In humans receiving intestinal transplantation (ITx), long-term multilineage blood chimerism often develops. Donor T cell macrochimerism (≥4%) frequently occurs without graft-versus-host disease (GVHD) and is associated with reduced rejection. Here we demonstrate that patients with macrochimerism had high graft-versus-host (GvH) to host-versus-graft (HvG) T cell clonal ratios in their allografts. These GvH clones entered the circulation, where their peak levels were associated with declines in HvG clones early post-transplant, suggesting that GvH reactions may contribute to chimerism and control HvG responses without causing GVHD. Consistently, donorderived T cells, including GvH clones, and CD34 + HSPCs were simultaneously detected in the recipients' bone marrow (BM) >100 days post-transplant. Individual GvH clones appeared in ileal mucosa or PBMCs before detection in recipient BM, consistent with an intestinal mucosal origin, where donor GvH-reactive T cells expanded early upon entry of recipient APCs into the graft. These results, combined cytotoxic single cell transcriptional profiles of donor T cells in recipient BM, suggest that tissue-resident GvH-reactive donor T cells migrated into the recipient circulation and BM, where they destroyed recipient hematopoietic cells through cytolytic effector functions and promoted engraftment of graft-derived HSPCs that maintain chimerism. These mechanisms suggest an approach to achieving intestinal allograft tolerance.
Patients receiving extracorporeal membrane oxygenation (ECMO) often require prolonged mechanical ventilation. Providers may be reluctant to perform tracheostomies on patients during ECMO due to their tenuous clinical status and systemic anticoagulation. We report our experience with performing open and percutaneous tracheostomies on patients supported on ECMO from August 2009 to December 2017. Of the 127 patients who underwent tracheostomy during ECMO support, the median age was 42 years (interquartile range [IQR], 29–54), 99 (78%) patients had venovenous (VV) cannulation, 22 (17%) patients had venoarterial (VA) cannulation, and six (5%) patients had hybrid configurations. Percutaneous tracheostomy was performed in 110 (87%) patients. Median-activated partial thromboplastin time (aPTT) at the time of tracheostomy was 47.5 seconds (IQR, 41–57.6 seconds). The median time from ECMO initiation to tracheostomy was 7 days (IQR, 4–11 days). A total of 55 patients (43%) received packed red blood cell (pRBC) transfusions within 48 hours after tracheostomy with a median transfusion of 2 units (IQR, 1–3). There was no procedural mortality. Overall, 88 (69%) patients survived to decannulation and 74 (58%) survived to hospital discharge. Our experience with the largest published series of tracheostomies during ECMO demonstrates that excellent outcomes can be achieved without significant morbidity.
Lymphatic malformations (LMs) are vascular anomalies thought to arise from dysregulated lymphangiogenesis. These lesions impose a significant burden of disease on affected individuals. LM pathobiology is poorly understood, hindering the development of effective treatments. In the present studies, immunostaining of LM tissues revealed that endothelial cells lining aberrant lymphatic vessels and cells in the surrounding stroma expressed the stem cell marker, CD133, and the lymphatic endothelial protein, podoplanin. Isolated patient-derived CD133+ LM cells expressed stem cell genes (NANOG, Oct4), circulating endothelial cell precursor proteins (CD90, CD146, c-Kit, VEGFR-2), and lymphatic endothelial proteins (podoplanin, VEGFR-3). Consistent with a progenitor cell identity, CD133+ LM cells were multipotent and could be differentiated into fat, bone, smooth muscle, and lymphatic endothelial cells in vitro. CD133+ cells were compared to CD133− cells isolated from LM fluids. CD133− LM cells had lower expression of stem cell genes, but expressed circulating endothelial precursor proteins and high levels of lymphatic endothelial proteins, VE-cadherin, CD31, podoplanin, VEGFR-3 and Prox1. CD133− LM cells were not multipotent, consistent with a differentiated lymphatic endothelial cell phenotype. In a mouse xenograft model, CD133+ LM cells differentiated into lymphatic endothelial cells that formed irregularly dilated lymphatic channels, phenocopying human LMs. In vivo, CD133+ LM cells acquired expression of differentiated lymphatic endothelial cell proteins, podoplanin, LYVE1, Prox1, and VEGFR-3, comparable to expression found in LM patient tissues. Taken together, these data identify a novel LM progenitor cell population that differentiates to form the abnormal lymphatic structures characteristic of these lesions, recapitulating the human LM phenotype. This LM progenitor cell population may contribute to the clinically refractory behavior of LMs.
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