Anti-inflammatory immune competence in the acutely malnourished weanling mouse

Monk, Jennifer Michelle
Journal Title
Journal ISSN
Volume Title
University of Guelph

This thesis is an investigation centered on identifying the potential underlying contributors toward the classically depressed inflammatory cell-mediated form of immune competence in acute (i.e., wasting) protein energy malnutrition (PEM). Two metabolically distinct weight loss pathologies, marasmus (energy deficit) and incipient kwashiorkor (dietary protein deficit), which mimic the critical features of the human condition were reproduced in weanling C57BL/6J mice. In the advanced stages of carcass energy losses we demonstrated the dominance of a type-2 polarizing influence within the effector/memory T cell compartment, wherein systemic production of interferon(IFN)-[gamma] was depressed and intereukin(IL)-4 production was sustained. The hormonal response to wasting pathology, which exerts a permissive influence on the aforementioned polarization phenomenon, prompted an investigation into the anti-inflammatory and tolerogenic form of immune competence. Using appropriately crafted assay strategies, blood levels of a triad of hormones glucocorticoids (GC), transforming growth factor (TGF)-[beta] and IL-10 were determined to rise early and remain elevated despite advancing weight loss. Thus, this hormonal triad is positioned temporally to act in both an initiating and sustaining capacity in acute malnutrition. Mechanistically, the elevated blood IL-10 levels in acute PEM are likely attributed to new cytokine production, as evidenced by increased or sustained levels of mRNA expression in lymphoid organs and a systemic cytokine protein production rate that is at least sustained throughout the duration of wasting pathology. Anti-inflammatory immune competence consists of tiers, wherein the aforementioned outcomes represent a primary tier. The capacity to produce IL-10 above constitutive levels, i.e., second tier responses to stimuli, in the innate and combined innate and adaptive arms of the immune system were depressed in the advanced stages of weight loss wherein carcass energy losses were the most pronounced. Overall, the outcomes of this thesis provide the experimental basis supporting the proposition that malnutrition-associated immune depression represents a regulated pathophysiology wherein the anti-inflammatory and tolerogenic form of immune competence is preserved and likely to play an initiating role in inflammatory immune depression. A new model emerges wherein the adaptive benefit conferred via a triad of anti-inflammatory hormones is the active suppression of inflammatory immune responses generated against catabolically released self-antigens.

anti-inflammatory, immune competence, malnutrition, weanling mouse, marasmus, incipient kwashiorkor