Experimental approaches to analysis of immune dysregulation in human allergic disease

Over the last 40 years, much attention has been directed towards identification of the immunologic, genetic and environmental factors that predispose towards development of allergic disease. An implicit assumption in many such studies is that clinical tolerance reflects from immunologic tolerance. Here we critically review the conceptual background and experimental data arguing for the alternative hypothesis that failure to develop atopic disease reflects the success of type 1 dominated immunity that constitutively impedes development of type 2 responses to environmental antigens, hence, clinical immediate hypersensitivity. We report that endogenous production of type 1 chemokines such as IP-10 by non-atopic individuals may play a substantive 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 quantitatively different IFNgamma:IL-4 ratios in primary culture of human PBMC. In parallel, physiologic stimuli such as grass pollen or cat antigen were used to evaluate the impact of IP-10 on CD4 T cell dependant, chloroquine-sensitive cytokine synthesis. IFNgamma responses by non-atopic subjects were markedly increased in the presence of nM concentrations of rhIP-10 while type 2 cytokine synthesis remained unaffected. Optimal rIP-10 concentrations for promoting expression and maintenance of type 1 cytokine synthesis in vitro (0.1 to 10 ng/ml) were at or well below those generally used for chemotaxis (5 to 100 ng/ml). Collectively, our findings suggest a potential role for this T cell focused chemokine in maintaining the default type 1 responses usually caused to environmental antigens in non-atopic subjects. These may play a role in determining the relative susceptibility of individuals to develop atopic disease. Taken together with recent reports of other roles played by chemokines in shaping the nature of immune responses, the data suggest that constitutive, endogenous type 1 chemokine synthesis may play a homeostatic role in inhibiting development of atopic disease.