Maternal immunomodulation as a strategy to protect offspring against asthma

Studies of traditional European and US farming populations have documented major reductions in asthma prevalence in children of mothers exposed during pregnancy to microbial breakdown products present in farm dust and unprocessed foods. The mechanisms driving protection appear associated with enhancement of innate immune competence in the offspring leading to optimisation of immunoregulatory and effector cell function. The potential to therapeutically harness this environmental phenomenon represents a plausible strategy in the primary prevention of asthma. Using preclinical mouse models, we sought to identify if a safe ǀ microbial-derived immunomodulatory therapeutic could recapitulate the "farm effect" phenomenon. We demonstrate that maternal oral treatment during pregnancy with the clinically-approved bacterial-derived immunomodulator OM-85, markedly reduces the susceptibility of offspring to development of allergic airways inflammation initiated at weaning. This was exemplified by attenuation of granulocytic infiltration and airways hyperresponsiveness following airways challenge. Protection was linked to the recruitment of T-regulatory cells to airways mucosa exhibiting enhanced CTLA-4 and Foxp3 expression, with parallel attenuation of local cDC trafficking to airway draining lymph nodes and inflammation associated recruitment and activation. Moreover, these offspring display a striking attenuation of the inflammatory response in the bone marrow myeloid precursor compartments, consistent with the reduced mobilisation of cDC bone marrow reserves and granulocytic accumulation within the airways. The mechanistic actions of OM-85 on bone marrow precursors could be traced back to in utero development, whereby maternal OM-85 treatment boosts myeloid progenitor cells within fetal bone marrow whilst simultaneously accelerating DC functional immune competence as evident by upregulated IA/IE expression. In vitro validation of OM-85-induced immunomodulatory effects on bone marrow DCs further identified an enhanced capacity for homeostatic regulation via attenuation of IA/IE and CD86 hyperresponsiveness to LPS stimulation. Our results demonstrate for the first time that oral treatment of mothers during pregnancy with a bacterial-derived therapeutic transplacentally accelerates functional immunocompetence of the fetal innate myeloid compartment, which subsequently protects offspring against the development of allergic airways inflammation.