A needed Convention against trafficking in human organs

More than 114 000 organ transplants are done annually in over 100 countries. Estimating that 5—10% of kidney transplants result from commercial transactions, WHO has warned against the worldwide “trade for profit in human organs”, which tarnishes this life-saving therapy. Although legislation forbidding organ sales exists in most countries, progress has been impeded by weak enforcement and the absence of comprehensive binding international instruments to harmonise regulations and improve cross-national cooperation. The Convention against Trafficking in Human Organs, soon to be adopted by the Council of Europe, provides a solution to these problems by identifying distinct activities that constitute “trafficking in human organs”, which ratifying states are obligated to criminalise. The central concept is “the illicit removal of organs”, which consists of removal without the free, informed, and specific consent of a living donor; removal from a deceased donor other than as authorised under domestic law; removal when a living donor (or a third party) has been offered or received a financial gain or comparable advantage; or removal from a deceased donor when a third party has been offered or received a financial gain or comparable advantage (read more).

Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy

Background : Patients with a rare genetic disease may receive renal transplantation (KTx) without a correct diagnosis of causal nephropathy and therefore develop unexpected and even severe complications. Aim of the study was to describe the cases of rare genetic disorders diagnosed after KTx, in order to draw clinical lessons for the transplant physician.
Methods : We retrospectively assessed all patients who had received a diagnosis of a rare genetic disorder after KTx.
Results : In our Center, more than 30% (278/911) of KTx recipients were diagnosed with a causal nephropathy: prevalence of rare genetic disorders in this group was 4.32% (12/278), including 2,8 dihydroxyadeninuria (2,8 DHA)-disease (n=2), HNF-1B associated nephropathy (n=2), UMOD-related nephropathy (n=5), Fabry disease (n=1), INF2 focal segmental glomerulosclerosis (n=1) and Senior-Loken syndrome (n=1). 2,8 DHA-nephropathy relapsed in both patients causing an acute renal failure and jeopardising the graft.
Conclusions : KTx recipients without a diagnosis of causal nephropathy appear to be a selected population in which rare genetic diseases might be more common than expected. As even a belated diagnosis after KTx can have a significant impact on graft and patient survival and on other family members, this possibility should be evaluated in KTx recipients without a known causal nephropathy (read more)

Pretransplant IgG Reactivity to Apoptotic Cells Correlates With Late kidney Allograft Loss

Preexisting serum antibodies have long been associated with graft loss in transplant recipients. While most studies have focused on HLA-specific antibodies, the contribution of non-HLA-reactive antibodies has been largely overlooked. We have recently characterized mAbs secreted by B cell clones derived from kidney allograft recipients with rejection that bind to apoptotic cells. Here, we assessed the presence of such antibodies in pretransplant serum from 300 kidney transplant recipients and examined their contribution to the graft outcomes. Kaplan–Meier survival analysis revealed that patients with high pretransplant IgG reactivity to apoptotic cells had a significantly increased rate of late graft loss. The effect was only apparent after approximately 1 year posttransplant. Moreover, the association between pretransplant IgG reactivity to apoptotic cells and graft loss was still significant after excluding patients with high reactivity to HLA. This reactivity was almost exclusively mediated by IgG1 and IgG3 with complement fixing and activating properties. Overall, our findings support the view that IgG reactive to apoptotic cells contribute to presensitization. Taking these antibodies into consideration alongside anti-HLA antibodies during candidate evaluation would likely improve the transplant risk assessment (read more)

Complement Component C3 Activation: The Leading Cause of the Prozone Phenomenon Affecting HLA Antibody Detection on Single-Antigen Beads

Background : Luminex-based anti-HLA IgG detection on single-antigen flow beads (SAFB) represents a valuable tool for characterization of allosensitization patterns. Assay interpretation, however, may be impeded by false-low test results caused by the prozone effect. Recent experimental data have related this artifact to direct blockade of IgG detection by complement component C1 as a possible candidate mechanism.
Methods : To dissect a causative role of C1 complex formation and subsequent steps of classical complement activation, native or modified sera obtained from transplant candidates with HLA class I sensitization were evaluated applying SAFB-based IgG, IgM, C1q, C1r, C1s, or C4 and C3 split product detection, respectively.
Results : Evaluating a total of 1,164 single-antigen reactions, serum dilution (1:10) revealed an 11% incidence of the prozone effect as defined by a greater than 100% increase in IgG mean fluorescence intensity. Prozoning was found to be related to the amount of antibody-triggered C1q, C4 or C3 split product deposition, and was eliminated by serum modifications affecting the integrity of the C1 complex (dithiotreitol, ethylenediaminetetraacetic acid, heat inactivation). Remarkably, the same effect was achieved without C1 disintegration, either by serum treatment with methylamine to block C4 and C3 split product binding or by cobra venom factor to trigger C3 consumption.
Conclusions : Our results reinforce a central role of C1 as a trigger of prozoning. However, we provide evidence that C1 may exert its effects only indirectly, namely via inducing C3 fragment deposition, which by coating of the bead surface may block the binding of IgG detection reagents (read more)

Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts

Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome (read more).

Late-Onset Colitis after Cord Blood Transplantation Is Consistent with Graft-Versus-Host Disease: Results of a Blinded Histopathological Review

Cord colitis syndrome after umbilical cord blood transplantation (UCBT) involves late-onset diarrhea, absence of infection or GVHD, chronic active colitis, and granulomatous inflammation that responds to antibiotics. We tested the hypothesis that Seattle recipients of UCBT had late-occurring colitis distinct from GVHD and colitis in other allograft recipients. We conducted a blinded histological review of 153 colon biopsy specimens from 45 UCBT recipients and 45 matched allografted controls obtained between day +70 and day +365 post-transplantation. Diarrhea was the primary indication for biopsy in 10 UCBT recipients and 11 controls. No histological differences were seen between UCBT recipients and controls with diarrhea or between the entire cohort of UCBT recipients and their controls. Distorted mucosal architecture and apoptotic crypt cells typical of GVHD were common in both groups; Paneth cell metaplasia and granulomas were rare findings. Chronic active colitis was present in 58% of the UCBT recipients and in 62% of controls. No UCBT recipient with diarrhea was treated with antibiotics, and all recipients responded to systemic corticosteroids. Colitis occurring after day +70 in allografted controls was related to acute GVHD, independent of the source of donor cells. We could not identify a histologically distinct cord colitis syndrome in either the UCBT or the non–cord blood allograft recipients (read more).

Fully Automated Artificial Pancreas Finally Within Reach

Even with increasingly effective treatments and glucose monitors, most individuals with type 1 diabetes still cannot achieve recommended glucose control goals. Many experts believe that the best near-term solution for patients will be a system that can independently restore insulin and glucose balance.
“Artificial pancreas systems will be the most revolutionary advance in diabetes care since the discovery of insulin,” said Aaron Kowalski, PhD, a vice president at the Juvenile Diabetes Research Foundation (JDRF), a global organization that funds type 1 diabetes research.
An artificial pancreas is based on a simple concept: an automated system to dispense insulin and other pancreatic hormones based on real-time changes in blood sugar levels. But researchers face numerous challenges in turning the concept into reality (read more).

The Influence Of Non-Hla Antibodies Directed Against Angiotensin Ii Type 1-Receptor (At1r) On Early Renal Transplant Outcomes

Non-HLA antibodies (Abs) targeting vascular receptors are thought to have an impact on renal transplant injury. Anti-Angiotensin II type 1-receptor activating antibodies (anti-AT1R) have been mentioned to stimulate a severe vascular rejection but the pre-transplant screening has not been introduced yet.
The aim of our study was to assess the incidence and importance of anti-AT1R antibodies and their influence on renal transplant in the first year of observation.
We prospectively evaluated the presence of anti-AT1R antibodies in 117 consecutive renal transplant recipients in pre- and post-transplant screening.
Anti-AT1R antibodies were observed in 27/117(23%) of the analyzed recipients already before transplantation. The function of renal transplant was considerably worse in anti-AT1R(+) group. The patients with anti-AT1R Abs >9 U/mL lost their graft more often.
Biopsy proven AR was described in 4/27(15%) pts in the anti-AT1R(+) group and 13/90(14.4%) in the anti-AT1R(-) group but more severe cases of Banff IIB or AMR were more often observed in anti-AT1R (+) 4/27(15%) vs. 1/90(1.1%) in anti-AT1R(+) (p=0.009).
Patients with anti-AT1R Abs level >9U/mL run a higher risk of graft failure independently of classical immunological risk factors. The recipients with anti-AT1R Abs developed more severe acute rejections described as IIB or AMR in Banff classification. More recipients among the anti-AT1R positive ones lost the graft. Our study suggests monitoring of anti-AT1R Abs before renal transplantation for assessment of immunologic risk profiles and the identification of patients highly susceptible to immunologic events, graft failure and graft loss (read more)

Stromal cells–are they really useful for GVHD?

Mesenchymal stromal cells (MSCs) have immunomodulatory effects and are increasingly being used for the treatment of acute and chronic GVHD. Although they seem immuno-privileged, they induce alloresponses, but the risk of immunization is poorly characterized. After infusion, they first reach the lungs, liver and spleen, and are then difficult to trace. Several mechanisms are involved in stromal cells suppressing alloreactivity, such as induction of regulatory T cells, but whether or not this will also affect leukemic relapse or increase infections is not known. Although several encouraging pilot studies have been published, there have been few prospective randomized trials. There may be a bias in the literature, as negative results are seldom published, and there have been few comparative studies with other immunosuppressive regimens. Most animal models have failed to show any effect on GVHD. Several questions remain to be answered for optimization of stromal cell therapy. Which source is optimal–BM, fat, cord or decidua? Can stromal cells be replaced by exosomes, which culture conditions are most appropriate and at what passage and how frequently should cells be administered? More research is required to move stromal cell therapy forward to become an established treatment for acute and chronic GVHD (read more)

HLA Monomers as a Tool to Monitor Indirect Allorecognition

Background : Recognition of donor antigens can occur through two separate pathways: the direct pathway (non-self HLA on donor cells) and the indirect pathway (self-restricted presentation of donor derived peptides on recipient cells). Indirect allorecognition is important in the development of humoral rejection; therefore, there is an increasing interest in the monitoring of indirect alloreactive T-cells. We have used an in vitro model to determine the optimal requirements for indirect presentation and assessed the risk for semidirect presentation in this system. 

Methods : HLA-typed monocyte-derived dendritic cells (moDCs) were incubated with cellular fragments or necrotic cells and incubated with either indirect or direct alloreactive T-cell clones. T-cell reactivity was measured through proliferation or cytokine secretion. HLA-typed moDC, monocytes, or PBMCs were incubated with HLA class I monomers, in combination with either direct/indirect T-cell clones. 

Results : Although both were efficiently taken up, alloreactivity was limited to the semi-direct pathway, as measured by allospecific CD4 (indirect) and CD8 T-cell clones (direct) when cells were used. In contrast, HLA-A2 monomers were not only efficiently taken up but also processed and presented by HLA-typed moDC, monocytes, and PBMCs. Activation was shown by a dose-dependent induction of IFN-γ production and proliferation by the CD4 T-cell clone. Antigen presentation was most efficient when the monomers were cultured for longer periods (24–48 hr) in the presence of the T-cells. Using this method, no reactivity was observed by the CD8 T-cell clone, confirming no semidirect alloreactivity. 

Conclusion : We have developed a system that could be used to monitor indirect alloreactive T-cells (read more)

De Novo Donor-Specific HLA Antibodies: Biomarkers of Pancreas Transplant Failure

This study assesses the role of posttransplant HLA antibody monitoring in the surveillance of pancreas transplant recipients. Four hundred thirty-three pancreas transplants were performed at the Oxford Transplant Centre 2006–2011 (317 simultaneous pancreas kidney [SPK] and 116 isolated pancreas [IP]). HLA antibody monitoring was performed at 0, 6 and 12 months and annually and during clinical events. There was no association between pancreas graft failure and recipient or donor characteristics. Posttransplant antibody status, available for 354 (81.8%) of recipients, demonstrated that 141 (39.8%) developed de novo HLA antibodies, of which 52 (36.9%) were de novo donor-specific HLA antibodies (DSA) (34 SPK, 18 IP). The development of antibodies to donor HLA, but not to nondonor HLA, was significantly associated with poorer graft outcomes, with 1- and 3-year graft survival inferior in SPK recipients (85.2% vs. 93.5%; 71.8% vs. 90.3%, respectively; log-rank p = 0.002), and particularly in IP recipients (50.0% vs. 82.9%; 16.7 vs. 79.4%, respectively; log-rank p = 0.001). In a multivariate analysis, development of de novoDSA emerged as a strong independent predictor of pancreas graft failure (hazard ratio 4.66, p < 0.001). This is the largest study to examine de novo HLA antibodies following pancreas transplantation and clearly defines a high-risk group in need of specific intervention (read more).