Transplacental immune modulation with a bacterial-derived agent protects against allergic airway inflammation

Abstract

Chronic allergic inflammatory diseases are a major cause of morbidity, with allergic asthma alone affecting over 300 million people worldwide. Epidemiological studies demonstrate that environmental stimuli are associated with either the promotion or prevention of disease. Major reductions in asthma prevalence are documented in European and US farming communities. Protection is associated with exposure of mothers during pregnancy to microbial breakdown products present in farm dusts and unprocessed foods and enhancement of innate immune competence in the children. We sought to develop a scientific rationale for progressing these findings toward clinical application for primary disease prevention. Treatment of pregnant mice with a defined, clinically approved immune modulator was shown to markedly reduce susceptibility of their offspring to development of the hallmark clinical features of allergic airway inflammatory disease. Mechanistically, offspring displayed enhanced dendritic cell-dependent airway mucosal immune surveillance function, which resulted in more efficient generation of mucosal-homing regulatory T cells in response to local inflammatory challenge. We provide evidence that the principal target for maternal treatment effects was the fetal dendritic cell progenitor compartment, equipping the offspring for accelerated functional maturation of the airway mucosal dendritic cell network following birth. These data provide proof of concept supporting the rationale for developing transplacental immune reprogramming approaches for primary disease prevention.

Transplacental innate immune training via maternal microbial exposure: the XBP1-ERN1 axis in programming dendritic cell precursors

“…Previous studies from our laboratory have additionally identified postnatal expansion of bone marrow myeloid progenitor (MP) cell populations as an effect of maternal treatment with OM-85 during pregnancy (8). Based on these findings, we hypothesised that the enhanced cDC population within fetal bone marrow following maternal OM-85 treatment would also be accompanied by concomitant upregulation of upstream MP subsets.…”

“…In summary, the data presented here builds on forerunner human (4,24) and experimental animal (8,34,35) studies providing evidence that non-pathogenic maternal microbial-associated exposures during pregnancy can be transcribed transplacentally into beneficial immune training signals for the developing fetus. We provide direct evidence that maternal OM-85 treatment during pregnancy transplacentally accelerates functional immunocompetence of fetal bone marrow cDCs and for the first time identify the transcription factor XBP1 as a putative driver of this immune training mechanism.…”

“…In this regard, we recently reported in The Journal of Clinical Investigation that oral treatment of pregnant mice with the microbial-derived immunomodulatory agent OM-85 reduces susceptibility of their offspring to the development of Th2-driven allergic airways inflammation, and identified the offspring bone marrow as the primary target for maternal treatment effects (8). In the study presented here, we sought to identify the transplacental immune training mechanisms underpinning this protection, focusing on the fetal bone marrow as a potential mechanistic target.…”

Training the Fetal Immune System Through Maternal Inflammation—A Layered Hygiene Hypothesis

“…For example, exposure to farm animal shed during pregnancy is also a major factor in modifying immune function and reducing risk of allergic disease in offspring (3) and correlates with enhanced induction of cord blood T regulatory cells (67). When modeled in mice, in a maternal TLR-dependent manner, endotoxin exposure during pregnancy ameliorates allergic sensitivities in the progeny of exposed dams (68) and increases tracheal Treg percentages (69). Conversely, anti-helminth therapy given during pregnancy correlates with increased allergic eczema in newborns, suggesting immune training afforded by the maternal environment impacts immunity to unrelated antigens (70).…”

High-Dimensional Immunophenotyping of Murine T-cell and B-cell Subsets

“…As such, a degree of emphasis was placed on effector, regulatory and memory subsets within T-cell and B-cell populations. In regards to Tcells, the conversion of peripheral naïve CD4 + T-cells to T-effector (Teff) cells is denoted by upregulation of the activation marker CD25, while concomitant upregulation of both CD25 and intracellular Foxp3 expression is essential for the peripheral induction of regulatory T cells (Treg) 7 , a process previously recognised in the protection against allergic airways inflammation following microbial-derived immunomodulation 8,9 . Furthermore, the expression of CD44 on splenic Treg has been implicated in promoting enhanced function 10 .…”