Summary
Induction of allograft tolerance has been considered the ultimate goal in organ transplantation. Although numerous protocols to induce allograft tolerance have been reported in mice, a ...chimerism‐based approach through donor haematopoietic stem cell transplantation has been the only approach to date that induced allograft tolerance reproducibly following kidney transplantation in man. Renal allograft tolerance has been achieved by induction of either transient mixed chimerism or persistent full donor chimerism. Although the risk of rejection may be low in tolerance achieved via durable full donor chimerism, the development of graft‐versus‐host disease (GVHD) has limited the wider clinical application of this approach. In contrast, tolerance induced by transient mixed chimerism has not been associated with GVHD, but the risk of allograft rejection is more difficult to predict after the disappearance of haematopoietic chimerism. Current efforts are directed towards the development of more clinically feasible and reliable approaches to induce more durable mixed chimerism in order to widen the clinical applicability of these treatment regimens.
Renal allograft tolerance has been achieved by induction of either transient mixed chimerism or persistent full donor chimerism. Current efforts are directed toward development of more clinically feasible and reliable approaches in order to widen the clinical applicability of these treatment regimens.
We present an improved search for neutrinoless double-beta (0νββ) decay of ^{136}Xe in the KamLAND-Zen experiment. Owing to purification of the xenon-loaded liquid scintillator, we achieved a ...significant reduction of the ^{110m}Ag contaminant identified in previous searches. Combining the results from the first and second phase, we obtain a lower limit for the 0νββ decay half-life of T_{1/2}^{0ν}>1.07×10^{26} yr at 90% C.L., an almost sixfold improvement over previous limits. Using commonly adopted nuclear matrix element calculations, the corresponding upper limits on the effective Majorana neutrino mass are in the range 61-165 meV. For the most optimistic nuclear matrix elements, this limit reaches the bottom of the quasidegenerate neutrino mass region.
Aims
To evaluate 0.75 mg of dulaglutide, a once‐weekly glucagon‐like peptide‐1 receptor agonist, compared with once‐daily insulin glargine for glycaemic control in Japanese patients with type 2 ...diabetes (T2D).
Methods
In this phase III, randomized, open‐label, parallel‐group, 26‐week study, 361 patients with inadequately controlled T2D receiving sulphonylureas and/or biguanides, aged ≥20 years, with glycated haemoglobin (HbA1c) levels 7.0–10.0% (53–86 mmol/mol), inclusive, were randomized (1 : 1) to receive dulaglutide or glargine. Participants and investigators were not masked to treatment allocation. The primary measure was change from baseline in HbA1c at 26 weeks, analysed using a mixed‐effects model for repeated measures, with a predefined non‐inferiority margin of 0.4%.
Results
At week 26, least‐squares (LS) mean (standard error) reductions in HbA1c were −1.44 (0.05)% −15.74 (0.55) mmol/mol in the dulaglutide group and −0.90 (0.05)% −9.84 (0.55) mmol/mol in the glargine group. The mean between‐group treatment difference in HbA1c was −0.54% (95% CI −0.67, −0.41) −5.90 mmol/mol (95% CI −7.32, −4.48); p < 0.001. Dulaglutide significantly reduced body weight compared with glargine at week 26 (LS mean difference −1.42 kg, 95% CI −1.89, −0.94; p < 0.001). The most frequent adverse events with dulaglutide treatment were nasopharyngitis and gastrointestinal symptoms. The incidence of hypoglycaemia was significantly lower with dulaglutide 47/181 (26%) compared with glargine 86/180 (48%), p < 0.001.
Conclusion
In Japanese patients with T2D uncontrolled on sulphonylureas and/or biguanides, once‐weekly dulaglutide was superior to once‐daily glargine for reduction in HbA1c at 26 weeks. Although dulaglutide increased gastrointestinal symptoms, it was well tolerated, with an acceptable safety profile.
Molecular testing represents a promising adjunct for the diagnosis of antibody‐mediated rejection (AMR). Here, we apply a novel gene expression platform in sequential formalin‐fixed paraffin‐embedded ...samples from nonhuman primate (NHP) renal transplants. We analyzed 34 previously described gene transcripts related to AMR in humans in 197 archival NHP samples, including 102 from recipients that developed chronic AMR, 80 from recipients without AMR, and 15 normal native nephrectomies. Three endothelial genes (VWF, DARC, and CAV1), derived from 10‐fold cross‐validation receiver operating characteristic curve analysis, demonstrated excellent discrimination between AMR and non‐AMR samples (area under the curve = 0.92). This three‐gene set correlated with classic features of AMR, including glomerulitis, capillaritis, glomerulopathy, C4d deposition, and DSAs (r = 0.39–0.63, p < 0.001). Principal component analysis confirmed the association between three‐gene set expression and AMR and highlighted the ambiguity of v lesions and ptc lesions between AMR and T cell–mediated rejection (TCMR). Elevated three‐gene set expression corresponded with the development of immunopathological evidence of rejection and often preceded it. Many recipients demonstrated mixed AMR and TCMR, suggesting that this represents the natural pattern of rejection. These data provide NHP animal model validation of recent updates to the Banff classification including the assessment of molecular markers for diagnosing AMR.
Gene expression analysis performed on samples from a nonhuman primate model of renal transplantation validates histological and molecular features of antibody‐mediated rejection observed in humans.
We have previously reported successful induction of renal allograft tolerance via a mixed chimerism approach in nonhuman primates. In those studies, we found that costimulatory blockade with ...anti‐CD154 mAb was an effective adjunctive therapy for induction of renal allograft tolerance. However, since anti‐CD154 mAb is not clinically available, we have evaluated CTLA4Ig as an alternative agent for effecting costimulation blockade in this treatment protocol. Two CTLA4Igs, abatacept and belatacept, were substituted for anti‐CD154 mAb in the conditioning regimen (low dose total body irradiation, thymic irradiation, anti‐thymocyte globulin and a 1‐month posttransplant course of cyclosporine CyA). Three recipients treated with the abatacept regimen failed to develop comparable lymphoid chimerism to that achieved with anti‐CD154 mAb treatment and these recipients rejected their kidney allografts early. With the belatacept regimen, four of five recipients developed chimerism and three of these achieved long‐term renal allograft survival (>861, >796 and >378 days) without maintenance immunosuppression. Neither chimerism nor long‐term allograft survival were achieved in two recipients treated with the belatacept regimen but with a lower, subtherapeutic dose of CyA. This study indicates that CD28/B7 blockade with belatacept can provide a clinically applicable alternative to anti‐CD154 mAb for promoting chimerism and renal allograft tolerance.
This study shows that belatacept promotes induction of mixed chimerism and renal allograft tolerance in nonhuman primates.
Tolerance induction to prevent allograft rejection is a long‐standing clinical goal. However, convincing and dependable tolerance identification remains elusive. Hypothesizing that intragraft RNA ...expression is informative in both rejection and tolerance, we profile intrarenal allograft RNA expression in a mixed chimerism renal allograft model of cynomolgus monkeys and identify biologically significant tolerance. Analysis of 67 genes identified 3 dominant factors, each with a different pattern of gene expressions, relating to T cell–mediated rejection (TCMR), chronic antibody‐mediated rejection (CAMR), or Tolerance. Clustering these 3 factors created 9 groups. One of the 9 clustered groups, the Tolerance cluster, showed the lowest probability of terminal rejection, the longest duration of allograft survival, and the lowest relative risk of terminal rejection. The Tolerance factor consists of a novel set of gene expressions including cytokine and immunoregulatory genes adding mechanistic insights into tolerance. The Tolerance factor could not be identified within current pathologic diagnostic categories. The TCMR and CAMR factors are dominant to the Tolerance factor, causing rejection even if the Tolerance factor is present. These 3 factors determine the probability of terminal rejection or tolerance. This novel a posteriori approach permits identification of pathways of rejection, including tolerance.
RNA expression profiling of renal allografts identifies tolerance.
Ovarian clear cell carcinoma (OCCC) shows unique clinical features including an association with endometriosis and poor prognosis. We previously reported that the contents of endometriotic cysts, ...especially high concentrations of free iron, are a possible cause of OCCC carcinogenesis through iron-induced persistent oxidative stress. In this study, we conducted gene expression microarray analysis using 38 ovarian cancer cell lines and identified genes commonly expressed in both OCCC cell lines and clinical samples, which comprise an OCCC gene signature. The OCCC signature reproducibly predicts OCCC specimens in other microarray data sets, suggesting that this gene profile reflects the inherent biological characteristics of OCCC. The OCCC signature contains known markers of OCCC, such as hepatocyte nuclear factor-1beta (HNF-1beta) and versican (VCAN), and other genes that reflect oxidative stress. Expression of OCCC signature genes was induced by treatment of immortalized ovarian surface epithelial cells with the contents of endometriotic cysts, indicating that the OCCC signature is largely dependent on the tumor microenvironment. Induction of OCCC signature genes is at least in part epigenetically regulated, as we found hypomethylation of HNF-1beta and VCAN in OCCC cell lines. This genome-wide study indicates that the tumor microenvironment induces specific gene expression profiles that contribute to the development of distinct cancer subtypes.
Blockade of the CD40–CD154 costimulatory signal is an attractive strategy for immunosuppression and tolerance induction in organ transplantation. Treatment with anti‐CD154 monoclonal antibodies ...(mAbs) results in potent immunosuppression in nonhuman primates (NHPs). Despite plans for future clinical use, further development of these treatments was halted by complications. As an alternative approach, we have been focusing on the inhibition of the counter receptor, CD40 and have shown that a novel human anti‐CD40 mAb, ASKP1240, markedly prolongs renal allograft survival in NHPs, although allografts eventually underwent chronic allograft nephropathy. On the basis of our previous findings that a CD40–CD154 costimulation blockade induces tolerance to hepatic, but not cardiac, allografts in rodents, we tested here our hypothesis that a blockade of CD40 by ASKP1240 allows acceptance of hepatic allografts in NHPs. A 2‐week ASKP1240 induction treatment prolonged liver allograft survival in NHPs; however, the graft function deteriorated due to chronic rejection. In contrast, a 6‐month ASKP1240 maintenance monotherapy efficiently suppressed both cellular and humoral alloimmune responses and prevented rejection on the hepatic allograft. No serious side effects, including thromboembolic complications, were noted in the ASKP1240‐treated monkeys. We conclude that CD40 blockade by ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.
The authors find that the blockade of CD40 by ASKP1240 ameliorated cellular and humoral alloimmune responses and prevented rejection on hepatic allograft in nonhuman primates, and conclude that ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.
ABSTRACT In the late stages of nuclear burning for massive stars (M > 8 M ), the production of neutrino-antineutrino pairs through various processes becomes the dominant stellar cooling mechanism. As ...the star evolves, the energy of these neutrinos increases and in the days preceding the supernova a significant fraction of emitted electron anti-neutrinos exceeds the energy threshold for inverse beta decay on free hydrogen. This is the golden channel for liquid scintillator detectors because the coincidence signature allows for significant reductions in background signals. We find that the kiloton-scale liquid scintillator detector KamLAND can detect these pre-supernova neutrinos from a star with a mass of 25 M at a distance less than 690 pc with 3 significance before the supernova. This limit is dependent on the neutrino mass ordering and background levels. KamLAND takes data continuously and can provide a supernova alert to the community.
The lack of a reliable immunosuppressive regimen that effectively suppresses both renal and islet allograft rejection without islet toxicity hampers a wider clinical application of simultaneous ...islet–kidney transplantation (SIK). Seven MHC‐mismatched SIKs were performed in diabetic cynomolgus monkeys. Two recipients received rabbit antithymocyte globulin (ATG) induction followed by daily tacrolimus and rapamycin (ATG/Tac/Rapa), and five recipients were treated with anti‐CD40 monoclonal antibody (mAb) and rapamycin (aCD40/Rapa). Anti‐inflammatory therapy, including anti–interleukin‐6 receptor mAb and anti–tumor necrosis factor‐α mAb, was given in both groups. The ATG/Tac/Rapa recipients failed to achieve long‐term islet allograft survival (19 and 26 days) due to poor islet engraftment and cytomegalovirus pneumonia. In contrast, the aCD40/Rapa regimen provided long‐term islet and kidney allograft survival (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The aCD40/Rapa regimen was also tested in four kidney‐alone transplant recipients. All four recipients achieved long‐term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). The combination of anti‐CD40 mAb and rapamycin is an effective and nontoxic immunosuppressive regimen that uses only clinically available agents for kidney and islet recipients.
In this preclinical study, authors identify the combination of anti‐CD40 monoclonal antibody and rapamycin as an effective and nontoxic immunosuppressive regimen for simultaneous islet–kidney transplantation.
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