MODULATION OF THE NEONATAL T CELL-MEDIATED IMMUNE RESPONSE BY MATERNALLY DERIVED STRESS HORMONES

Open Access
Author:
Zahwa, Hassan
Graduate Program:
Cell and Molecular Biology
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
June 02, 2008
Committee Members:
  • Ralph Lauren Keil, Committee Member
  • Todd Schell, Committee Member
  • Joan S Long, Committee Member
  • Robert Harold Bonneau, Committee Chair
Keywords:
  • stress
  • neonatal immune
  • T cell adaptive immunity
  • Herpes Simplex Virus
  • maternal stress
Abstract:
A simple National Library of Medicine title search for the term “psychological stress” returns over 1400 titles, the majority of which address the impact of stress on the adult immune system. Despite this plethora of psychological stress-related publications, only a handful address the impact of stress on neonatal immunity. Neonates are vaccinated within hours of delivery to generate an immune response that is maintained in some instances for the remainder of the individual’s life. Neonates begin to receive vaccinations while they are almost entirely dependent on their mother for nutrition and care. Maternally derived hormones, reflecting the mother’s psychological and physical conditions, are passed to the neonate via the breast milk. This passage could potentially expose the neonate to several immunomodulatory peptides, namely glucocorticoids and epinephrine. These hormones are known to hinder the adult immune response in the context of infection. The neonate is no exception, as exposure to maternally derived stress hormones hinders the primary T cell mediated adaptive immune response to herpes simplex virus type-1 infection (HSV-1). Neonatal exposure to stress-like levels of glucocorticoids increased HSV-related morbidity and mortality via type II glucocorticoid receptor dependent mechanisms. When examined ex vivo, this exposure 1) reduced overall splenic cellularity, 2) hindered the ability to CTL to expand clonally, 3) express adequate levels of IL2Rα, 4) lyse HSV-infected cells, and 5) produce pro-inflammatory cytokines. The hindrance of the primary immune response to HSV-1 infection is extended to the CTL memory repertoire. Moreover, these effects on the primary and memory HSV-specific T cell repertoires were reversed with the administration of a glucocorticoid receptor antagonist. The administration of a glucocorticoid receptor antagonist prevented the HSV-related mortality. These findings clearly demonstrate a role for glucocorticoids in the modulation of the neonatal immune system in response to infection. These findings warrant an in-depth review of the clinical practices related to neonatal immunization. Moreover, these findings also shed some light on the importance of managing post-partum maternal stress as exposure of the neonate to maternally derived hormones imprints the neonate’s immune system with both immediate and lifelong consequences.