Improved Graft Survival Research Articles

Multiple Injections of Adipose-Derived Stem Cells Improve Graft Survival in Human-to-Rat Skin Xenotransplantation through Immune Modulation.

Adipose-derived stem cells (ADSCs) exert immunomodulatory effects in the treatment of transplant rejection. This study aimed to evaluate the effects of ADSCs on the skin graft survival in a human-to-rat xenograft transplantation model and to compare single and multiple injections of ADSCs. Full-thickness human skin xenografts were transplanted into the backs of Sprague-Dawley rats. The rats were injected subcutaneously on postoperative days 0, 3, and 5. The injections were as follows: triple injections of phosphate-buffered saline (PBS group), a single injection of ADSCs and double injections of PBS (ADSC × 1 group), and triple injections of ADSCs (ADSC × 3 group). The immunomodulatory effects of ADSCs on human skin xenografts were assessed. Triple injections of ADSCs considerably delayed cell-mediated xenograft rejection compared with the PBS and ADSC × 1 groups. The vascularization and collagen type 1-3 ratios in the ADSC × 3 group were significantly higher than those in the other groups. In addition, intragraft infiltration of CD3-, CD4-, CD8-, and CD68-positive cells was reduced in the ADSC × 3 group. Furthermore, in the ADSC × 3 group, the expression levels of proinflammatory cytokine interferon-gamma (IFN-γ) were decreased and immunosuppressive prostaglandin E synthase (PGES) was increased in the xenograft and lymph node samples. This study presented that triple injections of ADSCs appeared to be superior to a single injection in suppressing cell-mediated xenograft rejection. The immunomodulatory effects of ADSCs are associated with the downregulation of IFN-γ and upregulation of PGES in skin xenografts and lymph nodes.

Human adipose-derived stem cells can optimize the filling material in rats.

Human adipose-derived stem cells have been identified as a promising candidate for cell-assisted therapy to improve graft survival. To objective of the study was to add human adipose-derived stem cells into filling materials. The filling materials were prepared and divided into 6 groups: fat particles with phosphate buffer saline or human adipose-derived stem cells; acellular dermal matrix particles with phosphate buffer saline or human adipose-derived stem cells; mixture of fat particles and acellular dermal matrix particles with phosphate buffer saline or human adipose-derived stem cells. The survival rate, vascular density and histological at 2, 6 and 12 weeks were investigated. Human adipose-derived stem cells significantly improved survival rate in each group at 6 and 12 weeks, and it significantly increased the vascular density in the fat particles and porcine acellular dermal matrix combined group and porcine acellular dermal matrix group at three time points, but human adipose-derived stem cells did not have a significant effect in the fat particles group. Human adipose-derived stem cells as assisted cells added into filling material can improve survival rate and vascular density in rats.

Inhibition of Ferroptosis Enables Safe Rewarming of HEK293 Cells following Cooling in University of Wisconsin Cold Storage Solution

The prolonged cooling of cells results in cell death, in which both apoptosis and ferroptosis have been implicated. Preservation solutions such as the University of Wisconsin Cold Storage Solution (UW) encompass approaches addressing both. The use of UW improves survival and thus extends preservation limits, yet it remains unclear how exactly organ preservation solutions exert their cold protection. Thus, we explored cooling effects on lipid peroxidation and adenosine triphosphate (ATP) levels and the actions of blockers of apoptosis and ferroptosis, and of compounds enhancing mitochondrial function. Cooling and rewarming experiments were performed in a cellular transplantation model using Human Embryonic Kidney (HEK) 293 cells. Cell viability was assessed by neutral red assay. Lipid peroxidation levels were measured by Western blot against 4-Hydroxy-Nonenal (4HNE) and the determination of Malondialdehyde (MDA). ATP was measured by luciferase assay. Cooling beyond 5 h in Dulbecco’s Modified Eagle Medium (DMEM) induced complete cell death in HEK293, whereas cooling in UW preserved ~60% of the cells, with a gradual decline afterwards. Cooling-induced cell death was not precluded by inhibiting apoptosis. In contrast, the blocking of ferroptosis by Ferrostatin-1 or maintaining of mitochondrial function by the 6-chromanol SUL150 completely inhibited cell death both in DMEM- and UW-cooled cells. Cooling for 24 h in UW followed by rewarming for 15 min induced a ~50% increase in MDA, while concomitantly lowering ATP by >90%. Treatment with SUL150 of cooled and rewarmed HEK293 effectively precluded the increase in MDA and preserved normal ATP in both DMEM- and UW-cooled cells. Likewise, treatment with Ferrostatin-1 blocked the MDA increase and preserved the ATP of rewarmed UW HEK293 cells. Cooling-induced HEK293 cell death from hypothermia and/or rewarming was caused by ferroptosis rather than apoptosis. UW slowed down ferroptosis during hypothermia, but lipid peroxidation and ATP depletion rapidly ensued upon rewarming, ultimately resulting in complete cell death. Treatment throughout UW cooling with small-molecule Ferrostatin-1 or the 6-chromanol SUL150 effectively prevented ferroptosis, maintained ATP, and limited lipid peroxidation in UW-cooled cells. Counteracting ferroptosis during cooling in UW-based preservation solutions may provide a simple method to improve graft survival following cold static cooling.

#3629 EFFECTS OF METFORMIN IN KIDNEY TRANSPLANT RECIPIENTS TAKING TACROLIMUS WITH POST-TRANSPLANTATION DIABETES MELLITUS

Abstract Background and Aims Tacrolimus is a pivotal maintenance immunosuppressive drug in kidney transplantation (KT). Although diabetogenic property of tacrolimus is still an inevitable concern, it can reduce the risk of acute rejection and improve graft survival compared to cyclosporine. Metformin, despite limited randomized controlled trial, has been found to be safe and effective in patients with post-transplantation diabetes mellitus (PTDM). We aimed to investigate the effect of metformin on acute rejection and graft survival in kidney transplant recipients taking tacrolimus. Method 442 PTDM patients who were prescribed tacrolimus between 2000 and 2018 were collected. We conducted propensity score matching between the metformin and non-metformin group and evaluated the effects of metformin on the occurrence of T-cell mediated rejection (TCMR) and antibody-mediated rejection (ABMR), and graft survival with Cox proportional hazard model. Results During the average follow up of 8.7 years, 90 patients were diagnosed as PTDM within one year after KT. Among 442 patients taking tacrolimus, 297 patients were treated with metformin for the average of 4.4 years. After 1:1 matching, cumulative incidences of TCMR (p = 0.008) and graft failure (p = 0.005) in the metformin group was lower than the non-metformin group, while no significant difference was observed in ABMR. Metformin use was associated with a reduced risk of TCMR (HR 0.43, 95% CI 0.21-0.88, p = 0.021) and graft failure (HR 0.39, 95% CI 0.19-0.79, p = 0.009). There was no significant difference in t (tubulitis), i (interstitial inflammation), and v (endarteritis) scores of TCMR between the metformin and the non-metformin group. Conclusion Our study demonstrates that combination therapy with metformin and tacrolimus in kidney transplant recipients with PTDM is associated with a lower risk of acute rejection and graft failure.

Improved graft survival by using three-dimensional (3-D) printing of intra-abdominal cavity to prevent large-for-size syndrome in liver transplantation

Sunghae PARK, Jinsoo RHU*, Gyu-Seong CHOI, Jong Man KIM, Jae-Won JOH, Sang Oh YUN, Namkee OH, Sung Jun JO, Sunghyo AN, Seung Wook HAN. Ann Hepatobiliary Pancreat Surg 2023;27:S82. https://doi.org/10.14701/ahbps.2023S1.OP-4-2

Complement activation and kidney transplantation; a complex relationship

Although kidney transplantation is the best treatment for end stage kidney disease, the benefits are limited by factors such as the short fall in donor numbers, the burden of immunosuppression and graft failure. Although there have been improvements in one-year outcomes, the annual rate of graft loss beyond the first year has not significantly improved, despite better therapies to control the alloimmune response. There is therefore a need to develop alternative strategies to limit kidney injury at all stages along the transplant pathway and so improve graft survival. Complement is primarily part of the innate immune system, but is also known to enhance the adaptive immune response. There is increasing evidence that complement activation occurs at many stages during transplantation and can have deleterious effects on graft outcome. Complement activation begins in the donor and occurs again on reperfusion following a period of ischemia. Complement can contribute to the development of the alloimmune response and may directly contribute to graft injury during acute and chronic allograft rejection. The complexity of the relationship between complement activation and allograft outcome is further increased by the capacity of the allograft to synthesise complement proteins, the contribution complement makes to interstitial fibrosis and complement’s role in the development of recurrent disease. The better we understand the role played by complement in kidney transplant pathology the better placed we will be to intervene. This is particularly relevant with the rapid development of complement therapeutics which can now target different the different pathways of the complement system. Combining our basic understanding of complement biology with preclinical and observational data will allow the development and delivery of clinical trials which have best chance to identify any benefit of complement inhibition.

Evaluation of NAG, NGAL, and KIM-1 as Prognostic Markers of the Initial Evolution of Kidney Transplantation.

Kidney transplantation is the best option for end-stage chronic kidney disease. Transplant viability is conditioned by drugs' nephrotoxicity, ischemia-reperfusion damage, or acute rejection. An approach to improve graft survival is the identification of post-transplant renal function prognostic biomarkers. Our objective was to study three early kidney damage biomarkers (N-acetyl-d-glucosaminidase, NAG; neutrophil gelatinase-associated lipocalin, NGAL; and kidney injury molecule-1, KIM-1) in the initial period after transplantation and to identify possible correlations with main complications. We analysed those biomarkers in urine samples from 70 kidney transplant patients. Samples were taken on days 1, 3, 5, and 7 after intervention, as well as on the day that renal function stabilised (based on serum creatinine). During the first week after transplant, renal function improved based on serum creatinine evolution. However, increasing levels of biomarkers at different times during that first week could indicate tubular damage or other renal pathology. A relationship was found between NGAL values in the first week after transplantation and delayed graft function. In addition, higher NAG and NGAL, and lower KIM-1 values predicted a longer renal function stabilisation time. Therefore, urinary NAG, NGAL, and KIM-1 could constitute a predictive tool for kidney transplant complications, contributing to improve graft survival rates.

Histopathology of the Host Cornea Following Penetrating Keratoplasty.

To study the ultra-structural changes in the diseased corneal cells by histopathology, electron microscopy, and immunohistochemistry using conventional antisera and monoclonal antibodies with the ultimate goal of justifying pre-treatment and post-treatment advice and, if necessary, modifying the post-operative treatment for improved graft survival. Thirty cases registered for penetrating keratoplasty were worked up for routine systemic and ophthalmic criteria. A full-thickness diseased cornea was subjected to histopathology after suitable staining and fixation, including electron microscopic and immunohistochemical studies where possible. The ages ranged from four to 60 years. The majority (26%) were in the age group of 31-40 years. The most frequent causes of corneal pathology that underwent keratoplasty include post-traumatic corneal scarring (40%), followed by pseudophakic bullous keratopathy (16.7%). In almost all cases, the histopathology confirmed the existing clinical diagnosis. Histopathology helped to confirm one doubtful case of Fuchs' dystrophy and to contradict one clinical diagnosis of pseudophakic bullous keratopathy, which turned out to be epithelization of the anterior chamber. The results underline the significance of the histopathological study of these corneal conditions to increase the post-surgical survival of the corneal graft.

Letter to the Editor: Can ex-situ normothermic perfusion improve graft survival among donation after circulatory death liver allografts?

To the editor, We read with great interest the manuscript by Ibeabuchi et al recently published in Liver Transplantation.1 The authors found that ex-situ normothermic liver perfusion (ENLP) improved graft survival compared to static cold storage among donation after circulatory death (DCD) liver allografts by identifying the United Network of Organ Sharing database. This was consistent with the results of a randomized trial, which confirmed that ENLP was associated with a 50% lower level of graft injury, with these benefits being greatest in the DCD subgroup.2 Besides, considering that ENLP DCDs were performed at 20 (19.8%) of the 101 centers, the authors conducted a subanalysis restricted to the 20 centers to eliminate potential baseline differences in graft outcomes related to center experience, and the results were largely unchanged. Despite this, the results should still be interpreted with caution. The number of ENLP DCDs performed among these 20 centers ranged from 1 to 10 (median: 2; interquartile range: 1–4.5). In only a few cases in each center, it was not clear in what circumstances ENLP was selected, which inevitably led to significant limitations. All the time, the time window for evaluating the feasibility of donor livers is relatively short, and the time for surgery is severely limited. These all lead to the urgency of liver transplantation and sometimes to the fact that part of the liver available for transplantation has to be wasted. The advantages of ENLP are to create a more physiological environment in vitro and maintain the normal physiological function of donor livers, which can provide opportunities for precise evaluation and intervention treatment of donor livers. ENLP intervention allows longer total preservation times, achieves higher organ use rates, and may indeed be a promising option for organ preservation in vitro.3 However, the ENLP process is relatively complex and requires advanced equipment and technological capabilities. Once problems occur in the operation process, it is likely to cause further damage to the liver. Meanwhile, ENLP does not appear to be suitable for split liver transplantation because it may increase the warm ischemia time through additional rewarming steps. Last, whether ENLP is required for the full duration of livers’ preservation or can equally well be applied after a short period of static cold storage when the livers reach the transplant center.

A new slow-releasing formulation of butyrate prolongs allograft survival

Abstract The microbiota consists of diverse microbes producing metabolites that can influence the immune system locally as well as systemically. These bioactive metabolites (postbiotics) have therapeutic potential and may prove useful to facilitate graft acceptance. Short-chain fatty acids (SCFA) promote intestinal homeostasis and have been linked to health and disease. The Hubbell-Nagler laboratories at the University of Chicago have developed a micelle-based platform that can deliver the SCFA butyrate systemically, with long-term retention and induction of tolerogenic responses. We hypothesized that the administration of this butyrate formulation will improve graft survival by suppressing the alloimmune response. Our preliminary data showed that only oral delivery of the butyrate formulation prolonged survival of a C57Bl/6 male to female minor-mismatched skin graft significantly, whereas sub-cutaneous and intra-peritoneal administration were ineffective. Improved graft survival was associated with diminished production of TNFα by splenic and skin-draining lymph node myeloid cells upon LPS stimulation, suggesting that butyrate modulates the myeloid compartment to reduce levels of pro-inflammatory cytokines. The postbiotic also enhanced survival of a BALB/c to C57Bl/6 major-mismatched skin graft, without the use of immunosuppressive drugs, and resulted in lower levels of donor-specific alloantibodies. Prolonging the administration of butyrate post-transplantation ameliorated graft survival even further, confirming the micelle-based platform has therapeutic potential. Current efforts focus on determining if the butyrate formulation drives myeloid cell polarization toward an anti-inflammatory phenotype. This project was supported by grant NIH/NIAID 2R01AI115716

Evaluation of the efficacy of HEMO2life®, a marine OXYgen carrier for Organ Preservation (OxyOp2) in renal transplantation: study protocol for a multicenter randomized trial

BackgroundPreventing ischemia‒reperfusion injury (IRI) is a major issue in kidney transplantation, particularly for transplant recipients receiving a kidney from extended criteria donors (ECD). The main consequence of IRI is delayed graft function (DGF). Hypoxia is one of the key factors in IRI, suggesting that the use of an oxygen carrier as an additive to preservation solution may be useful. In the OxyOp trial, we showed that the organs preserved using the oxygen carrier HEMO2life® displayed significantly less DGF. In the OxyOp2 trial, we aim to definitively test and quantify the efficacy of HEMO2life® for organ preservation in a large population of kidney grafts.MethodsOxyOp2 is a prospective, multicenter, randomized, comparative, single-blinded, parallel-group study versus standard of care in renal transplantation. After the selection of a suitable donor according to the inclusion/exclusion criteria, both kidneys will be used in the study. Depending on the characteristics of the donor, both kidneys will be preserved either in static cold storage (standard donors) or on machine perfusion (for ECD and deceased-after-cardiac-death donors (DCD)). The kidneys resulting from one donor will be randomized: one to the standard-of-care arm (organ preserved in preservation solution routinely used according to the local practice) and the other to the active treatment arm (HEMO2life® on top of routinely used preservation solution). HEMO2life® will be used for ex vivo graft preservation at a dose of 1 g/l preservation solution. The primary outcome is the occurrence of DGF, defined as the need for renal replacement therapy during the first week after transplantation.DiscussionThe use of HEMO2life® in preservation solutions is a novel approach allowing, for the first time, the delivery of oxygen to organs. Improving graft survival by limiting ischemic lesions is a major public-health goal in the field of organ transplantation.Trial registrationClinicalTrials.gov, ID: NCT04181710. registered on November 29, 2019.

CD154:CD11b blockade increases MPEC differentiation of virus-specific CD8 +T cells

Abstract CD154 pathway blockade has been shown to significantly improve graft survival in transplantation. Recently, CD11b was identified as an alternate receptor for CD154. CD154:CD11b interactions promote rejection by increasing the recruitment of innate and adaptive immune cells into the allograft. However, the effects of CD154:CD11b blockade on the protective immune response to infection during immunosuppression has not been elucidated. To address this, MHV68, a murine homolog of EBV, was used to assess the antigen-specific CD8 +T cell response. Naïve B6 mice were infected with MHV68 and treated on days 0, 2, 4, and 6 with a peptide inhibitor of CD154:CD11b binding (cM7). cM7 treatment resulted in an increase in tetramer +antigen-specific CD8 +T cells 10 days post-infection that exhibited an increase in gene expression associated with activation and antigen processing. To determine if this increase was a result of enhanced proliferation, CTV-labeled OT-I T cells were stimulated in vitro in the presence or absence of CD154:CD11b blockade. Results indicated that CD154:CD11b blockade did not impact proliferation. Instead, cM7 treatment in vitro resulted in an increase in the expression of CD69, CD25, and CD44, and in vivo resulted in an increase in CD127 hiKLRG1 loMPECs. In conclusion, these data demonstrate that CD154:CD11b blockade enhances the quantity and quality of virus-specific CD8 +T cells during protective immunity. We speculate that this could be due to the inhibition of terminal differentiation of antigen-specific T cells resulting in enhanced differentiation of high quality memory precursors, or could be due to an altered balance of CD154:CD40 vs CD154:CD11b binding, resulting in an increase in CD40-driven costimulation. Supported by grants from NIH (R01 AI152516)

Comparison of Graft Survival Between Full-Thickness and Lamellar Pig-to-Monkey Corneal Xenotransplantation from the Same Genetically Engineered Pig Model with Minimal Immunosuppression

The graft survival rate of full-thickness corneal xenotransplantation (XTP) with minimal immunosuppression in genetically engineered pigs is unknown, whereas lamellar corneal XTP shows satisfactory results. We compared graft survival between full-thickness and lamellar transplantations in the same genetically engineered pig. Six pig-to-monkey corneal transplantations were performed on 3 transgenic pigs. Two corneas harvested from 1 pig were transplanted into 2 monkeys using full-thickness and lamellar corneal xenotransplantation. The transgenic donor pigs used were α1,3-galactosyltransferase gene-knockout+membrane cofactor protein (GTKO+CD46) in one recipient and GTKO+CD46+ thrombomodulin (TBM) in the other. The graft survival time for GTKO+CD46 XTP was 28 days. With the addition of TBM, the survival differences between lamellar and full-thickness XTP were 98 days versus 14 days and >463 days (ongoing) versus 21 days, respectively. An excessive number of inflammatory cells was observed in failed grafts, but none were in the recipient's stromal bed. Unlike full-thickness corneal XTP, lamellar xenocorneal transplantation does not exhibit surgical complications, such as retrocorneal membrane or anterior synechia. The graft survival of lamellar XTP in this study was not as good as in our previous experiments, although the survival period was superior to that of full-thickness XTP. The difference in graft survival based on transgenic type is not definitive. Further studies using transgenic pigs and minimal immunosuppression need to focus on improving graft survival of lamellar XTP and using a larger sample size to determine the potential of full-thickness corneal XTP.

MTOR Inhibition Impairs the Activation and Function of Belatacept-Resistant CD4+CD57+ T Cells In Vivo and In Vitro.

Calcineurin inhibitors have improved graft survival in solid-organ transplantation but their use is limited by toxicity, requiring a switch to another immunosuppressor in some cases. Belatacept is one option that has been shown to improve graft and patient survival despite being associated with a higher risk of acute cellular rejection. This risk of acute cellular rejection is correlated with the presence of belatacept-resistant T cells. We performed a transcriptomic analysis of in vitro-activated cells to identify pathways affected by belatacept in belatacept-sensitive cells (CD4+CD57-) but not in belatacept-resistant CD4+CD57+ T cells. mTOR was significantly downregulated in belatacept-sensitive but not belatacept-resistant T cells. The inhibition of mTOR strongly decreases the activation and cytotoxicity of CD4+CD57+ cells. In humans, the use of a combination of mTOR inhibitor and belatacept prevents graft rejection and decreases the expression of activation markers on CD4 and CD8 T cells. mTOR inhibition decreases the functioning of belatacept-resistant CD4+CD57+ T cells in vitro and in vivo. It could potentially be used in association with belatacept to prevent acute cellular rejection in cases of calcineurin intolerance.

Can ex-situ normothermic perfusion improve graft survival compared to static cold storage among donation after circulatory death liver allografts?

Limited data suggest that ex-situ normothermic liver perfusion (ENLP) may improve the outcomes of donation after circulatory death (DCD) liver transplants compared to static cold storage (SCS). All adult DCD liver transplants performed between 2016 and 2021 were identified in the United Network of Organ Sharing database. ENLP liver transplants were compared to SCS using inverse probability of treatment weighting to balance clinical and demographic confounders. The primary analysis simulated intention-to-treat with inverse probability of treatment weighting-adjusted Cox models. Compared to SCS DCDs (N = 3,079), recipients of ENLP DCDs (N = 65) had lower Model of End Stage Liver Disease scores at transplant (16.5 v. 18.8, p = 0.033), longer wait times (468 ± 720 vs. 246 ± 467d; p < 0.001), and received livers from donors with a greater BMI (29.2 vs. 27.5; p = 0.008). ENLP preservation was associated with a lower risk of graft failure (HR 0.31 vs. SCS, 95% CI:0.12-0.86, p = 0.023) and a lower incidence of retransplantation. A sub-analysis restricted to the 20 centers performing ENLP, encompassing 946 SCS DCDs, demonstrated similar results: (HR 0.33 vs. SCS, 95% CI: 0.13-0.94, p = 0.021). Among 111 patients who required retransplantation and where the etiology of graft failure was identified, graft failure due to ischemic cholangiopathy was noted in 1 ENLP and 46 SCS. In this retrospective analysis of the early US DCD ENLP experience, there may exist a graft survival benefit to transplants performed with ENLP compared to SCS.

Assessing the Impact of Prophylactic Eculizumab on Renal Graft Survival in Atypical Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare cause of end-stage kidney disease and associated with poor outcomes after kidney transplantation from early disease recurrence. Prophylactic eculizumab treatment at the time of transplantation is used in selected patients with aHUS. We report a retrospective case note review describing transplant outcomes in patients with aHUS transplanted between 1978 and 2017, including those patients treated with eculizumab. The National Renal Complement Therapeutics Centre database identified 118 kidney transplants in 86 recipients who had a confirmed diagnosis of aHUS. Thirty-eight kidney transplants were performed in 38 recipients who received prophylactic eculizumab. The cohort not treated with eculizumab comprised 80 transplants in 60 recipients and was refined to produce a comparable cohort of 33 transplants in 32 medium and high-risk recipients implanted since 2002. Complement pathway genetic screening was performed. Graft survival was censored for graft function at last follow-up or patient death. Graft survival without eculizumab treatment is described by complement defect status and by Kidney Disease: Improving Global Outcomes risk stratification. Prophylactic eculizumab treatment improved renal allograft survival ( P = 0.006) in medium and high-risk recipients with 1-y survival of 97% versus 64% in untreated patients. Our data supports the risk stratification advised by Kidney Disease: Improving Global Outcomes. Prophylactic eculizumab treatment dramatically improves graft survival making transplantation a viable therapeutic option in aHUS.

Matching for HLA-DR excluding diabetogenic HLA-DR3 and HLA-DR4 predicts insulin independence after pancreatic islet transplantation.

In pancreatic islet transplantation, the exact contribution of human leukocyte antigen (HLA) matching to graft survival remains unclear. Islets may be exposed to allogenic rejection but also the recurrence of type 1 diabetes (T1D). We evaluated the HLA-DR matching, including the impact of diabetogenic HLA-DR3 or HLA-DR4 matches. We retrospectively examined the HLA profile in 965 transplant recipients and 2327 islet donors. The study population was obtained from patients enrolled in the Collaborative Islet Transplant Registry. We then identified 87 recipients who received a single-islet infusion. Islet-kidney recipients, 2nd islet infusion, and patients with missing data were excluded from the analysis (n=878). HLA-DR3 and HLA-DR4 were present in 29.7% and 32.6% of T1D recipients and 11.6% and 15.8% of the donors, respectively. We identified 52 T1D islet recipients mismatched for HLA-DR (group A), 11 with 1 or 2 HLA-DR-matches but excluding HLA-DR3 and HLA- DR4 (group B), and 24 matched for HLA-DR3 or HLA-DR4 (group C). Insulin-independence was maintained in a significantly higher percentage of group B recipients from year one through five post-transplantation (p<0.01). At five-year post-transplantation, 78% of group B was insulin-independent compared to 24% (group A) and 35% (group C). Insulin-independence correlated with significantly better glycemic control (HbA1c <7%), fasting blood glucose, and reduced severe hypoglycemic events. Matching HLA-A-B-DR (≥3) independently of HLA- DR3 or HLA-DR4 matching did not improve graft survival. This study suggests that matching HLA-DR but excluding the diabetogenic HLA-DR3 and/or 4 is a significant predictor for long-term islet survival.

The effectiveness and safety of antibody induction immunosuppression in a large cohort of United States pediatric liver transplant recipients

Data on the potential benefits and risks of induction therapy in pediatric liver transplantation (LT) are limited. This was a retrospective cohort study of 2748 pediatric LT recipients at 26 children’s hospitals between January 1, 2006 to May 31, 2017 using data from the pediatric health information system linked to the United Network for Organ Sharing database. The induction regimen was obtained from the pediatric health information system day-by-day pharmacy resource utilization. Cox proportional hazards evaluated the association of induction regimen (none/corticosteroid-only, nondepleting, and depleting) on patient and graft survival. Additional outcomes, including opportunistic infections and posttransplant lymphoproliferative disorder, were studied using multivariable logistic regression. Overall, 64.9% received none/corticosteroid-only induction, whereas 28.1% received nondepleting, 8.3% received depleting, and 2.5% other antibody regimens. Differences in patient characteristics were small, but center practices were heterogeneous. Compared with none/corticosteroid-only induction, nondepleting induction was associated with reduced acute rejection (odd ratio [OR], 0.53; P <.001) but with the increased posttransplant lymphoproliferative disorder (OR, 1.75; P =.021). Depleting induction was associated with improved graft survival (hazard ratio [HR], 0.64; P =.028) but with increased noncytomegalovirus opportunistic infections (OR, 1.46; P =.046). Depleting induction is underused yet may offer long-term benefits in this large multicenter cohort. Greater consensus guidance in this aspect of pediatric LT care is warranted.

Adult spinal cord tissue transplantation combined with local tacrolimus sustained‐release collagen hydrogel promotes complete spinal cord injury repair

The strategy of replacing a completely damaged spinal cord with allogenic adult spinal cord tissues (aSCs) can potentially repair complete spinal cord injury (SCI) in combination with immunosuppressive drugs, such as tacrolimus (Tac), which suppress transplant rejection and improve graft survival. However, daily systemic administration of immunosuppressive agents may cause harsh side effects. Herein, a localized, sustained Tac-release collagen hydrogel (Col/Tac) was developed to maximize the immune regulatory efficacy but minimize the side effects of Tac after aSC transplantation in complete SCI recipients. Thoracic aSCs of rat donors were transplanted into the complete thoracic spinal cord transection rat recipients, after which Col/Tac hydrogel was implanted. The Tac-encapsulated collagen hydrogel exhibited suitable mechanical properties and long-term sustained Tac release behaviour. After Col/Tac hydrogel implantation in SCI rats with aSC transplantation, the recipients' survival rate significantly improved and the side effects on tissues were reduced compared with those with conventional Tac medication. Moreover, treatment with the Col/Tac hydrogel exhibited similarly reduced immune rejection levels by regulating immune responses and promoted neurogenesis compared to daily Tac injections, and thus improved functional restoration. Localized delivery of immunosuppressive agents by the Col/Tac hydrogel may be a promising strategy for overcoming immune rejection of transplants, with significant potential for clinical application in the future.

Predictive value of portal fibrosis and inflammation in transplanted liver grafts treated with hypothermic oxygenated perfusion.

Hypothermic oxygenated perfusion (HOPE) has become widespread for the preservation of liver grafts, making tangled the relationship among the use of extended criteria donors (ECD), graft histology and transplant outcome. To prospectively validate the impact of the graft histology on transplant outcome in recipient receiving liver grafts from ECD after HOPE. Ninety-three ECD grafts were prospectively enrolled; 49 (52.7 %) were perfused with HOPE according to our protocols. All clinical, histological and follow-up data were collected. Grafts with portal fibrosis stage ≥3 according to Ishak's (evaluated with Reticulin stain) had a significantly higher incidence of early allograft dysfunction (EAD) and 6-month-dysfunction (p=0.026 and p=0.049), with more days in Intensive Care Unit (p=0.050). Lobular fibrosis correlated with post-liver transplant kidney function (p=0.019). Moderate-to-severe chronic portal inflammation was correlated with graft survival on both multivariate and univariate analyses (p<0.001), but this risk factor is sensibly reduced by the execution of HOPE. The use of liver grafts with portal fibrosis stage ≥3 implies a higher risk of post-transplant complications. Portal inflammation represents an important prognostic factor as well, but the execution of HOPE represents a valid tool to improve graft survival.