Impact of HLA matching on the outcome of simultaneous pancreas-kidney transplantation

Background. Simultaneous pancreas-kidney (SPK) transplantation has become the therapy of choice for type 1 diabetic patients with end-stage renal disease. The current analysis examined the impact of human leukocyte antigen (HLA) matching on graft outcome following SPK transplantation. The study population was obtained from patients enrolled in the Euro-SPK 001 study. Methods. The effect of HLA matching on graft function and survival was assessed in 180 SPK recipients in whom complete donor-recipient HLA data were available. A group of 45 patients with 0-3 HLA mismatches (MM) was compared with a group of 135 patients with 4-6 MM. Results. There were no differences in 3-year kidney, pancreas or patient survival between the 0-3 and 4-6 MM groups. Biological parameters of kidney and pancreas graft function were similar in both groups. Significantly more patients with 0-3 MM (66%) were rejection-free at 3 years than was the case among those with 4-6 MM (41%; P = 0.003). The relative risk of acute rejection was 2.6 times higher among patients with 4-6 MM than among those with 0-3 MM. Conclusions. There was no evidence that HLA matching was associated with improved kidney or pancreas survival. However, a higher rate of acute rejection was observed with poor HLA match, which may impact long-term surviva

Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-Cadherin interaction and prolong function of transplanted encapsulated islets in mice

Background: Multipotent mesenchymal stromal cells (MSC) enhance viability and function of islets of Langerhans. We aimed to examine the interactions between human MSC and human islets of Langerhans that influence the function of islets. Methods: Human MSC and human islets (or pseudoislets, obtained after digestion and reaggregation of islet cells) were cocultured with or without cellular contact and glucose-stimulated insulin secretion assays were performed to assess cell function. The expression of several adhesion molecules, notably ICAM-1 and N-cadherin on islets and MSC, was investigated by qPCR. The role of N-cadherin was analyzed by adding an anti-N-cadherin antibody in islets cultured with or without MSC for 24 h followed by insulin measurements in static incubation assays. Islets and MSC were coencapsulated in new hydrogel microspheres composed of calcium alginate and covalently crosslinked polyethylene glycol. Encapsulated cells were transplanted intraperitoneally in streptozotocin-induced diabetic mice and glycemia was monitored. Islet function was evaluated by the intraperitoneal glucose tolerance test. Results: In vitro, free islets and pseudoislets cocultured in contact with MSC showed a significantly increased insulin secretion when compared to islets or pseudoislets cultured alone or cocultured without cell-to-cell contact with MSC (p < 0.05). The expression of ICAM-1 and N-cadherin was present on islets and MSC. Blocking N-cadherin prevented the enhanced insulin secretion by islets cultured in contact with MSC whereas it did not affect insulin secretion by islets cultured alone. Upon transplantation in diabetic mice, islets microencapsulated together with MSC showed significantly prolonged normoglycemia when compared with islets alone (median 69 and 39 days,respectively, p < 0.01). The intraperitoneal glucose tolerance test revealed an improved glycemic response in mice treated with islets microencapsulated together with MSC compared to mice transplanted with islets alone (p < 0.001). Conclusions: MSC improve survival and function of islets of Lan gerhans by cell-to-cell contact mediated by the adhesion molecule N-cadherin

Synthesis strategies to extend the variety of alginate-based hybrid hydrogels for cell microencapsulation

The production of hydrogel microspheres (MS) for cell immobilization, maintaining the favorable properties of alginate gels but presenting enhanced performance in terms of in vivo durability and physical properties, is desirable to extend the therapeutic potential of cell transplantation. A novel type of hydrogel MS was produced by straightforward functionalization of sodium alginate (Na-alg) with heterotelechelic poly(ethylene glycol) (PEG) derivatives equipped with either end thiol or 1,2-dithiolane moieties. Activation of the hydroxyl moieties of the alginate backbone in the form of imidazolide intermediate allowed for fast conjugation to PEG oligomers through a covalent carbamate linkage. Evaluation of the modified alginates for the preparation of MS combining fast ionic gelation ability of the alginate carboxylate groups and slow covalentcross-linking provided by the PEG-end functionalities highlighted the influence of the chemical composition of the PEG-grafting units on the physical characteristics of the MS. The mechanical properties of the MS (resistance and shape recovery) and durability of PEG-grafted alginates in physiological environment can be adjusted by varying the nature of the end functionalities and the length of the PEG chains. In vitro cell microencapsulation studies and preliminary in vivo assessment suggested the potential of these hydrogels for cell transplantation applications

Third WHO Global Consultation on regulatory requirements for xenotransplantation clinical trials, Changsha, Hunan, China December 12-14, 2018: "The 2018 Changsha Communiqué" The 10-Year Anniversary of The International Consultation on Xenotransplantation

After feedback from the working parties, the final session focused on drafting proposed revisions of the WHO documents, and resulted in the formulation of the draft “Third WHO Global Consultation on Regulatory Requirements for Xenotransplantation Clinical Trials, The 2018 Changsha Communiqué.” This draft was submitted to WHO in February 2019 for WHO and World Health Assembly consideration. If approved, the 2018 Changsha Communiqué will then be posted on the websites of WHO, IXA, and TTS, and published in Xenotransplantation. This report includes summaries of the various sessions, followed by the abstracts of invited speakers from the update sessions

Thoracic epidural analgesia: a new approach for the treatment of acute pancreatitis?

This review article analyzes, through a nonsystematic approach, the pathophysiology of acute pancreatitis (AP) with a focus on the effects of thoracic epidural analgesia (TEA) on the disease. The benefit-risk balance is also discussed. AP has an overall mortality of 1 %, increasing to 30 % in its severe form. The systemic inflammation induces a strong activation of the sympathetic system, with a decrease in the blood flow supply to the gastrointestinal system that can lead to the development of pancreatic necrosis. The current treatment for severe AP is symptomatic and tries to correct the systemic inflammatory response syndrome or the multiorgan dysfunction. Besides the removal of gallstones in biliary pancreatitis, no satisfactory causal treatment exists. TEA is widely used, mainly for its analgesic effect. TEA also induces a targeted sympathectomy in the anesthetized region, which results in splanchnic vasodilatation and an improvement in local microcirculation. Increasing evidence shows benefits of TEA in animal AP: improved splanchnic and pancreatic perfusion, improved pancreatic microcirculation, reduced liver damage, and significantly reduced mortality. Until now, only few clinical studies have been performed on the use of TEA during AP with few available data regarding the effect of TEA on the splanchnic perfusion. Increasing evidence suggests that TEA is a safe procedure and could appear as a new treatment approach for human AP, based on the significant benefits observed in animal studies and safety of use for human. Further clinical studies are required to confirm the clinical benefits observed in animal studies

Hydrogels based on functionalized polysaccharides

The present invention relates to a functionalized hydrogel network grafted with at least one moiety for use in numerous fields, from cosmetics to surgery and medicine

CERN-MEDICIS: une nouvelle infrastructure pour la production de radioisotopes a usage medical [CERN-MEDICIS (Medical Isotopes Collected from ISOLDE): a new facility].

CERN-MEDICIS (Medical Isotopes Collected from ISOLDE) est une plateforme de recherche destinée à la production de radioisotopes biomédicaux. Inauguré en 2014, il produira progressivement un nombre croissant de radioisotopes grâce au faisceau de protons ISOLDE déjà existant. Ce projet réunit des spécialistes du cancer, des chirurgiens, des experts en médecine nucléaire, en radiochimie et radiopharmacie et les scientifiques du CERN. Les radioisotopes ainsi produits seront destinés à la recherche fondamentale contre le cancer, à des études précliniques ainsi qu'au développement de protocoles d'imagerie et de thérapie destinés aux patients.Le CERN, les HUG, le CHUV, l'ISREC et l'EPFL qui soutiennent ce projet seront les premiers bénéficiaires de ces radioisotopes novateurs dont la distribution sera ensuite étendue à d'autres centres européens. CERN-MEDICIS is a facility dedicated to research and development in life science and medical applications. The research platform was inaugurated in October 2014 and will produce an increasing range of innovative isotopes using the proton beam of ISOLDE for fundamental studies in cancer research, for new imaging and therapy protocols in cell and animal models and for preclinical trials, possibly extended to specific early phase clinical studies (phase 0) up to phase I trials. CERN, the University Hospital of Geneva (HUG), the University Hospital of Lausanne (CHUV), the Swiss Institute for Experimental Cancer (ISREC) at Swiss Federal Institutes of Technology (EPFL) that currently support the project will benefit of the initial production that will then be extended to other centers

Cross-Reactive Alginate Derivatives for the Production of Dual Ionic−Covalent Hydrogel Microspheres Presenting Tunable Properties for Cell Microencapsulation

The production of hydrogel micropsheres (MS) presenting physical, mechanical, and biological properties which can be modulated by their chemical composition is required to enlarge the panel of biomaterials for cell transplantation therapies. Functionalization of sodium alginate (Na-alg) with cross-reactive poly(ethylene glycol) (PEG) derivatives presenting terminal thiol and carbon electrophile functionalities provided novel polymers which upon simple one-step protocol formed hydrogel MS assembled by combination of Ca-alg interactions and sulfur−carbon covalent bonds. Several parameters such as the grafting degree on the alg backbone and the viscosity of the polymer solutions can be adjusted to provide optimal formulation for the capsule formation technology. Compared with pure Ca-alg MS, dual ionic−covalent MS displayed improved mechanical resistance and shape recovery performance. Importantly, under conditions which resulted in complete liquefaction of Ca-alg MS, chemically cross-linked Alg-PEG MS maintained stable spherical morphology. In addition, these hydrogels allowed excellent viability and functionality of microencapsulated Huh7 cells. After transplantation in the peritoneal cavity of immune competent mice, the dual ionic−covalent MS remained free-floating and maintained their integrity over 30 days

Microencapsulation of hepatocytes and mesenchymal stem cells for therapeutic applications

Encapsulated hepatocyte transplantation and encapsulated mesenchymal stem cell transplantation are newly developed potential treatments for acute and chronic liver diseases, respectively. Cells are microencapsulated in biocompatible semi-permeable alginate-based hydrogels. Microspheres protect cells against antibodies and immune cells, while allowing nutrients, small/medium size proteins and drugs to diffuse inside and outside the polymer matrix. Microencapsulated cells are assessed in vitro and designed for experimental transplantation and for future clinical applications. Here, we describe the protocol for microencapsulation of hepatocytes and mesenchymal stem cells within hybrid poly(ethylene glycol)-alginate hydrogels