IntroductionBone marrow (BM) is a complex tissue containing hematopoietic progenitor cells and a connective-tissue network of stromal cells. Marrow stroma includes a subpopulation of undifferentiated cells that are capable of becoming one of a number of phenotypes, including bone and cartilage, tendon, muscle, fat, and marrow stromal connective tissue that supports hematopoietic cell differentiation. 1,2 These cells are referred to as mesenchymal stem cells (MSCs), since they are known to have capacity of proliferation and differentiation into the mesenchymal lineage. Due to their potential for differentiation into different tissues, MSCs have emerged as a promising tool for clinical applications such as tissue engineering and cell and gene therapy. [3][4][5] Several reports underline the ability of MSCs to migrate. [6][7][8][9][10][11][12][13] MSCs are thought to migrate in the bloodstream to seed new sites of hematopoiesis and to various tissues during embryonic and fetal development. 14,15 MSCs are present in large numbers in human blood from at least 7 weeks' gestation and they persist until approximately 12 weeks' gestation. 14 Although circulating MSCs decrease after 12 weeks, there is evidence that a very lowfrequency population of circulating multipotent nonhematopoietic cells resembling the classical MSCs persist through to adult life. [16][17][18] MSCs migrate efficiently to hematopoietic tissues (BM and spleen) after transplantation in some experimental animal models, 19,20 whereas reports of BM homing in humans are inconsistent. [21][22][23][24][25][26] Of particular interest for tissue remodeling, intravenous delivery of MSCs results in their specific migration to a site of injury. [6][7][8]10,27 This ability of implanted MSCs to seek out the site of tissue damage has been demonstrated in bone or cartilage fracture, 28 myocardial infarction, 8,29 and ischemic cerebral injury. 6,10,11 Because MSCs have been shown to give rise to many tissues (such as bone, cartilage, fat, endothelia, muscle, brain, and pancreatic islet cells 30,31 ), migrating MSCs may represent a source of pluripotent cells that are constantly available for the repair of damaged organs. The mechanisms that guide homing of implanted cells are unclear. In this study, we examined the role of chemokines and their receptors in the migration of human MSCs. Moreover the interaction between human pancreatic islets and MSCs was investigated as a model of tissue cross talk. Material and methods Human bone marrow mesenchymal stem cell cultureHuman bone marrow mesenchymal stem cells (BM-MSCs) were obtained from Cambrex (Baltimore, MD). There were 3 different batches used for the study. Before use, the cells were analyzed for morphology, marker For personal use only. on May 11, 2018. by guest www.bloodjournal.org From expression, and osteogenic differentiation. All batches used had a fibroblastlike morphology in culture, were homogeneously CD73 ϩ , CD105 ϩ , HLA I ϩ , ␣V␤3 ϩ , ␣V␤5 ϩ , CD34 Ϫ , CD45 Ϫ , CD117 Ϫ , CD31 Ϫ , HLAII Ϫ , CD18 Ϫ , CD80...

Rapamycin has a unique and profound inhibitory effect on DC function, which seems to be at least in part mediated by the FKBP immunophilins.

SummaryPlasticity is a hallmark of macrophages, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic (M1) and alternative (M2). Rapamycin (RAPA) is crucial for survival and functions of myeloid phagocytes, but its effects on macrophage polarization are not yet studied. To address this issue, human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon-c or interleukin-4 (IL-4), respectively. The presence of RAPA (10 ng/ml) induced macrophage apoptosis in M2 but not in M1. Beyond the impact on survival in M2, RAPA reduced CXCR4, CD206 and CD209 expression and stem cell growth factor-b, CCL18 and CCL13 release. In contrast, in M1 RAPA increased CD86 and CCR7 expression and IL-6, tumour necrosis factor-a and IL-1b release but reduced CD206 and CD209 expression and IL-10, vascular endothelial growth factor and CCL18 release. In view of the in vitro data, we examined the in vivo effect of RAPA monotherapy (0Á1 mg/kg/day) in 12 patients who were treated for at least 1 month before islet transplant. Cytokine release by Toll-like receptor 4-stimulated peripheral blood mononuclear cells showed a clear shift to an M1-like profile. Moreover, macrophage polarization 21 days after treatment showed a significant quantitative shift to M1. These results suggest a role of mammalian target of rapamycin (mTOR) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2-related diseases through mTOR inhibitor treatment.

Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets released abundant CXCR1/2 ligands (CXCL1 and CXCL8). Accordingly, intrahepatic CXCL1 and circulating CXCL1 and CXCL8 were strongly induced shortly after islet infusion. Genetic and pharmacological blockade of the CXCL1-CXCR1/2 axis in mice improved intrahepatic islet engraftment and reduced intrahepatic recruitment of polymorphonuclear leukocytes and NKT cells after islet infusion. In humans, the CXCR1/2 allosteric inhibitor reparixin improved outcome in a phase 2 randomized, open-label pilot study with a single infusion of allogeneic islets. These findings indicate that the CXCR1/2-mediated pathway is a regulator of islet damage and should be a target for intervention to improve the efficacy of transplantation. IntroductionAchieving long-lasting insulin independence after portal vein islet transplantation has improved, but remains challenging. Nonspecific immune activation (1-6), along with preexisting and transplant-induced auto-and allospecific immune responses (7-9), are components affecting outcome; these are not fully suppressed by ongoing protocols of generalized immunosuppression. Increasing general immunosuppression potency is not ideal because of side effects. Consequently, the development of novel protocols that specifically target proinflammatory immune cell compartments that impede islet function and survival is compelling.