In mice and humans, the immunologic effects of developmental exposure to noninherited maternal antigens (NIMAs) are quite variable. This heterogeneity likely reflects differences in the relative levels of NIMA-specific T regulatory (T R ) versus T effector (T E ) cells. We hypothesized that maintenance of NIMA-specific T R cells in the adult requires continuous exposure to maternal cells and antigens (eg, maternal microchimerism [MMc]). To test this idea, we used 2 sensitive quantitative polymerase chain reaction (qPCR) tests to detect MMc in different organs of NI-MA d -exposed H2 b mice. MMc was detected in 100% of neonates and a majority (61%) of adults; nursing by a NIMA ؉ mother was essential for preserving MMc into adulthood. MMc was most prevalent in heart, lungs, liver, and blood, but was rarely detected in unfractionated lymphoid tissues. However, MMc was detectable in isolated CD4 ؉ , CD11b ؉ , and CD11c ؉ cell subsets of spleen, and in lineage-positive cells in heart. Suppression of delayed type hypersensitivity (DTH) and in vivo lymphoproliferation correlated with MMc levels, suggesting a link between T R and maternal cell engraftment. In the absence of neonatal exposure to NIMA via breastfeeding, MMc was lost, which was accompanied by sensitization to NIMA in some offspring, indicating a role of oral exposure in maintaining a favorable T R > T E balance. IntroductionImmunosuppressive drugs administered to prolong graft survival increase the risk of systemic infections 1 and may encourage tumor growth. 2,3 Taking advantage of natural tolerance induced by noninherited maternal antigens (NIMAs) is one of the more promising but still relatively unexplored approaches for reducing the immunosuppressive burden in organ and stem cell transplant recipients. The clinical benefits of developmentally acquired tolerance to NIMA were first noted by Owen et al 4 more than 50 years ago. Since then, tolerogenic effects of NIMA have been documented at both T-and B-cell levels in a variety of clinical settings. [5][6][7] The basis of the NIMA benefit to allograft survival is not clear. One possible explanation is that many normal babies go on to accept, as adults, a tiny transplant of cells from their mothers acquired during ontogeny and thus are already predisposed to accept a larger NIMA ϩ organ transplant. Although fetal and maternal circulations are completely separated, fetal tissue is bathed with maternal blood in animals with a hemochorial placenta (eg, mouse and human), 8,9 creating opportunities for bidrectional transfer of mature cells as well as hematopoetic and pluripotent progenitors. [10][11][12][13][14][15] Moreover, rare maternal cells in liver can be acquired through ingestion of colostrum after birth. 15 The low frequency of maternal cells present in adult offspring (Ͻ 0.1%) is called "microchimerism" (Mc), a term also applied to rare donor cells that emigrate from graft-to-host tissue after organ transplantation. It has been suggested that Mc, while providing a miniscule antigen "load" to the host,...

BackgroundIntimal hyperplasia is a common cause of many vasculopathies. There has been a recent surge of interest in the bromo and extra-terminal (BET) epigenetic “readers” including BRD4 since the serendipitous discovery of JQ1(+), an inhibitor specific to the seemingly undruggable BET bromodomains. The role of the BET family in the development of intimal hyperplasia is not known.MethodsWe investigated the effect of BET inhibition on intimal hyperplasia using a rat balloon angioplasty model.ResultsWhile BRD4 was dramatically up-regulated in the rat and human hyperplastic neointima, blocking BET bromodomains with JQ1(+) diminished neointima in rats. Knocking down BRD4 with siRNA, or treatment with JQ1(+) but not the inactive enantiomer JQ1(−), abrogated platelet-derived growth factor (PDGF-BB)-stimulated proliferation and migration of primary rat aortic smooth muscle cells. This inhibitory effect of JQ1(+) was reproducible in primary human aortic smooth muscle cells. In human aortic endothelial cells, JQ1(+) prevented cytokine-induced apoptosis and impairment of cell migration. Furthermore, either BRD4 siRNA or JQ1(+) but not JQ1(−), substantially down-regulated PDGF receptor-α which, in JQ1(+)-treated arteries versus vehicle control, was also reduced.ConclusionsBlocking BET bromodomains mitigates neointima formation, suggesting an epigenetic approach for effective prevention of intimal hyperplasia and associated vascular diseases.

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We evaluated the immunocompetence of human T cells in humanized NOD-scid IL2r-γ-null (Hu-NSG) mice bearing a human thymic organoid, after multilinegage reconstitution with isogeneic human leukocytes. Delayed type hypersensitivity (DTH) response was assessed by a direct footpad challenge of the immunized hu-NSG host, or by transfer of splenocytes from immunized hu-NSG, along with antigen, into footpads of CB17 SCID mice [trans-vivo (tv) DTH]. Both methods revealed cellular immunity to tetanus toxoid (TT) or collagen type V (ColV). Immunohistochemical analysis of the swollen footpads revealed infiltration of human CD45 + cells, including CD3 + T cells, CD68 + macrophages and murine Ly6G + neutrophils. We observed a significant correlation between % circulating human CD4 + cells and the direct DTH swelling response to TT. The tvDTH response to TT was inhibited by anti-IFNγ, while the tvDTH response to collagen V was inhibited by anti IL-17 antibody, mimicking the cytokine bias of adult human T cells to these antigens. Hu-NSG mice were also capable of mounting a B cell response (primarily IgM) to TT antigen. The activation of either Th1-or Th17 -dependent cellular immune response supports the utility of Hu-NSG mice as a surrogate model of allograft rejection and autoimmunity.