IntroductionMesenchymal stromal cells (MSCs) are multipotent stem cells able to differentiate into mesoderm-derived cells, 1 and exhibit immunoregulatory properties. 2 MSCs have been used in the context of allogeneic hematopoietic stem cell transplantation to improve hematopoietic engraftment, to prevent graft failure, and to reduce the incidence or severity of acute graft-versus-host disease (GVHD). [3][4][5] MSCs obtained from bone marrow (BM) can undergo in vitro expansion in medium containing either fetal calf serum (FCS), with or without fibroblast growth factor (FGF-2), or platelet lysate (PL). 6 However, little is known about the effect of donor selection or culture conditions on the functional properties and therapeutic potential of clinical-grade MSCs.Recent studies have suggested that MSCs can contribute to tumor growth and metastasis. 7 A related concern is the capacity of MSCs for oncogenic transformation. Mouse MSCs show chromosomal abnormalities and are highly susceptible to transformation associated with an increased telomerase activity and myc expression, and a loss of p53 and p16. [8][9][10] In contrast, human MSCs are more resistant to transformation in vitro with no genomic instability detected and no tumor induced after long-term in vivo transfer. [11][12][13][14][15] After 20 to 50 population doublings (PDs), human MSCs undergo replicative senescence, with telomere shortening and increased p16 expression. 16 They require the same steps to achieve transformation as for differentiated cells, suggesting that they are not prone to spontaneous transformation. 17 Nevertheless, one recent study described the transformation of human adipose tissue-derived MSCs with up-regulation of myc, repression of p16, acquisition of telomerase activity, 18 and generation of carcinoma in mice. 19 We investigated the immune properties and resistance to transformation of MSCs produced in 4 cell therapy facilities during 2 multicenter clinical trials designed to evaluate the capacity of BM-MSCs to prevent acute GVHD or to treat irradiationinduced lesions. MethodsDetails regarding methods are provided in the supplemental data (available on the Blood website; see the Supplemental Materials link at the top of the online article). For personal use only. on March 28, 2019. by guest www.bloodjournal.org From (1A to 11A) were done for the GVHD prevention clinical trial, and 4 (12A, 13A2) to treat accidentally irradiated patients. For irradiated patients, 5 supplemental MSC productions (12B to 16B) were done using human PL. 6 MSC production Growth kinetics and MSC characterizationGrowth kinetics was assessed by studying total fold increase, total number of PDs, and colony-forming unit-fibroblast. MSCs were screened for the expression of CD45, CD73, CD105, CD90, and human leukocyte antigen-DR (HLA-DR) and were also checked for their capacity to stimulate the growth of allogeneic peripheral blood mononuclear cells (PBMCs) and to inhibit alloantigen-driven proliferation of PBMCs. Cytogenetic analysisAt the end of the first (P ...

IntroductionSeveral subsets of stromal cells, in particular follicular dendritic cells (FDCs) and fibroblastic reticular cells (FRCs), are found within secondary lymphoid organs where they play a key role in the initiation and maintenance of efficient immune responses. FDCs are restricted to germinal centers (GCs) and allow B-cell migration, selection, and differentiation through a complex set of survival factors including BCR-mediated signal, chemokines, cytokines, and adhesion molecules. 1 B-cell selection relies on an affinitybased competition for the fixation of antigen, presented as immune complexes by CD21 hi CD35 hi FDCs. Only B cells with high-affinity BCR receive survival signals from FDCs, capture antigen, and present it to CD4 ϩ T cells that deliver additional survival and maturation signals. 2,3 Conversely, FRCs are less well characterized. They are tightly interconnected in the paracortex of lymph nodes (LNs) where they secrete and ensheath various extracellular matrix components, thus building an intricate network of conduits, connecting afferent lymphatic vessels to high endothelial venules (HEVs). 4 This conduit system allows the rapid transport of soluble antigens from the periphery to the resident myeloid immature dendritic cells (DCs). 5 In addition, part of this reticular network called cortical ridge favors B, T, and DC recruitment and reciprocal interactions, in particular through the production of constitutive and inflammatory chemokines. 6,7 CCL19, CCL21, and CXCL12 are involved in the migration of mature myeloid DCs and naive B and T cells, whereas CXCL9, CXCL10, and CCL5 are crucial for the migration of activated T cells and plasmacytoid DCs. [8][9][10] Strikingly, CCL19 and CCL21 are not synthesized by human HEVs but rather by stromal cells in the T-cell zone. 11,12 These chemokines further reach luminal surface of HEVs by endothelial uptake and transcytosis. FRCs provide therefore a favorable and highly specialized lymphoid environment for immune cell migration and activation.The ontogeny of FRCs and FDCs remains unclear, but these cells are supposed to be of mesenchymal origin. LN organogenesis in the mouse relies on the interaction between CD45 Ϫ VCAM-1 ϩ ICAM-1 ϩ mesenchymal cells and CD45 ϩ CD4 ϩ CD3 Ϫ lymphoid tissue inducer cells in the LN anlagen. 13 A prominent role is attributed to lymphotoxin-␤ receptor (LT␤R) triggering by membrane-bound LT␣1␤2 (LT) and to tumor necrosis factor receptor 1 (TNFR1)/tumor necrosis factor-␣ (TNF). 14,15 Adult lymphoid tissues are highly dynamic structures that retain several features of embryonic organization. 16 Functional mouse FRCs able to construct a reticular meshwork and to secrete inflammatory chemokines could be generated in vitro by stimulation of LN-derived stromal cell lines using a combination of TNF and LT. 17 In vivo, transgenic expression of LT or injection of newborn LN-derived The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefo...

Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.

IDO activity is increased during severe sepsis and septic shock and is associated with mortality. IDO production could be used to better characterize monocyte reprogramming in sepsis.

Peripheral B-lymphocytes undergo a series of changes during the first few years of life. Encounters with foreign antigens lead to maturation and differentiation. Several primary antibody deficiencies (PADs) affecting B-cell development are associated with abnormalities in the composition and/or differentiation of B-cell compartments. The most recent international classifications of primary immunodeficiencies (PIDs) and common variable immunodeficiencies (CVID) have highlighted the importance of B-cell immunophenotyping and age-specific reference intervals for diagnostic purposes. We established national reference values for memory B-cell subpopulations, on the basis of CD27 and surface IgD expression in the peripheral blood of 242 healthy children. We report here the absolute counts and percentages of naive, switched and non-switched memory B-cells for seven age groups, from neonates to adults. We found that the naive B-cells percentage declined between the ages of 6 months and 8 years, after which it remained stable at about 70–80%. Memory B-cells are already present at birth and their numbers increase throughout childhood, stabilizing between the ages of 12 and 18 years. The definition of reference intervals for pediatric B-cell levels should facilitate the screening and diagnosis of various B-cell immunodeficiencies. This multicenter study, providing national reference values, should thus facilitate immunological diagnosis in children.