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关键词： Nonmyeloablative   Allogeneic hematopoi   etic cell transplantation   Sickle cell disease   Alemtuzumab   Sirolimus   Immunodepletion   Mixed myeloid chime   rism  

摘要： Nonmyeloablative (NMA) conditioning is being used increasingly with success in matched related donor (MRD) and alternative donor allogeneic hematopoietic cell transplantation (allo-HCT) in individuals with sickle cell disease (SCD). Advantages include decrease toxicity and applicability in patients otherwise unable to tolerate conditioning regimens due to end-organ damage or age. We aimed to add to published data outcomes of two similar NMA conditioning protocols, termed Protocol 1 (*** ID NCT00061568) and Protocol 2 (*** ID: NCT02105766)) in mainly adult patients with SCD to evaluate the safety, toxicity, and success of these regimens in individuals at high-risk for poor transplantation-related outcomes. We also evaluated the tolerability and outcomes of Protocol 2, which included preconditioning immunodepletion, in patients at even higher risk of T cell-mediated rejection or plasma/B cell-mediated anti-donor erythrocyte antibody production-the latter due to ABO incompatibility or recipient RBC alloimmunization to a donor antigen. Finally, we evaluated the incidence and trajectory of mixed donor myeloid chimerism over time following allo-HCT. In this retrospective analysis of the 2 prospective phase 2 NMA transplant protocols, 91 individuals with SCD or transfusion-dependent b-thalassemia underwent MRD allo-HCT at the National Heart, Lung, and Blood Institute;regimens contained alemtuzumab, low-dose radiation, and sirolimus for graft-versus-host disease (GVHD) prophylaxis with or without preconditioning immunodepletion with pentostatin and oral cyclophosphamide (Protocol 2). In the total cohort of 91 transplantation recipients, outcomes were favorable with timely neutrophil and platelet engraftment (median, 21 days [range, 7 to 67 days] and 21 days [range, 10 to 112 days], respectively), minimal high-grade acute GVHD and their values. In analyzing each protocol separately, outcomes were comparable except for higher cytomegalovirus reac

关键词： allergen immunotherapy   allergic rhinitis   B-lymphocyte cell   house dust mite   mucosal-associated invariant T cells  

摘要： BackgroundMucosal-associated invariant T cells (MAIT) are emerging as important regulators at mucosal surfaces. While these cells have been linked to a Th1-biased immune response and support for B cells, their roles in allergic diseases characterised by type 2 inflammation remain elusive. The study seeks to characterise MAIT cells in house dust mite (HDM)-induced allergic rhinitis (AR) and subsequent allergen immunotherapy (AIT), aiming to elucidate their clinical significance in AR and potential to enhance AIT *** cells were assessed in patients with AR and individuals undergoing AIT. The ratio and cytokine-producing capacity of these cells were analysed to explore their correlations with AR progression and their responsiveness to HDM extracts and MAIT cell-specific *** AR patients, there was an increase in the ratios of circulating MAIT cells and tonsil follicular T helper-like MAIT cells, alongside a decrease in the IFN-gamma-producing MAIT cells. AIT restored their IFN-gamma producing capacity, which was further boosted by T cell receptor (TCR) activation using MAIT cell-specific agonist-loaded artificial antigen-presenting cells (aAPCs). Synergistic effects of aAPCs and HDM enhance MAIT cell activation and IFN-gamma production while reducing HDM-induced IgE levels in PBMC cocultures. Moreover, higher ratios of MAIT cells and IFN-gamma-producing MAIT cells correlated with decreased IgE and increased IgG4 and improved clinical outcomes during *** findings underscore the compromised IFN-gamma-producing MAIT cells in AR and their restoration following AIT and TCR stimulation, highlighting the cell's therapeutic potential and predictive value for clinical outcomes in AR and AIT.

摘要： Objectives: Insight into the immunopathology of polymyalgia rheumatica (PMR) is scarce and mainly derived from peripheral blood studies. The limited data available point towards macrophages as potential key players in PMR. This study aimed to identify the factors driving proinflammatory macrophage development and their functions in the immunopathology of PMR. Methods: Monocyte phenotypes were investigated by flow cytometry in peripheral blood (PMR, n = 22;healthy controls, n = 20) and paired subacromial-subdeltoid (SASD) bursal fluid (PMR, n = 9). Macrophages in SASD bursa were characterised by immunohistochemistry and immunofluorescence (PMR, n = 12;controls undergoing shoulder replacement surgery, n = 10). The functions of cytokines expressed in PMR-affected tissue were examined using macrophage differentiation cultures (PMR, n = 7;healthy controls, n = 7). Results: Monocytes (CD14highCD16- and CD14highCD16+) were increased in blood of PMR patients and activated in bursal fluid. Macrophages dominated immune infiltrates in PMRaffected tissue, expressing various proinflammatory cytokines. While interleukin (IL)-6 and interferon-gamma (IFN-gamma) expression was abundant in both PMR and control tissue, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) were significantly increased in PMR tissue. Macrophages in PMR-affected tissue showed an elevated CD206/folate receptor /3 ratio, reflecting a GM-CSF skewed signature. A combination of GM-CSF/M-CSF/IFN-gamma significantly boosted IL-6 production in vitro, while limited IL-6 production was observed without GM-CSF. Conclusions: The monocyte compartment is expanded and activated in PMR. Macrophages in PMRaffected tissue produce abundant proinflammatory cytokines such as IL-6. A network of locally expressed cytokines, including GM-CSF, M-CSF, and IFN-gamma, may drive the proinflammatory functions of these macrophages. Overall, macrophages may constitute key therapeutic