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OBJECTIVE To investigate the influence of primary graft function (PGF) on graft survival and metabolic control after islet transplantation with the Edmonton protocol. RESEARCH DESIGN AND METHODS A total of 14 consecutive patients with brittle type 1 diabetes were enrolled in this phase 2 study and received median 12,479 islet equivalents per kilogram of body weight (interquartile range 11,072-15,755) in two or three sequential infusions within 67 days (44-95). PGF was estimated 1 month after the last infusion by the beta-score, a previously validated index (range 0-8) based on insulin or oral treatment requirements, plasma C-peptide, blood glucose, and A1C. Primary outcome was graft survival, defined as insulin independence with A1C < or =6.5%. RESULTS All patients gained insulin independence within 12 days (6-23) after the last infusion. PGF was optimal (beta-score > or =7) in nine patients and suboptimal (beta-score < or =6) in five. At last follow-up, 3.3 years (2.8-4.0) after islet transplantation, eight patients (57%) remained insulin independent with A1C < or =6.5%, including seven patients with optimal PGF (78%) and one with suboptimal PGF (20%) (P = 0.01, log-rank test). Graft survival was not significantly influenced by HLA mismatches or by preexisting islet autoantibodies. A1C, mean glucose, glucose variability (assessed with continuous glucose monitoring system), and glucose tolerance (using an oral glucose tolerance test) were markedly improved when compared with baseline values and were significantly lower in patients with optimal PGF than in those with suboptimal PGF. CONCLUSIONS Optimal PGF was associated with prolonged graft survival and better metabolic control after islet transplantation. This early outcome may represent a valuable end point in future clinical trials.
OBJECTIVE To evaluate if baseline serum lipids are associated with islet graft survival in type 1 diabetes islet transplant (ITx) recipients. RESEARCH DESIGN AND METHODS Baseline fasting lipid profile was collected from 44 ITx recipients. Comparisons were performed between subjects below and above the median values of each lipid fraction. Differences in outcomes were compared by Kaplan-Meier curves and Cox regression analysis. RESULTS Subjects with baseline fasting plasma triglycerides and VLDL cholesterol above the median had shorter islet graft survival (triglycerides: 39.7 +/- 6.1 vs. 61.3 +/- 6.6 months, P = 0.029, and VLDL: 41.5 +/- 5.7 vs. 62.8 +/- 7.3 months, P = 0.032). Total, LDL, and HDL cholesterol did not influence islet function. Triglycerides (odds ratio 2.97 [95% CI 1.03-8.52], P = 0.044) maintained its association with graft failure after adjustments for confounders. CONCLUSIONS Higher baseline triglycerides are associated with earlier decline in islet graft function. Prospective clinical trials should address whether it is directly caused by lipotoxicity and if strategies focusing on lowering serum lipids may prolong islet graft survival.
The longest survival of a non-human primate with a life-supporting kidney graft to date has been 90 days, although graft survival > 30 days has been unusual. A baboon received a kidney graft from an α-1,3-galactosyltransferase gene-knockout pig transgenic for two human complement-regulatory proteins and three human coagulation-regulatory proteins (although only one was expressed in the kidney). Immunosuppressive therapy was with ATG+anti-CD20mAb (induction) and anti-CD40mAb+rapamycin+corticosteroids (maintenance). Anti-TNF-α and anti-IL-6R were administered. The baboon survived 136 days with a generally stable serum creatinine (0.6 to 1.6 mg/dl) until termination. No features of a consumptive coagulopathy (e.g., thrombocytopenia, decreased fibrinogen) or of a protein-losing nephropathy were observed. There was no evidence of an elicited anti-pig antibody response. Death was from septic shock (Myroides spp). Histology of a biopsy on day 103 was normal, but by day 136, the kidney showed features of glomerular enlargement, thrombi, and mesangial expansion. The combination of (i) a graft from a specific genetically engineered pig, (ii) an effective immunosuppressive regimen, and (iii) anti-inflammatory agents prevented immune injury and a protein-losing nephropathy, and delayed coagulation dysfunction. This outcome encourages us that clinical renal xenotransplantation may become a reality.
Camouflaging antigens on the surface of cells seems an appealing way to prevent activation of the immune system. We explored the possibility of preventing hyperacute rejection by chemically camouflaging endothelial cells (EC). In vitro as well as in vivo experiments were performed. First, the ability of mPEG coating to prevent antibody-antigen interactions was evaluated. Second, we tested the degree to which mPEG coating prevents activation of EC by stimuli such as TNF-alpha and LPS. Third, in vivo experiments were performed to test the ability of mPEG coating to prolong xenograft survival. We demonstrate that binding of several antibodies to EC or serum proteins can be inhibited by mPEG. Furthermore, binding of TNF-alpha as well as LPS to EC is blocked since mPEG treatment of EC inhibits the subsequent up-regulation of E-selectin by these stimuli. However, in vivo experiments revealed that currently this method alone is not sufficient to prevent hyperacute rejection.
Prolonged hypothermic storage causes ischemia-reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK-2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia-hypoxia challenge stabilized the HK-2 cellular structure, diminished cytoplasmic translocation of high-mobility group box (HMGB) 1 and suppressed NF-κB activation. In the syngeneic Lewis-to-Lewis rat model of kidney transplantation, xenon exposure to donors before graft retrieval or to recipients after engraftment decreased caspase-3 expression, localized HMGB-1 within nuclei and prevented TLR-4/NF-κB activation in tubular cells; serum pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced and renal function was preserved. Xenon treatment of graft donors or of recipients prolonged renal graft survival following IRI in both Lewis-to-Lewis isografts and Fischer-to-Lewis allografts. Xenon induced cell survival or graft functional recovery was abolished by HIF-1α siRNA. Our data suggest that xenon treatment attenuates DGF and enhances graft survival. This approach could be translated into clinical practice leading to a considerable improvement in long-term graft survival.
Background Although fat grafts are widely used for reconstruction and aesthetic purposes, their survival rates differ significantly. Centrifugation is one of the methods used to increase the survival of fat grafts. However, experimental studies examining the long-term outcomes of centrifugation duration are currently limited. Thus, in the present study, the effects of centrifugation duration on the survival of fat grafts were assessed using an animal model. Methods Thirty Sprague Dawley rats were included in the study and fat grafts were obtained from each specimen by excision from inguinal fat pads. Preparation protocols were administered as an en-bloc fat graft in Group 1, minced fat graft in Group 2, and fat graft centrifuged at 1,054 ×g for 2 minutes, 3 minutes, and 4 minutes in Group 3, 4, and 5, respectively. After 12 weeks of follow-up, grafts were harvested and were subjected to histopathological evaluation based on an established scoring system. Results En-block fat grafts were associated with necrosis, fibrosis, inflammation, vacuole formation, and alterations in adipocyte morphology. Among the three centrifugation groups, Group 3 demonstrated the best adipocyte viability and vascularity. However, graft weights decreased in all experimental groups. Conclusion The centrifugation process may have positive effects on adipocyte survival by means of purifying the fat graft and increasing adipocyte concentration. When the centrifugal durations were compared, 3-minute centrifuge yielded the most favorable results.
Risk indices such as the pancreas donor risk index (PDRI) and pre-procurement pancreas allocation suitability score (P-PASS) are utilised in solid pancreas transplantation however no review has compared all derived and validated indices in this field. We systematically reviewed all risk indices in solid pancreas transplantation to compare their predictive ability for transplant outcomes.
Although NKT cells expressing CD1d-reactive TCR exerted protective role in autoimmune diseases, the regulatory function of CD1d-dependent NKT cells in alloimmune responses has not been investigated thoroughly. Here, we demonstrated the regulatory effects of NKT cells using a pancreas islet transplantation model. CD40/CD154 blocking induced long-term graft survival in most B6 recipients, but B6.CD1d(-/-) recipients showed co-stimulation blockade-resistant rejection. Adoptive transfer of NKT cells into B6.CD1d(-/-) restored tolerizing capacity of co-stimulatory blockade. Activation of NKT cells was effective for the prolongation of graft survival and up-regulated membrane-bound TGF-beta expression transiently on their cell surface. The activated CD1d-dependent NKT cells inhibited alloantigen-driven cell proliferation through cell contacts and the beneficial effect of CD154 blocking for allograft survival was related to TGF-beta pathway. Thus, we can conclude that NKT cells are essential for the stable allograft survival and the regulatory function is dependent on, at least in part, TGF-beta engagement.
Extracellular vesicles (EVs) are specific subcellular vesicles released by cells under various environmental conditions. Tumescent liposuction is a commonly used procedure in plastic surgery practice. In the present study, we aimed to extract EVs derived from lipoaspirate fluid (LF-EVs) and characterize them using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. The global profiles of proteins and microRNAs from LF-EVs were identified, strongly suggesting a potential regulatory function of LF-EVs. In addition, we investigated the effects and mechanisms of LF-EVs on fat graft survival. Cell functional tests showed that LF-EVs promoted the proliferation, migration, and tube structure formation of human umbilical vein endothelial cells. LF-EVs also promoted the adipogenic differentiation of adipose tissue-derived stem cells. The results of animal experiments showed that the average weights of fat grafts in the LF-EVs-treated group were significantly higher than those in the control group. Histologically, there was less fibrosis, fewer cysts, and increased fat tissue survival in the LF-EVs group. Further investigations of angiogenic and adipogenic factors revealed that LF-EVs also promoted angiogenesis and exerted a pro-adipogenic effect in vivo. Our findings will help to elucidate the functions of LF-EVs and provide a reference dataset for future translational studies.
Corneal transplantation is the most frequent and successful form of tissue transplantation in adults (<10% rejection). In young children, any corneal opacity should be corrected as early as possible to prevent lifelong visual impairment. However, the corneal graft rejection rate is dramatically increased in infants younger than 12 months of age (up to 85% rejection), and immunosuppressive therapy is particularly challenging in this age group. Regulatory T cells (Tregs) are a well-characterized T cell subpopulation with the potential to prevent autoimmune disorders or transplant rejection. Antigen-specific Tregs were shown to inhibit graft rejection in adult stem cell transplantation. Less is known about the role of naïve Tregs.The purpose of the present study was to elucidate the relevance of naïve Tregs in juvenile corneal transplantation in a baby rat keratoplasty model that reproduces the accelerated rejection in young patients.
Fat grafting is an increasingly popular method of augmentation/reconstruction of soft tissue defects. However, the clinical unpredictability and high resorption rates of the grafts remain problematic. Cellular stress from the harvest and the ensuing ischemic episode may be the cause of this. Cellular stress activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway. In response to cellular stress, the p38 pathway can lead to apoptosis and can negatively regulate cell proliferation. Inhibition of p38 in ex vivo experiments has been shown to promote the expansion of human cord blood hematopoietic stem cell and improve the adipogenesis process through its upstream regulator, Shp2. Because of its wide-ranging cell regulation and antiinflammatory properties, large-scale clinical trials using p38 inhibitors are also currently being performed, especially for therapeutic effect in chronic obstructive pulmonary disease and asthma. The rationale for our study was that the treatment of fat grafts with p38 inhibitor would (a) prevent apoptosis of adipose-derived stem cells in the fat grafts, (b) increase adipose-derived stem cells proliferation, and (c) stimulate the release of several angiogenic factors and promote revascularization.
The association between sarcopenia of kidney transplant recipients and outcome after kidney transplantation (KT) has not yet been fully understood and is still considered controversial. The aim of our study was to analyze the impact of pre-transplant sarcopenia on graft function, postoperative complication rates, and survival of the patients after renal transplantation.
The shortage of deceased donor kidneys for transplants is an ongoing concern. Prior studies support transplanting kidneys from deceased donors with acute kidney injury (AKI), but those investigations have been subject to selection bias and small sample sizes. Current allocation practices of AKI kidneys in the United States are not well characterized.
The variations in outcome and frequent occurrence of kidney allograft failure continue to pose important clinical and research challenges despite recent advances in kidney transplantation. The aim of this systematic review was to examine the current application of machine learning models in kidney transplantation and perform a meta-analysis of these models in the prediction of graft survival.
Currently, the sole treatment option for patients with heart failure is transplantation. The battle of prolonging graft survival and modulating innate and adaptive immune responses is still being waged in the clinic and in research labs. The transcription factor Nrf2 controls major cell survival pathways and is central to moderating inflammation and immune responses. In this study the effect of Nrf2 levels in host recipient C57BL/6 mice on Balb/c allogeneic graft survival was examined. Importantly, Nrf2(-/-) recipient mice could not support the graft for longer than 7.5 days on average, whereas activation of Nrf2 by sulforaphane in Nrf2(+/+) hosts prolonged graft survival to 13 days. Several immune cells in the spleen of recipient mice were unchanged; however, CD11b(+) macrophages were significantly increased in Nrf2(-/-) mice. In addition, IL-17 mRNA levels were elevated in grafts transplanted into Nrf2(-/-) mice. Although Nrf2 appears to play a crucial role in graft survival, the exact mechanism is yet to be fully understood.
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