T Cell Cytokine Changes During IL-4 Receptor Treatment for Asthma

Overview

Asthma is a chronic inflammatory disorder of the airways characterized by reversible airflow obstruction. Fourteen million people (6.4%) in the United States report having asthma, and from 1980 to 1994 the prevalence of self-reported asthma in the United States increased 75%. Interleukin-4 (IL-4) plays a key role in this response by promoting IgE production, upregulating IgE receptors, upregulating adhesion receptors such as VCAM-1, promoting Th2 cell development and promoting mucus secretion. A soluble form of the receptor for IL-4 (IL-4R) that has antagonist activity has been developed for clinical use. Soluble IL-4R acts by competing with endogenous cell bound IL-4R for free IL-4, thus inhibiting IL-4 function. IL-4 is required for the development of allergen specific Th2 memory cells. Less well understood are the factors required for maintenance of Th2 responses. The maintenance of polarized Th2 responses to allergens have been postulated to require IL-4 itself, by acting as an anti-apoptotic/survival factor or by differentiating naive allergen specific T cells to the Th2 phenotype. Subjects on sIL-4 therapy represent a unique patient group that possess allergen specific Th2 cells, but in which the capacity for IL-4 to promote further Th2 cell survival or differentiation has been blocked. This is a single site adjunct study proposed to study subjects ages 14 years and older who are enrolled at the NIH Clinical Center on a multicenter trial of IL-4R in moderate to severe asthma (Phase II Efficacy Study of Aerosolized Recombinant Human IL-4 Receptor in Asthma). A maximum of 40 subjects will be enrolled. We hypothesize that effective blocking of such Th2 priming would result in a decreased frequency of both allergen specific Th2 cells as well as mitogen activated Th2 cells. Determination of the fate of Th2 cell responses during long term IL-4R therapy may have important implications both for future development of anti-cytokine therapies as well as for understanding the T cell biology of allergic diseases and asthma.

Asthma is a chronic inflammatory disorder of the airways characterized by reversible airflow obstruction. Fourteen million people (6.4%) in the United States report having asthma, and from 1980 to 1994 the prevalence of self-reported asthma in the United States increased 75%. Interleukin-4 (IL-4) plays a key role in this response by promoting IgE production, upregulating IgE receptors, upregulating adhesion receptors such as VCAM-1, promoting Th2 cell development and promoting mucus secretion. A soluble form of the receptor for IL-4 (IL-4R) that has antagonist activity has been developed for clinical use. Soluble IL-4R acts by competing with endogenous cell bound IL-4R for free IL-4, thus inhibiting IL-4 function. IL-4 is required for the development of allergen specific Th2 memory cells. Less well understood are the factors required for maintenance of Th2 responses. The maintenance of polarized Th2 responses to allergens have been postulated to require IL-4 itself, by acting as an anti-apoptotic/survival factor or by differentiating naive allergen specific T cells to the Th2 phenotype. Subjects on sIL-4 therapy represent a unique patient group that possess allergen specific Th2 cells, but in which the capacity for IL-4 to promote further Th2 cell survival or differentiation has been blocked. This is a single site adjunct study proposed to study subjects ages 14 years and older who are enrolled at the NIH Clinical Center on a multicenter trial of IL-4R in moderate to severe asthma (Phase II Efficacy Study of Aerosolized Recombinant Human IL-4 Receptor in Asthma). A maximum of 40 subjects will be enrolled. We hypothesize that effective blocking of such Th2 priming would result in a decreased frequency of both allergen specific Th2 cells as well as mitogen activated Th2 cells. Determination of the fate of Th2 cell responses during long term IL-4R therapy may have important implications both for future development of anti-cytokine therapies as well as for understanding the T cell biology of allergic diseases and asthma.