Maternal Nutrition During Pregnancy: Intake of Nutrients Important for Bone Health.

Objectives Maternal nutrition during pregnancy plays an important role in predisposing offspring to the development of chronic disease in adulthood, including osteoporosis. Our aim was to investigate maternal dietary intakes during pregnancy, with a focus on nutrients important for skeletal development in the offspring. Methods In this case-control study, cases were pregnant women recruited for the Vitamin D in Pregnancy Study (n = 350, age 20-40 years) and controls were non-pregnant peers participating in the Geelong Osteoporosis Study (n = 305, age 20-40 years). Dietary intakes of nutrients were quantified using a validated food frequency questionnaire. Results Compared to controls, cases consumed more energy [median (interquartile range): 7831 (6506-9461) vs. 7136 (6112-8785) kJ/day]; median intakes for cases were greater for carbohydrates [206.2 (172.5-249.9) vs. 188.2 (147.7-217.5) g/day], fat [77.9 (60.3-96.6) vs. 72.1 (53.3-87.4) g/day], potassium [2860 (2363-3442) vs. 2606 (2166-3442) mg/day] and calcium [1022 (819-1264) vs. 918 (782-1264) mg/day] (all p ≤ 0.05). However, pregnant women were not consuming greater amounts of those nutrients which had an increased demand (protein, magnesium, phosphorus and zinc). Similarly, this translated to the likelihood of achieving national recommendations for corresponding nutrients. Conclusions for Practice Compared to their non-pregnant peers, pregnant women were more likely to meet dietary recommendations for calcium and potassium; however, this was not the pattern observed for protein, magnesium and zinc. Future public health messages should perhaps focus on increasing awareness of the importance of all these nutrients during pregnancy.

A retinoic acid--rich tumor microenvironment provides clonal survival cues for tumor-specific CD8(+) T cells.

While vitamin A has been implicated in host resistance to infectious disease, little is known about the role of vitamin A and its active metabolite, retinoic acid (RA) in host defenses against cancer. Here, we show that local RA production within the tumor microenvironment (TME) is increased up to 5-fold as compared with naïve surrounding tissue, with a commensurate increase in RA signaling to regionally infiltrating tumor-reactive T cells. Conditional disruption of RA signaling in CD8(+) T cells using a dominant negative retinoic acid receptor α (dnRARα) established that RA signaling is required for tumor-specific CD8(+) T-cell expansion/accumulation and protective antitumor immunity. In vivo analysis of antigen-specific CD8(+) T-cell responses revealed that early T-cell expansion was RA-independent; however, late T-cell expansion and clonal accumulation was suppressed strongly in the absence of RA signaling. Our findings indicate that RA function is essential for the survival of tumor-reactive CD8(+) T cells within the TME.

Mast cells condition dendritic cells to mediate allograft tolerance.

Peripheral tolerance orchestrated by regulatory T cells, dendritic cells (DCs), and mast cells (MCs) has been studied in several models including skin allograft tolerance. We now define a role for MCs in controlling DC behavior ("conditioning") to facilitate tolerance. Under tolerant conditions, we show that MCs mediated a marked increase in tumor necrosis factor (TNFα)-dependent accumulation of graft-derived DCs in the dLN compared to nontolerant conditions. This increase of DCs in the dLN is due to the local production of granulocyte macrophage colony-stimulating factor (GM-CSF) by MCs that induces a survival advantage of graft-derived DCs. DCs that migrated to the dLN from the tolerant allograft were tolerogenic; i.e., they dominantly suppress T cell responses and control regional immunity. This study underscores the importance of MCs in conditioning DCs to mediate peripheral tolerance and shows a functional impact of peripherally produced TNFα and GM-CSF on the migration and function of tolerogenic DCs.

Dendritic cells require the NF-kappaB2 pathway for cross-presentation of soluble antigens.

NF-kappaB-inducing kinase (NIK) is responsible for activation of the non-canonical p100 processing pathway of NF-kappaB activation. This kinase has been shown to be critical for activation of this pathway after signaling through several TNF family members including CD40. The functional importance of this pathway in CD40 and TLR-induced dendritic cell (DC) differentiation was studied in vivo in the alymphoplasia (Aly) mouse. The Aly mouse expresses a mutant NIK molecule that prohibits the induction of the non-canonical pathway. We show that while MHC class II presentation and in vivo migration of Aly DCs is intact, these cells are unable to cross-prime CD8+ T cells to exogenous Ag. Gene expression array analysis of DCs matured in vivo indicates multiple defects in Ag processing pathways after maturation and provide a global view of the genes that are regulated by the NF-kappaB2 pathway in DCs. These experiments indicate a possible role for NIK in mediating cross-priming of soluble Ag. In addition, our findings explain the profound immune unresponsiveness of the Aly mouse.

Mast cells are essential intermediaries in regulatory T-cell tolerance.

Contrary to the proinflammatory role of mast cells in allergic disorders, the results obtained in this study establish that mast cells are essential in CD4+CD25+Foxp3+ regulatory T (T(Reg))-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of T(Reg) cells, acquire a unique genetic signature dominated by the expression of mast-cell-gene products. We also show that mast cells are crucial for allograft tolerance, through the inability to induce tolerance in mast-cell-deficient mice. High levels of interleukin (IL)-9--a mast cell growth and activation factor--are produced by activated T(Reg) cells, and IL-9 production seems important in mast cell recruitment to, and activation in, tolerant tissue. Our data indicate that IL-9 represents the functional link through which activated T(Reg) cells recruit and activate mast cells to mediate regional immune suppression, because neutralization of IL-9 greatly accelerates allograft rejection in tolerant mice. Finally, immunohistochemical analysis clearly demonstrates the existence of this novel T(Reg)-IL-9-mast cell relationship within tolerant allografts.

Analysis of the underlying cellular mechanisms of anti-CD154-induced graft tolerance: the interplay of clonal anergy and immune regulation.

Although it has been shown that CD4(+)CD25(+) regulatory T cells (T(reg)) contribute to long-term graft acceptance, their impact on the effector compartment and the mechanism by which they exert suppression in vivo remain unresolved. Using a CD4(+) TCR transgenic model for graft tolerance, we have unveiled the independent contributions of anergy and active suppression to the fate of immune and tolerant alloreactive T cells in vivo. First, it is shown that anti-CD154-induced tolerance resulted in the abortive expansion of the alloreactive, effector T cell pool. Second, commensurate with reduced expansion, there was a loss of cytokine production, activation marker expression, and absence of memory T cell markers. All these parameters defined the tolerant alloreactive T cells and correlated with the inability to mediate graft rejection. Third, the tolerant alloreactive T cell phenotype that is induced by CD154 was reversed by the in vivo depletion of T(reg). Reversal of the tolerant phenotype was followed by rapid rejection of the allograft. Fourth, in addition to T(reg) depletion, costimulation of the tolerant alloreactive T cells or activation of the APC compartment also reverted alloreactive T cell tolerance and restored an activated phenotype. Finally, it is shown that the suppression is long-lived, and in the absence of anti-CD154 and donor-specific transfusion, these T(reg) can chronically suppress effector cell responses, allowing long-lived graft acceptance.