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Concept: Organ transplant

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

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

78

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

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

73

Background Delayed graft function, which is reported in up to 50% of kidney-transplant recipients, is associated with increased costs and diminished long-term graft function. The effect that targeted mild hypothermia in organ donors before organ recovery has on the rate of delayed graft function is unclear. Methods We enrolled organ donors (after declaration of death according to neurologic criteria) from two large donation service areas and randomly assigned them to one of two targeted temperature ranges: 34 to 35°C (hypothermia) or 36.5 to 37.5°C (normothermia). Temperature protocols, which were initiated after authorization was obtained for the organ to be donated and for the donor’s participation in the study, ended when organ donors left the intensive care unit for organ recovery in the operating room. The primary outcome was delayed graft function in the kidney recipients, which was defined as the requirement for dialysis during the first week after transplantation. Secondary outcomes were the rates of individual organs transplanted in each treatment group and the total number of organs transplanted from each donor. Results The study was terminated early, on the recommendation of an independent data and safety monitoring board, after the interim analysis showed efficacy of hypothermia. At trial termination, 370 organ donors had been enrolled (180 in the hypothermia group and 190 in the normothermia group). A total of 572 patients received a kidney transplant (285 kidneys from donors in the hypothermia group and 287 kidneys from donors in the normothermia group). Delayed graft function developed in 79 recipients of kidneys from donors in the hypothermia group (28%) and in 112 recipients of kidneys from donors in the normothermia group (39%) (odds ratio, 0.62; 95% confidence interval, 0.43 to 0.92; P=0.02). Conclusions Mild hypothermia, as compared with normothermia, in organ donors after declaration of death according to neurologic criteria significantly reduced the rate of delayed graft function among recipients. (Funded by the Health Resources and Services Administration; ClinicalTrials.gov number, NCT01680744 .).

Concepts: Chronic kidney disease, Kidney, Nephrology, Organ, Hypothermia, Organ transplant, Kidney transplantation, Organ donation

70

Allografts of retinal pigment epithelial (RPE) cells have been considered for the treatment of ocular diseases. We recently started the transplantation of induced pluripotent stem cell (iPSC)-derived RPE cells for patients with age-related macular degeneration (autogenic grafts). However, there are at least two problems with this approach: (1) high cost, and (2) uselessness for acute patients. To resolve these issues, we established RPE cells from induced iPSCs in HLA homozygote donors. In vitro, human T cells directly recognized allogeneic iPSC-derived RPE cells that expressed HLA class I/II antigens. However, these T cells failed to respond to HLA-A, -B, and -DRB1-matched iPSC-derived RPE cells from HLA homozygous donors. Because of the lack of T cell response to iPSC-derived RPE cells from HLA homozygous donors, we can use these allogeneic iPSC-derived RPE cells in future clinical trials if the recipient and donor are HLA matched.

Concepts: Stem cell, Stem cells, Cell biology, Retina, Organ transplant, Induced pluripotent stem cell, Macular degeneration, Retinal pigment epithelium

46

Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.

Concepts: Bone marrow, Multiple sclerosis, Organ transplant, Hematopoietic stem cell transplantation, Hematopoietic stem cell