The Problem: Maternal asthma is an important risk factor for development of asthma in children, but mechanisms are poorly characterized. We have developed a murine model of maternal transmission of susceptibility to asthma which will allows for the first time testing of specific postulates about maternal effects. Similar to epidemiologic data for humans, we find that babies from 'asthmatic' mother mice (ovalbumin model) can easily be rendered 'asthmatic' (enhanced airway hyperresponsiveness, and allergic pulmonary inflammation) by exposure to inhaled allergen, while normal baby mice cannot. Hypothesis: Our central hypothesis is that maternal transmission of asthma susceptibility occurs via mediator(s) transferred both during gestation and via nursing. The most likely 'suspects' are cytokines (e.g., Th2-mediators such as IL-4, 5, 13), but the role of antibodies, immune cells, and antigen also merit investigation. Experimental Plan:
Aim 1 will complete the substantial pilot studies to test the hypotheses that: 1) maternal asthma causes increased susceptibility to asthma in newborns; 2) maternal transmission of asthma risk includes allergen-specific and broader allergen non-specific components; 3) transfer of component(s) via breast milk are necessary, but not sufficient, for increased susceptibility; 4) susceptibility will be abrogated by treatment with Th1-promoting agents such as the cytokines IL- 12 and 18 or CpG oligonucleotides.
Aim 2 will test the hypotheses that breast milk promotes susceptibility via transfer of a) cytokines; b) antibody; c) immune cells; d) allergen; or e) a combination of these putative mediators. By combining adoptive nursing by normal mice and oral replacement of suspect mediators, we will identify which agents play a mechanistic role.
Aim 3 will test the hypotheses that transplacental transfer of a) cytokines; b) antibody; c) immune cells; d) allergen; or e) a combination promotes susceptibility to asthma in newborns. For cytokines implicated, we will test causality by via neutralizing antibodies given during gestation. Significance: This research is relevant to the public health question of how maternal asthma promotes development of asthma in children and to the pathophysiology of allergy in early life.
