Islet transplantation is an appropriate treatment for selected individuals with type 1 diabetes mellitus and hypoglycaemia unawareness. The gold standard of maintenance immunosuppression to prevent allograft rejection is calcineurin inhibitor-based therapy; however, side effects warrant exploration of alternative immunosuppression. The co-stimulatory blocker belatacept and the mammalian target of rapamycin inhibitor sirolimus have demonstrated clinical benefit in solid organ transplantation, but efficacy in human islet transplantation is unknown. We conducted a non-randomised, phase 2, multi-centre, open-label clinical study. Participants with type 1 diabetes receiving at least one islet transplant were treated with belatacept/sirolimus (bela/siro) and compared with a contemporaneous cohort treated with tacrolimus/mycophenolate mofetil (tac/MMF). The primary outcome was freedom from hypoglycaemia, with positive C-peptide and HbA1c <53 mmol/mol (7.0

African American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared with other racial and ethnic populations, highlighting the need to identify causative factors. Here, in the Genomics of Chronic Allograft Rejection cohort, pretransplant blood RNA sequencing revealed a cluster of four consecutive missense single-nucelotide polymorphisms (SNPs), within the leukocyte immunoglobulin-like receptor B3 (LILRB3) gene, strongly associated with death-censored graft loss. This SNP cluster (named LILRB3-4SNPs) encodes missense mutations at amino acids 617-618 proximal to a SHP1/2 phosphatase-binding immunoreceptor tyrosine-based inhibitory motif. The LILRB3-4SNPs cluster is specifically enriched within AA individuals and exhibited a strong association with death-censored graft loss and estimated glomerular filtration rate decline in the AA participants from multiple transplant cohorts. In two large Biobanks (BioMe and All-of-Us), the LILRB3-4SNPs cluster was associated with the early onset of end-stage renal disease and acted synergistically with the apolipoprotein L1 (APOL1) G1/G2 allele to accelerate disease progression. The SNPs were also linked to multiple immune-related diseases in AA individuals. Last, on multiomics analysis of blood and biopsies, recipients with LILRB3-4SNPs showed enhanced inflammation and monocyte ferroptosis. While larger and prospective studies are needed, our data provide insights on the genetic variation underlying kidney transplant outcomes.

ARTICLE HIGHLIGHTS:Current research and development are ushering in a new era of novel islet β-cell replacement therapies that can no longer be considered solely a rescue treatment for those with unstable glucose management. Clinical trial design must ensure that the application of islet β-cell replacement is broadened beyond the indication of severe hypoglycemia given the potential for establishing insulin-independent normoglycemia. It is imperative that people with type 1 diabetes and their clinicians are at the center of the risk-benefit equipoise as evidence for the safety of cellular products, transplant sites, and immune protection strategies accumulates and an increasing number of options for intervention become available.

CD4(+)Foxp3(+) regulatory T cells (Tregs) play an essential role in suppressing transplant rejection, but their role within the graft and heterogeneity in tolerance are poorly understood. Here, we compared phenotypic and transcriptomic characteristics of Treg populations within lymphoid organs and grafts in an islet xenotransplant model of tolerance. We showed Tregs were essential for tolerance induction and maintenance. Tregs demonstrated heterogeneity within the graft and lymphoid organs of tolerant mice. A subpopulation of CD127(hi) Tregs with memory features were found in lymphoid organs, presented in high proportions within long -surviving islet grafts, and had a transcriptomic and phenotypic profile similar to tissue Tregs. Importantly, these memory -like CD127(hi) Tregs were better able to prevent rejection by effector T cells, after adoptive transfer into secondary Rag(-/-) hosts, than naive Tregs or unselected Tregs from tolerant mice. Administration of IL -7 to the CD127(hi)Treg subset was associated with a strong activation of phosphorylation of STAT5. We proposed that memory -like CD127(hi) Tregs developed within the draining lymph node and underwent further genetic reprogramming within the graft toward a phenotype that had shared characteristics with other tissue or tumor Tregs. These findings suggested that engineering Tregs with these characteristics either in vivo or for adoptive transfer could enhance transplant tolerance.

The objective of this study was to validate the performance of Tutivia, a peripheral blood gene expression signature, in predicting early acute rejection (AR) post–kidney transplant. Recipients of living or deceased donor kidney transplants were enrolled in a nonrandomized, prospective, global, and observational study (NCT04727788). The main outcome was validation of the area under the curve (AUC) of Tutivia vs serum creatinine at biopsy alone, or Tutivia + serum creatinine at biopsy. Of the 151 kidney transplant recipients, the mean cohort age was 53 years old, and 64% were male. There were 71% (107/151) surveillance/protocol biopsies and 29% (44/151) for-cause biopsies, with a 31% (47/151) overall rejection rate. Tutivia (AUC 0.69 [95% CI: 0.59-0.77]) and AUC of Tutivia + creatinine at biopsy (0.68 [95% CI: 0.59-0.77]) were greater than the AUC of creatinine at biopsy alone (0.51.4 [95% CI: 0.43-0.60]). Applying a model cut-off of 50 (scale 0-100) generated a high- and low-risk category for AR with a negative predictive value of 0.79 (95% CI: 0.71-0.86), a positive predictive value of 0.60 (95% CI: 0.45-0.74), and an odds ratio of 5.74 (95% CI: 2.63-12.54). Tutivia represents a validated noninvasive approach for clinicians to accurately predict early AR, beyond the current standard of care.

Purpose/Objective(s) There is growing interest in combined stereotactic radiosurgery (SRS) with immune checkpoint inhibitors (ICI). Given the potential for significant clinical neurologic deterioration with injury to eloquent areas, understanding the impact of modern systemic therapy on risk of RN in eloquent locations is critical. In this exploratory analysis, we aimed to evaluate if SRS to brain metastases with concurrent immunotherapy increases the risk of RN in patients with NSCLC. We hypothesized that SRS and concurrent ICI are associated with a higher rate of RN in eloquent brain areas compared to metastases treated without concurrent ICI. Materials/Methods We retrospectively reviewed patients with NSCLC with brain metastases treated from 2015-2020 with SRS. Treatment was delivered using Linac-based SRS at a single institution. Metastases were classified as eloquent or non-eloquent as per the Spetzler-Martin grading system. Diagnosis of RN was determined on review of radiologic and clinical findings. Concurrent ICI was defined as immunotherapy within 30 days prior, during, or following SRS. Analysis for RN was conducted on a metastasis-level basis. RN proportion rates between concurrent/non-concurrent ICI was evaluated using chi-square statistics in both eloquent and non-eloquent brain regions. Results 148 patients treated with SRS to 388 brain metastases were included with median age of 61 years and median follow up of 14 months. Most metastases were treated to 20 Gy in 1 fraction (72%) or 27 Gy in 3 fractions (18%). Concurrent ICI was used in 27% of patients with 48% receiving ICI prior to SRS. Of the metastases treated, 364 (94%) were classified as non-eloquent of which 27% were treated with concurrent ICI. The risk of RN was 8.99% and 9.28% for metastases treated without and with concurrent ICI, respectively for the non-eloquent brain metastases (P = 0.93). 29% of eloquent metastases were treated with concurrent ICI. The risk of RN for eloquent brain metastases was 17.65% vs 14.29% without vs with concurrent ICI (P = 0.84). The difference in RN incidence for metastases within eloquent locations and non-eloquent locations was not statistically significant (16.7% vs. 9.1%, P = 0.22) Conclusion Our findings demonstrate that SRS to eloquent brain metastases in combination with ICI is safe in patients with NSCLC. SRS, single or multi-fraction, with concurrent ICI is not associated with a higher risk of RN in either eloquent or non-eloquent brain regions among patients treated for NSCLC. Prospective studies are needed to validate these findings and to evaluate if these results can be generalized to other malignancies.

The pathogenesis of allograft (dys)function has been increasingly studied using ‘omics’-based technologies, but the focus on individual organs has created knowledge gaps that neither unify nor distinguish pathological mechanisms across allografts. Here we present a comprehensive study of human pan-organ allograft dysfunction, analyzing 150 datasets with more than 12,000 samples across four commonly transplanted solid organs (heart, lung, liver and kidney, n = 1,160, 1,241, 1,216 and 8,853 samples, respectively) that we leveraged to explore transcriptomic differences among allograft dysfunction (delayed graft function, acute rejection and fibrosis), tolerance and stable graft function. We identified genes that correlated robustly with allograft dysfunction across heart, lung, liver and kidney transplantation. Furthermore, we developed a transfer learning omics prediction framework that, by borrowing information across organs, demonstrated superior classifications compared to models trained on single organs. These findings were validated using a single-center prospective kidney transplant cohort study (a collective 329 samples across two timepoints), providing insights supporting the potential clinical utility of our approach. Our study establishes the capacity for machine learning models to learn across organs and presents a transcriptomic transplant resource that can be employed to develop pan-organ biomarkers of allograft dysfunction. A comprehensive analysis of omics data from biopsies and blood samples from more than 12,000 cases of heart, lung, liver and kidney transplants provides insights into shared mechanisms of allograft dysfunction across organs.

Intra-hepatic islet transplantation for type-1 diabetes is limited by the need for multiple infusions and poor islet viability post-transplantation. The development of alternative transplantation sites is necessary to improve islet survival, and facilitate monitoring and retrieval. We tested a clinically proven Biodegradable Temporizing Matrix (BTM), a polyurethane-based scaffold, to generate a well vascularized intracutaneous ‘neo-dermis’ within the skin for islet transplantation. In murine models, BTM did not impair syngeneic islet renal-subcapsular transplant viability or function, and facilitated diabetes cure for over 150 days. Further, BTM supported functional neonatal porcine islet transplants into RAG-1-/- mice for 400 days. Hence, BTM is non-toxic for islets. two-photon intravital imaging used to map vessel growth through time identified dense vascular networks, with significant collagen deposition and increases in vessel mass up to 30 days post-BTM implantation. In a pre-clinical porcine skin model, BTM implants created a highly-vascularized intracutaneous site by day 7 post-implantation. When syngeneic neonatal porcine islets were transplanted intracutaneously the islets remained differentiated as insulin producing cells, maintained normal islet architecture, secreted c-peptide, and survived for over 100 days. Here we show that BTM facilitates formation of an islet-supportive intracutaneous ‘neo-dermis’ in a porcine pre-clinical model, as an alternative islet transplant site.

This file includes Supplementary Tables S1-S5. Table S1: Eligible neoadjuvant chemotherapy breast cancer datasets. Table S2: Reference breast cancer datasets for gene expression normalization. Table S3: List of duplicate samples excluded from study. Table S4: Test characteristics of a reduced gene model. Table S5: RPS values for study patients.

Background Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0 center dot 9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. Methods BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). Findings Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0 center dot 74 [95% CI 0 center dot 66 to 0 center dot 84; p<0 center dot 0001]; adjusted risk difference 10 center dot 1% [95% CI 3 center dot 5 to 16 center dot 6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0 center dot 5%, 95% CI -1 center dot 8 to 0 center dot 9; p=0 center dot 48). Interpretation Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. Copyright (c) 2023 Published by Elsevier Ltd. All rights reserved.

Nuclear factor κB (NF-κB) activation is a deleterious molecular mechanism that drives acute kidney injury (AKI) and manifests in transplanted kidneys as delayed graft function. The TNFAIP3 gene encodes A20, a cytoplasmic ubiquitin ligase and a master negative regulator of the NF- κB signaling pathway. Common population-specific TNFAIP3 coding variants that reduce A20's enzyme function and increase NF- κB activation have been linked to heightened protective immunity and autoimmune disease, but have not been investigated in AKI. Here, we functionally identified a series of unique human TNFAIP3 coding variants linked to the autoimmune genome-wide association studies single nucleotide polymorphisms of F127C; namely F127C;R22Q, F127C;G281E, F127C;W448C and F127C;N449K that reduce A20's anti-inflammatory function in an NF- κB reporter assay. To investigate the impact of TNFAIP3 hypomorphic coding variants in AKI we tested a mouse Tnfaip3 hypomorph in a model of ischemia reperfusion injury (IRI). The mouse Tnfaip3 coding variant I325N increases NF- κB activation without overt inflammatory disease, providing an immune boost as I325N mice exhibit enhanced innate immunity to a bacterial challenge. Surprisingly, despite exhibiting increased intra-kidney NF- κB activation with inflammation in IRI, the kidney of I325N mice was protected. The I325N variant influenced the outcome of IRI by changing the dynamic expression of multiple cytoprotective mechanisms, particularly by increasing NF- κB-dependent anti-apoptotic factors BCL-2, BCL-XL, c-FLIP and A20, altering the active redox state of the kidney with a reduction of superoxide levels and the enzyme super oxide dismutase-1, and enhancing cellular protective mechanisms including increased Foxp3+ T cells. Thus, TNFAIP3 gene variants represent a kidney and population-specific molecular factor that can dictate the course of IRI.