Cow's milk protein sensitisation in neonatal necrotising enterocolitis is replaced by increased transforming growth factor-beta1 response after recovery: a mechanism for tolerance induction

Abstract

<h3>Background</h3> The authors have previously made a novel observation of cow9s milk protein (CMP) sensitisation of the peripheral blood mononuclear cells (PBMCs) in acute necrotising enterocolitis (NEC).1 These findings may be of clinical relevance in view of the association between NEC and formula feeding. The role of regulatory/tolerogenic cytokines has not been investigated, neither the fate of this phenomenon following recovery form NEC. <h3>Objective</h3> Evidence of cow9s milk protein specific, effector and regulatory, cytokine response is investigated in preterm infants in acute NEC, and at term compared to healthy preterm controls. <h3>Methods</h3> 28 preterm infants, 14 stage II or III modified Bell9s classification NEC babies (median postconceptional age (PCA); 32.5 (range 29–36 weeks)) and 14 PCA-matched healthy controls (median PCA; 32.5 (range 29–36) weeks) were recruited. Unstimulated, and antigen (casein and β-lactoglobulin (β-lg))- and mitogen-stimulated interferon (IFN)-γ, interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-beta1-secreting cells in PBMCs were counted by the single-cell enzyme linked immunospot (ELISPOT) assay. <h3>Results</h3> During the acute-stage disease, preterm NEC babies showed a general pattern of higher responses to PHA compared to healthy preterm controls (10 fold increase) for IFN-γ, IL-4, IL-10 (p=0.002) and threefold for TGF-β1, strong responses to β-lg (10-fold increase) for IFN-γ, IL-4 and IL-10 (p=0.002) and 3 fold for TGF-beta1 and a smaller (fivefold) casein responses (p=0.002) and threefold for TGF-beta1. At term, following clinical recovery in NEC cases, the IFN-γ, IL-4, IL-10 response to β-lg and casein declined (between 3 and 10-fold), whereas TGF-beta1 secretion response had increased by eight and sixfold (p=0.002). <h3>Conclusion</h3> The change in cytokine response profile to dietary antigens (fall in IFN-γ, IL-4, IL-10, increase in TGF-beta1) from acute disease to term (recovered from NEC) may represent a mechanism by which infants become tolerant to CMP, following initial sensitisation.