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Concept: Organ transplant

151

Untreated articular cartilage defects may lead to chronic joint degeneration and functional disability. In the past decade, several cartilage repair techniques have emerged for the treatment of cartilage lesions. Among these techniques, mosaicplasty was introduced by the senior author into the clinical practice in 1992. This article does not intend to give a review or a comparison of currently existing surgical techniques which aim to repair symptomatic focal defects; however, it focuses on the procedures used in the everyday practice in the authors' institute, namely microfracture, mosaicplasty, autologous chondrocyte implantation (ACI), osteochondral allograft transplantation and biodegradable osteochondral scaffolds. It gives a brief summary of these well-described techniques, summarizes the authors' clinical experience and available data on the clinical outcome, and the rehabilitation protocol following different procedures, with a special emphasis on mosaicplasty.

Concepts: Cartilage, Knee, Organ transplant, Knee cartilage replacement therapy, Autologous chondrocyte implantation, Chondrocyte, Articular cartilage damage, Articular cartilage repair

149

We previously reported that bone marrow grafts from matched sibling donors resulted in best graft-versus-host disease-free, relapse-free survival at 1-year post allogeneic hematopoietic cell transplantation. However, pediatric patients comprised the majority of bone marrow graft recipients in that study. To better define this outcome in adults and pediatric patients at 1- and 2-years post- allogeneic hematopoietic cell transplantation, we pooled data from University of Minnesota and Hopital Saint-Louis in Paris, France (n=1901). Graft-versus-host disease-free, relapse-free survival was defined as absence of grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease (requiring systemic therapy or extensive stage), relapse and death. In adults, bone marrow from matched sibling donors (n=123) had best graft-versus-host disease-free, relapse-free survival at 1- and 2-years, compared with peripheral blood stem cell from matched sibling donors (n=540) or other graft/donor types. In multivariate analysis, peripheral blood stem cell from matched sibling donors resulted in a 50% increased risk of events contributing to graft-versus-host disease-free, relapse-free survival at 1- and 2-years than bone marrow from matched sibling donors. With limited numbers of peripheral blood stem cell grafts in pediatric patients (n=12), graft-versus-host disease-free, relapse-free survival did not differ between bone marrow and peripheral blood stem cell graft from any donor. While not all patients have a matched sibling donor, graft-versus-host disease-free, relapse-free survival may be improved by preferential use of bone marrow for adults with malignant diseases. Alternatively, novel graft-versus-host disease prophylaxis regimens are needed to substantially impact graft-versus-host disease-free, relapse-free survival with the use of peripheral blood stem cell.

Concepts: Medicine, Cancer, Stem cell, Bone marrow, Graft-versus-host disease, Organ transplant, Hematopoietic stem cell transplantation, Hematopoietic stem cell

148

The use of dipeptidyl peptidase-4 (DPP-4) inhibitors is increasing among renal transplant patients with diabetes. However, the glucose-lowering efficacies of various DPP-4 inhibitors and their effects on blood cyclosporine levels have not been fully investigated. We compared the glucose-lowering efficacies of DPP 4 inhibitors and evaluate their effects on the blood levels of cyclosporine in renal transplant recipients with diabetes.

Concepts: Chronic kidney disease, Kidney, Blood sugar, Organ transplant, Dipeptidyl peptidase-4, Dipeptidyl peptidase-4 inhibitors, Dipeptidyl peptidase-4 inhibitor

148

41st Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2015), Istanbul, Turkey, 22-25 March 2015 The European Society for Blood and Marrow Transplantation (EBMT) is the leading scientific society for professionals involved in hematopoietic stem-cell transplantation (HSCT) and represents 563 transplant centers from 57 countries within and outside Europe. Each year, the EBMT Annual Meeting brings together over 4,500 scientists, physicians, nurses, biologists, technicians and patients to discuss scientific data that build on past achievements in the field of HSCT. The procedure offers the chance of long-term remission of hematological and lymphoid cancers, but patients are at increased risk of serious infections, especially after allogeneic HSCT. These infections include the invasive fungal infections that were among the important topics discussed during EBMT 2015.

Concepts: Immune system, Bone marrow, Chemotherapy, Hematology, Organ transplant, Hematopoietic stem cell transplantation, Turkey, Scientist

146

We recently reported isolation of viable rat amniotic fluid-derived stem (AFS) cells [1]. Here, we tested the therapeutic benefits of AFS cells in a rodent model of ischemic stroke. Adult male Sprague-Dawley rats received a 60-minute middle cerebral artery occlusion (MCAo). Thirty-five days later, animals exhibiting significant motor deficits received intravenous transplants of rat AFS cells or vehicle. At days 60-63 post-MCAo, significant recovery of motor and cognitive function was seen in stroke animals transplanted with AFS cells compared to vehicle-infused stroke animals. Infarct volume, as revealed by hematoxylin and eosin (H&E) staining, was significantly reduced, coupled with significant increments in the cell proliferation marker, Ki67, and the neuronal marker, MAP2, in the dentate gyrus (DG) [2] and the subventricular zone (SVZ) of AFS cell-transplanted stroke animals compared to vehicle-infused stroke animals. A significantly higher number of double-labeled Ki67/MAP2-positive cells and a similar trend towards increased Ki67/MAP2 double-labeling were observed in the DG and SVZ of AFS cell-transplanted stroke animals, respectively, compared to vehicle-infused stroke animals. This study reports the therapeutic potential of AFS cell transplantation in stroke animals, possibly via enhancement of endogenous repair mechanisms.

Concepts: Cell division, Stroke, Cerebrum, Middle cerebral artery, Anterior cerebral artery, Dentate gyrus, Neurogenesis, Organ transplant

139

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.

Concepts: Disease, Infectious disease, Infection, Graft-versus-host disease, Rheumatoid arthritis, Organ transplant, Hematopoietic stem cell transplantation, Juvenile idiopathic arthritis

120

Novel interventions that reestablish endogenous insulin secretion and thereby halt progressive end-organ damage and prolong survival of patients with autoimmune Type 1 diabetes mellitus (T1DM) are urgently needed. While this is currently accomplished with allogeneic pancreas or islet transplants, their utility is significantly limited by both the scarcity of organ donors and life-long need for often-toxic antirejection drugs. Coadministering islets with bone marrow-derived mesenchymal stem cells (MSCs) that exert robust immune-modulating, anti-inflammatory, anti-apoptotic, and angiogenic actions, improves intrahepatic islet survival and function. Encapsulation of insulin-producing cells to prevent immune destruction has shown both promise and failures. Recently, stem cell-derived insulin secreting β-like cells induced euglycemia in diabetic animals, although their clinical use would still require encapsulation or anti-rejection drugs. Instead of focusing on further improvements in islet transplantation, we demonstrate here that the intraperitoneal administration of islet-sized “Neo-Islets” (NIs), generated by in vitro coaggregation of allogeneic, culture-expanded islet cells with high numbers of immuno-protective and cyto-protective MSCs, resulted in their omental engraftment in immune-competent, spontaneously diabetic nonobese diabetic (NOD) mice. This achieved long-term glycemic control without immunosuppression and without hypoglycemia. In preparation for an Food and Drug Administration-approved clinical trial in dogs with T1DM, we show that treatment of streptozotocin-diabetic NOD/severe combined immunodeficiency mice with identically formed canine NIs produced durable euglycemia, exclusively mediated by dog-specific insulin. We conclude that this novel technology has significant translational relevance for canine and potentially clinical T1DM as it effectively addresses both the organ donor scarcity (>80 therapeutic NI doses/donor pancreas can be generated) and completely eliminates the need for immunosuppression. Stem Cells Translational Medicine 2017.

Concepts: Insulin, Diabetes mellitus, Diabetes mellitus type 1, Islets of Langerhans, Glucagon, Pancreas, Diabetes, Organ transplant

80

Background In previous analyses of BENEFIT, a phase 3 study, belatacept-based immunosuppression, as compared with cyclosporine-based immunosuppression, was associated with similar patient and graft survival and significantly improved renal function in kidney-transplant recipients. Here we present the final results from this study. Methods We randomly assigned kidney-transplant recipients to a more-intensive belatacept regimen, a less-intensive belatacept regimen, or a cyclosporine regimen. Efficacy and safety outcomes for all patients who underwent randomization and transplantation were analyzed at year 7 (month 84). Results A total of 666 participants were randomly assigned to a study group and underwent transplantation. Of the 660 patients who were treated, 153 of the 219 patients treated with the more-intensive belatacept regimen, 163 of the 226 treated with the less-intensive belatacept regimen, and 131 of the 215 treated with the cyclosporine regimen were followed for the full 84-month period; all available data were used in the analysis. A 43% reduction in the risk of death or graft loss was observed for both the more-intensive and the less-intensive belatacept regimens as compared with the cyclosporine regimen (hazard ratio with the more-intensive regimen, 0.57; 95% confidence interval [CI], 0.35 to 0.95; P=0.02; hazard ratio with the less-intensive regimen, 0.57; 95% CI, 0.35 to 0.94; P=0.02), with equal contributions from the lower rates of death and graft loss. The mean estimated glomerular filtration rate (eGFR) increased over the 7-year period with both belatacept regimens but declined with the cyclosporine regimen. The cumulative frequencies of serious adverse events at month 84 were similar across treatment groups. Conclusions Seven years after transplantation, patient and graft survival and the mean eGFR were significantly higher with belatacept (both the more-intensive regimen and the less-intensive regimen) than with cyclosporine. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00256750 .).

Concepts: Renal failure, Kidney, Nephrology, Renal physiology, Renal function, Organ transplant, Electrolyte, Bristol-Myers Squibb

77

Relapses in acute myelogenous leukemia (AML) are a result of quiescent leukemic stem cells (LSCs) in marrow stromal niches, where they resist chemotherapy. LSCs employ CXCL12/CXCR4 to home toward protective marrow niches. Heparin disrupts CXCL12-mediated sequestration of cells in the marrow. CX-01 is a low-anticoagulant heparin derivative. In this pilot study, we combined CX-01 with chemotherapy for the treatment of AML. Induction consisted of cytarabine and idarubicin (7 + 3) with CX-01. Twelve patients were enrolled (median age, 56 years; 3 women). Three, 5, and 4 patients had good-, intermediate-, and poor-risk disease, respectively. Day 14 bone marrows were available on 11 patients and were aplastic in all without detectable leukemia. Eleven patients (92%) had morphologic complete remission after 1 induction (CR1). Eight patients were alive at a median follow-up of 24 months (4 patients in CR1). Three patients received an allogeneic stem cell transplant in CR1. Median disease-free survival was 14.8 months. Median overall survival was not attained at the maximum follow-up time of 29.4 months. No CX-01-associated serious adverse events occurred. Median day to an untransfused platelet count of at least 20 × 109/L was 21. CX-01 is well tolerated when combined with intensive therapy for AML and appears associated with enhanced count recovery and treatment efficacy.

Concepts: Bone marrow, Cure, Chemotherapy, Leukemia, Organ transplant, Acute myeloid leukemia, Blood disorders, Myeloid sarcoma

73

There is an ongoing controversy as to whether major histocompatibility complex (MHC) matching is a solution for allogeneic stem cell transplantation. In the present study, we established retinal pigment epithelial (RPE) cells from induced pluripotent stem cells (iPSCs) in MHC homozygote donors. We observed no rejection signs in iPSC-derived RPE allografts of MHC-matched animal models without immunosuppression, whereas there were immune attacks around the graft and retinal tissue damage in MHC-mismatched models. In an immunohistochemical examination of MHC-mismatched allografts, the transplanted RPE sheets/cells were located in the subretinal space, but the RPE exhibited inflammatory and hypertrophic changes, and many inflammatory cells, e.g., Iba1(+) cells, MHC class II(+) cells, and CD3(+) T cells, invaded the graft area. Conversely, these inflammatory cells poorly infiltrated the area around the transplanted retina if MHC-matched allografts were used. Thus, cells derived from MHC homozygous donors could be used to treat retinal diseases in histocompatible recipients.

Concepts: Stem cell, Stem cells, Cell biology, Major histocompatibility complex, Retina, Organ transplant, Induced pluripotent stem cell, Retinal pigment epithelium