Purpose:
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.
Study summary:
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.
Criteria:
Patients must be 14 years of age or older.
Must be participating in 99-I-0115 "Phase II Efficacy Study of Aerosolized Recombinant
Human IL-4 Receptor in Asthma".
If younger than 18 years old, must weigh 50 kg or more.
Must have HIV seronegativity.
Must not have hemoglobin less than 12 g/dL.