non-atopic subjects. Polyclonal activators (superantigen TSST-1, anti-CD3, PHA) were used to activate distinct intracellular signaling pathways, inducing quanti tatively different IFN gamma:IL-4 ratios in primary culture of human PBMC. In parallel, physiologic stimuli such as grass pollen or cat antigen were u sed to evaluate the impact of IF-10 on CD4 T cell dependant, chloroquine-se nsitive cytokine synthesis. IFN gamma responses by non-atopic subjects were markedly increased in the presence of nM concentrations of rhIP-10 while t ype 2 cytokine synthesis remained unaffected. Optimal rIP-10 concentrations for promoting expression and maintenance of type 1 cytokine synthesis in v itro (0.1 to 10 ng/ml) were at or well below those generally used for chemo taxis (5 to 100 ng/ml). Collectively, our findings suggest a potential role for this T cell focused chemokine in maintaining the default type 1 respon ses usually caused to environmental antigens in non-atopic subjects. These may play a role in determining the relative susceptibility of individuals t o develop atopic disease. Taken together with recent reports of other roles played by chemokines in shaping the nature of immune responses, the data s uggest that constitutive, endogenous type 1 chemokine synthesis may play a homeostatic role in inhibiting development of atopic disease. (C) 2000 Else vier Science B.V. All rights reserved.