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Secretory IgA Kinetics in a Healthy Model of Transamniotic Fetal Immunotherapy (TRAFIT)
Ashlyn E Whitlock, MD1,2 , Kamila Moskowitzova, MD1,2, Daniel F Labuz, MD1,2, Ina Kycia, PhD1,2, David Zurakowski, PhD1,2, Nikki Sewal1, Kate Mullin1, Dario O Fauza, MD, PhD1,2
1Boston Childrens Hospital, Boston, MA; 2Harvard Medical School, Boston, MA
Background: The transamniotic route has been recently shown experimentally to be a viable alternative for the administration of immunoglobulins to the fetus, though only with immunoglobulin-G. We sought to determine whether secretory immunoglobulin-A (SIgA), a larger dimer molecule that is responsible for mucosal immunity and known to prevent necrotizing enterocolitis, would also be amenable to transamniotic delivery.
Methods: Fetuses (n=94) from time-dated Sprague-Dawley dams (n=7) received intra-amniotic injections on gestational-day 17 (E17, term=E21-22) of either saline (n=15) or a solution of 1mg/mL human SIgA (n=79). Animals were euthanized at either E18 (n=13), E19 (n=11), E20 (n=13), or E21 (n=42) for quantification of IgA by ELISA at gestational membranes, placenta, and select fetal anatomical sites. Statistical analysis was by Mann-Whitney U-test with Bonferroni-adjusted significance.
Results: Overall survival was 89.4% (84/94). None of the saline-injected animals had detectable human IgA, confirming its lack of rodent homology. SIgA-injected fetuses showed human IgA in the stomach aspirate, intestinal wall, lungs, liver, and serum at all time points. Overall, IgA levels were significantly higher in the gastric aspirate and in the intestine than in all other sites (p<0.001), with intestinal levels remaining stable through E18-E21 (p=0.09-0.62). Serum and placental levels were consistently low throughout, reaching near zero levels by E21.
Conclusion: The chronology of exogenous secretory-IgA kinetics after intra-amniotic injection suggests fetal uptake by ingestion, leading to consistent levels in the gastrointestinal-tract. Transamniotic fetal immunotherapy with secretory-IgA may become a novel strategy for enhancing neonatal mucosal immunity, possibly contributing to the prevention of necrotizing enterocolitis.
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