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Current status of clinical islet transplantation.

ABSTRACT: Islet transplantation (IT) is today a well-established treatment modality for selected patients with type 1 diabetes mellitus (T1DM). After the success of the University of Alberta group with a modified approach to the immune protection of islets, the international experience grew along with the numbers of transplants in highly specialized centers. Yet, long-term analysis of those initial results from the Edmonton group indicated that insulin-independence was not durable and most patients return to modest amounts of insulin around the fifth year, without recurrent hypoglycemia events. Many phenomena have been identified as limiting factor for the islet engraftment and survival, and today all efforts are aimed to improve the quality of islets and their engrafting process, as well as more optimized immunosuppression to facilitate tolerance and ultimately, better long term survival. This brief overview presents recent progress in IT. A concise historical perspective is provided, along with the latest efforts to improve islet engraftment, immune protection and ultimately, prolonged graft survival. It is apparent that as the community continues to work together further optimizing IT, it is hopeful a cure for T1DM will soon be achievable.

SUBMITTER: Pepper AR

PROVIDER: S-EPMC3879523 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Current status of clinical islet transplantation.

Pepper Andrew R AR Gala-Lopez Boris B Ziff Oliver O Shapiro Am James AJ

World journal of transplantation 20131201 4

Islet transplantation (IT) is today a well-established treatment modality for selected patients with type 1 diabetes mellitus (T1DM). After the success of the University of Alberta group with a modified approach to the immune protection of islets, the international experience grew along with the numbers of transplants in highly specialized centers. Yet, long-term analysis of those initial results from the Edmonton group indicated that insulin-independence was not durable and most patients return ...[more]

PMID: 24392308

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Project description:Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin-independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters--including time until insulin independence, insulin independence at one year, and C-peptide levels over one year--remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Clinicaltrials.gov NCT00623610.

Project description:PURPOSE:A clinical trial of intestinal transplantation (Itx) under tacrolimus and prednisone immunosuppression was initiated in June 1990 in children with irreversible intestinal failure and who were dependent on total parenteral nutrition (TPN). METHODS:Fifty-five patients (28 girls, 27 boys) with a median age of 3.2 years (range, 0.5 to 18 years) received 58 intestinal transplants that included isolated small bowel (SB) (n = 17), liver SB (LSB) (n=33), and multivisceral (MV) (n=8) allografts. Nine patients also received bone marrow infusion, and there were 20 colonic allografts. Azathioprine, cyclophosphamide, or mycophenolate mofetil were used in different phases of the series. Indications for Itx included: gastroschisis (n=14), volvulus (n=13), necrotizing enterocolitis (n=6), intestinal atresia (n=8), chronic intestinal pseudoobstruction (n=5), Hirschsprung's disease (n=4), microvillus inclusion disease (n=3), multiple polyposis (n=1), and trauma [n=1). RESULTS:Currently, 30 patients are alive (patient survival, 55%; graft survival, 52%). Twenty-nine children with functioning grafts are living at home and off TPN, with a mean follow-up of 962 (range, 75 to 2,424) days. Immunologic complications have included liver allograft rejection (n=18), intestinal allograft rejection (n=52), posttransplant lymphoproliferative disease (n=16), cytomegalovirus (n=16) and graft-versus-host disease (n=4). A combination of associated complications included intestinal perforation (n=4), biliary leak (n=3), bile duct stenosis (n=1), intestinal leak (n=6), dehiscence with evisceration (n=4), hepatic artery thrombosis (n=3), bleeding (n=9), portal vein stenosis (n=1), intraabdominal abscess (n=11), and chylous ascites (n=4). Graft loss occurred as a result of rejection (n=8), infection (n=12), technical complications (n=8), and complications of TPN after graft removal (n=3). There were four retransplants (SB, n=1; LSB n=3). CONCLUSIONS:Intestinal transplantation is a valid therapeutic option for patients with intestinal failure suffering complications of TPN. The complex clinical and immunologic course of these patients is reflected in a higher complication rate as well as patient and graft loss than seen after heart, liver, and kidney transplantation, although better than after lung transplantation.

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Current status of clinical islet transplantation.

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Current status of clinical islet transplantation.

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