Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19 B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology.

The vascular response to pro-atherosclerotic factors is a multifactorial process involving endothelial cells (ECs), macrophages (MACs), and smooth muscle cells (SMCs), although the mechanism by which these cell types communicate with each other in response to environmental cues is yet to be understood. Here, we show that miR-155, which is significantly expressed and secreted in Krüppel-like factor 5 (KLF5)-overexpressing vascular smooth muscle cells (VSMCs), is a potent regulator of endothelium barrier function through regulating endothelial targeting tight junction protein expression. VSMCs-derived exosomes mediate the transfer of KLF5-induced miR-155 from SMCs to ECs, which, in turn, destroys tight junctions and the integrity of endothelial barriers, leading to an increased endothelial permeability and enhanced atherosclerotic progression. Moreover, overexpression of miR-155 in ECs inhibits endothelial cell proliferation/migration and re-endothelialization in vitro and in vivo and thus increases vascular endothelial permeability. Blockage of the exosome-mediated transfer of miR-155 between these two cells may serve as a therapeutic target for atherosclerosis.

SummaryUmbilical cord blood transplant (UCBT) is associated with impaired early immune reconstitution. This might be explained by a lower T‐cell dose infused, the naivety of cord blood T‐cells and the use of in vivo T‐cell depletion. We studied the pattern of early immune reconstitution and the clinical outcome of children undergoing unrelated UCBT when in vivo T‐cell depletion was omitted. Thirty children affected by malignancies (46%) or immunodeficiencies (54%) underwent an unrelated UCBT. Prospective assessment of immune reconstitution and clinical outcome was performed. We observed an unprecedented CD4+ T‐cell reconstitution, with a median cell count at 30 and 60 d post UCBT of 0·3 × 109/l and 0·56 × 109/l, respectively. Early T‐cell expansion was thymic‐independent, with a rapid shift from naïve to central memory phenotype and early regulatory T‐cell recovery. Viral infections were frequent (63%) but resolved rapidly in most cases and virus‐specific T‐lymphocytes were detected within 2 months post‐UCBT. Acute graft‐versus‐host disease (GvHD) was frequent (grade II = 34%, grade III–IV = 16%) but steroid responsive, and the incidence of chronic GvHD was low (14%). The omission of in vivo T‐cell depletion promotes a unique thymic‐independent CD4+ T‐cell reconstitution after unrelated UCBT in children. We postulate that this relates to the specific immunological and ontological qualities of fetal‐derived lymphocytes.

Differential cytokine levels support tears as a useful indicator of immune mechanisms occurring during AC. The striking similarities in chemokine profiles between tears and fibroblasts suggest these cells as likely sources of chemokines in tears.

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