Regulatory T cell (Treg)-based therapy is a promising approach to treat many immune-mediated disorders such as autoimmune diseases, organ transplant rejection, and graft-versus-host disease (GVHD). Challenges to successful clinical implementation of adoptive Treg therapy include difficulties isolating homogeneous cell populations and developing expansion protocols that result in adequate numbers of cells that remain stable, even under inflammatory conditions. We investigated the potential of discarded human thymuses, routinely removed during pediatric cardiac surgery, to be used as a novel source of therapeutic Tregs. Here, we show that large numbers of FOXP3 þ Tregs can be isolated and expanded from a single thymus. Expanded thymic Tregs had stable FOXP3 expression and long telomeres, and suppressed proliferation and cytokine production of activated allogeneic T cells in vitro. Moreover, expanded thymic Tregs delayed development of xenogeneic GVHD in vivo more effectively than expanded Tregs isolated based on CD25 expression from peripheral blood. Importantly, in contrast to expanded blood Tregs, expanded thymic Tregs remained stable under inflammatory conditions. Our results demonstrate that discarded pediatric thymuses are an excellent source of therapeutic Tregs, having the potential to overcome limitations currently hindering the use of Tregs derived from peripheral or cord blood.

Objective-Atherosclerotic plaque rupture can lead to severe complications such as myocardial infarction and stroke.Myeloid related protein (Mrp)-14, Mrp-8, and Mrp-8/14 complex are inflammatory markers associated with myocardial infarction. It is, however, unknown whether Mrps are associated with a rupture-prone plaque phenotype. In this study, we determined the association between Mrp-14, -8, -8/14 plaque levels and plaque characteristics. Methods and Results-In 186 human carotid plaques, levels of Mrp-14, -8, and -8/14 were quantified using ELISA. High levels of Mrp-14 were found in lesions with a large lipid core, high macrophage staining, and low smooth muscle cell and collagen amount. Plaques with high levels of Mrp-14 contained high interleukin (IL)-6, IL-8, matrix metalloprotease (MMP)-8, MMP-9, and low MMP-2 concentrations. Mrp-8 and Mrp-8/14 showed a similar trend. Within plaques, a subset of nonfoam macrophages expressed Mrp-8 and Mrp-14 and the percentage of Mrp-positive macrophages was higher in rupture-prone lesions compared to stable ones. In vitro, this subset of macrophages does not acquire a foamy phenotype when fed oxLDL. Conclusion-Mrp-14 is strongly associated with the histopathologic features and the inflammatory status of rupture-prone atherosclerotic lesions, identifying Mrp-14 as a local marker for these plaques.

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These observations suggest that, after clinical heart transplantation, FOXP3+ T cells do not prevent acute rejection, but rather are a response to antidonor effector T-cell activity.

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IL-21 is a critical cytokine for IL-2 dependent immune processes. Blockade of the IL-21 pathway may provide a new perspective for the treatment of allogeneic responses in patients after transplantation.

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During MS, phagocytosing myelin-containing macrophages arise and lie in close proximity to T cells. To date, it has not been addressed whether these myelin-laden macrophages have the capacity to present antigens to T cells and whether this contributes to inflammation in disease. We demonstrate that in vitro-generated human and mouse myelin-laden macrophages expressed MHC class I and II and costimulatory molecules and are thus well equipped for antigen presentation. Human myelin-laden macrophages exhibited normal endocytosis of particulate and soluble antigens. In addition, human myelin-laden macrophages elicited active T cell proliferation of naïve as well as memory T cells. Furthermore, mouse myelin-laden macrophages induced primary antigen-specific CD4(+) T cell proliferation in vivo but transiently diminished IFN-γ release. Functionally, MOG peptide-loaded myelin-laden mouse macrophages modestly but significantly reduced the severity of MOG peptide-induced EAE. These data show that myelin uptake results in the induction of a population of macrophages that retains antigen-presenting capacity and limits autoimmune-mediated disease.