Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)-CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1-restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection

Unusual presentation of urban leptospirosis complicated by a septic shock

Leptospirosis, an infectious zoonosis, is common to tropical areas. The clinical presentation varies from flu-like symptoms to a serious presentation called Weil’s syndrome. Fever and conjunctival suffusion are present in the majority of patients. This case report describes a resident of New York City who presented initially with gastroenteritis symptoms without fever or conjunctival suffusion to develop septic shock before being diagnosed with leptospirosis. Keywords: Urban leptospirosis, Unusual presentation, Weil’s syndrome, Sepsi

Maverick total disc replacement in a real-world patient population: a prospective, multicentre, observational study

International audienc

Integrated Kidney Exosome Analysis for the Detection of Kidney Transplant Rejection

Kidney transplant patients require life-long surveillance to detect allograft rejection. Repeated biopsy, albeit the clinical gold standard, is an invasive procedure with the risk of complications and comparatively high cost. Conversely, serum creatinine or urinary proteins are noninvasive alternatives but are late markers with low specificity. We report a urine-based platform to detect kidney transplant rejection. Termed iKEA (integrated kidney exosome analysis), the approach detects extracellular vesicles (EVs) released by immune cells into urine; we reasoned that T cells, attacking kidney allografts, would shed EVs, which in turn can be used as a surrogate marker for inflammation. We optimized iKEA to detect T-cell-derived EVs and implemented a portable sensing system. When applied to clinical urine samples, iKEA revealed high level of CD3-positive EVs in kidney rejection patients and achieved high detection accuracy (91.1%). Fast, noninvasive, and cost-effective, iKEA could offer new opportunities in managing transplant recipients, perhaps even in a home setting

Aménagement et environnement

Fréquemment assimilé aux politiques publiques qui ont accompagné la reconstruction postérieure à la Seconde Guerre mondiale, l'aménagement du territoire tel qu'on le concevait alors visait la modernisation du pays. Il était pensé comme facteur de progrès a priori et reposait sur une conception techniciste qui voyait dans des ingénieurs les seules autorités compétentes, excluant l'expérience des populations. Les nuisances et les bouleversements de tous ordres induits par les aménagements étaient considérés comme négligeables, le prix à payer dans l'intérêt général. Leur contestation ne pouvait être motivée que par l'ignorance ou l'égoïsme. Les dix-neuf contributions réunies dans ce livre proposent une vision nouvelle des aménagements territoriaux. Pensant les territoires comme des champs de négociation où s'affrontent des forces variées, elles cherchent à inclure dans l'étude de leur aménagement la façon dont l'environnement, que les sociétés cherchent à maîtriser et à mettre au service de leurs desseins, réagit à son tour à la transformation imposée. Considérant des aménagements effectués à toutes les périodes de l'histoire, elles cherchent à identifier leur impact économique, social, environnemental ou même culturel, y compris sur le long terme. Une tentative ambitieuse, tant il est vrai que même lorsque les aménagements passés sont identifiés comme des échecs, voire comme des réalisations néfastes, par leurs auteurs eux-mêmes, il est bien rare que cela soit exprimé publiquement

Regulatory T cells engineered with TCR signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter

Adoptive cell transfer of ex vivo expanded regulatory T cells (T-r(egs)) has shown immense potential in animal models of auto- and alloimmunity. However, the effective translation of such T-reg therapies to the clinic has been slow. Because T-reg homeostasis is known to require continuous T cell receptor (TCR) ligation and exogenous interleukin-2 (IL-2), some investigators have explored the use of low-dose IL-2 injections to increase endogenous T-reg responses. Systemic IL-2 immunotherapy, however, can also lead to the activation of cytotoxic T lymphocytes and natural killer cells, causing adverse therapeutic outcomes. Here, we describe a drug delivery platform, which can be engineered to autostimulate T-regs with IL-2 in response to TCR-dependent activation, and thus activate these cells in sites of antigen encounter. To this end, protein nanogels (NGs) were synthesized with cleavable bis(N-hydroxysuccinimide) cross-linkers and IL-2/Fc fusion (IL-2) proteins to form particles that release IL-2 under reducing conditions, as found at the surface of T cells receiving stimulation through the TCR. T-regs surface-conjugated with IL-2 NGs were found to have preferential, allograft-protective effects relative to unmodified T-regs or T-regs stimulated with systemic IL-2. We demonstrate that murine and human NG-modified T-regs carrying an IL-2 cargo perform better than conventional T-regs in suppressing alloimmunity in murine and humanized mouse allotransplantation models. In all, the technology presented in this study has the potential to improve T-reg transfer therapy by enabling the regulated spatiotemporal provision of IL-2 to antigen-primed T-regs