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Date of Award

Fall 2011

Degree Type

Thesis

Degree Name

Master of Science in Medical Sciences (MSMS)

Department

Health Sciences

Supervisor

Manel Jordana

Co-Supervisor

Dawn Bowdish, Martin Stampfli

Language

English

Committee Member

Dawn Bowdish, Martin Stampfli

Abstract

Background: Early infancy is a critical period during which the interplay between host and environmental factors influences susceptibility to allergic sensitization, a process that can also be construed as a failure to induce tolerance. Indeed, allergic asthma emerges, in most instances, in early childhood although the specific intervals of protection or susceptibility remain to be elucidated. We found that exposure to a concentration of allergen, house dust mite (HDM), that normally induces robust airway inflammation in adult mice elicits negligible immune-inflammatory responses in infant mice.

Methods: We investigated immune-inflammatory responses in mice exposed to 25 μg of HDM intranasally for 10 consecutive days at different points in development (3, 4, 5 and 7 weeks of age). We delineated the immune cell profile in the lungs of naïve mice from birth to adulthood, focusing on markers of immune maturation and immunosuppression. Moreover, we studied the impact of T-regulatory cell (Treg) depletion with the use of α-CD25 antibodies administered intraperitoneally one day prior to the start of HDM exposures, and then again on day 6 of the above protocol.

Results: Our data show that there is a progressive acquisition of immune-inflammatory responsiveness to HDM in BALB/c mice as exposures are initiated later in development, evidenced by total cell number and eosinophilia in the BAL and serum HDM-specific IgG1 levels. Additionally, there is an immunological shift that occurs in the infant lung during development in that the early immunosuppressive environment, defined by T-regulatory cells and immunosuppressive alveolar macrophages, subsides as the capacity to respond to ensuing immune challenges, defined by natural killer (NK) cell, dendritic cell (DC) and alveolar macrophage (AM) maturation, increases. Specifically, in regards to the immunosuppressive lung environment during infancy, we identified higher baseline levels of CD25+Foxp3+CD101+ and CD25+Foxp3high Tregs, i.e. those with more potent suppressive ability. These populations also expand following HDM exposure in both adult and infant mice. Interestingly, 2 week-old infant mice depleted of Tregs or exposed to a very high dose of HDM (125 μg) overcome the natural immunosuppressive environment resulting in the acquisition of HDM responsiveness, as manifested by robust Th2 immune-inflammatory responses, comparable to that observed in 8 week-old adult mice.

Conclusion/Implications: Together, our data suggest that the hyporesponsiveness to HDM very early in life may be explained by two connected events: a) the inherent immunosuppressive environment in the lung, and b) the immaturity of the machinery for effective immune responses. Furthermore, we demonstrate that a disruption in the homeostatic immune balance in infancy, Treg depletion in this case, may lead to the imprinting of aberrant immune-inflammatory responses, like allergen sensitization. Thus, the inherent immunosuppressive environment in infancy may have long-term implications on allergen responsiveness.

McMaster University Library

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