Independence of exogenous insulin following immunoablation and stem cell reconstitution in newly diagnosed diabetes type I

Snarski, Emilian; Milczarczyk, Alicja; Torosian, Tigran; Paluszewska, Monika; Urbanowska, Elżbieta; Król, Małgorzata; Boguradzki, Piotr; Jedynasty, Krystyna; Franek, Edward; Wiktor-Jedrzejczak, W

doi:10.1038/bmt.2010.147

Cited by 85 publications

(62 citation statements)

References 9 publications

(11 reference statements)

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“…Clinical evidence suggests that strategies employing BM or UCB stem cells can potentially benefit diabetic patients via beta cell regenerative or immunomodulatory mechanisms [8,9]. However, Haller and colleagues recently reported that i.v.…”

Section: Discussionmentioning

confidence: 99%

Intrapancreatic delivery of human umbilical cord blood aldehyde dehydrogenase-producing cells promotes islet regeneration

et al. 2012

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Aims/hypothesis We sought to investigate the stimulation of islet regeneration by transplanted human umbilical cord blood (UCB) cells purified according to high aldehyde dehydrogenase (ALDH) activity (ALDH hi ), a conserved characteristic of multiple progenitor lineages. We hypothesised that direct intrapancreatic (iPan) delivery of ALDH hi progenitors would augment islet regeneration via timely and localised exposure to islet-regenerative stimuli. Methods Cells were purified from UCB based on flow cytometry for low ALDH activity (ALDH lo ) vs ALDH hi . UCB ALDH lo or ALDH hi cells were compared for surface marker expression, as well as haematopoietic, endothelial and multipotent stromal progenitor content in vitro. UCB ALDH lo or ALDH hi cells were i.v. or iPan injected into streptozotocin-treated non-obese diabetic/severe combined immune-deficient mice temporally monitored for blood glucose, serum insulin and glucose tolerance. Human cell recruitment and survival in the pancreas, insulin content, islet-associated cell proliferation and islet vascularisation were documented in situ.Results UCB-derived ALDH hi cells were highly enriched for haematopoietic and endothelial progenitor frequency, and showed increased expression of progenitor and myeloid cell surface markers. Although i.v. transplantation of ALDH hi cells demonstrated low pancreas engraftment and only transient blood glucose lowering capacity, iPan injected ALDH hi cells reversed established hyperglycaemia, increased serum insulin and improved the response to a glucose challenge. iPan injected ALDH hi cells surrounded damaged islets at early time points and increased islet-associated cell proliferation, resulting in the recovery of beta cell mass. Conclusions/interpretation iPan delivery of UCB ALDH hi cells potentiated islet-associated cell proliferation, insulin production and islet revascularisation, resulting in the recovery of host islet function. Elucidation of the progenitor-specific pathways stimulated during islet regeneration may provide new approaches to promote islet expansion during diabetes.

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Section: Discussionmentioning

confidence: 99%

Intrapancreatic delivery of human umbilical cord blood aldehyde dehydrogenase-producing cells promotes islet regeneration

et al. 2012

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“…Several clinical trials-designed based on the preclinical successful targeting of components of innate and adaptive immune responses-performed thus far have failed to cure T1D (3,8); only in the anti-CD3 monoclonal antibody (mAb) trial (using teplizumab in the Protégé Study) did 5% of individuals become insulin independent (9). In this daunting scenario, a trial conducted by Voltarelli et al (10) succeeded in exploiting hematopoietic stem cells (HSCs) to treat new-onset T1D and achieved encouraging results, paving the way for another three trials, which were initiated worldwide (11,12). The rationale for the use of HSCs in treating subjects with T1D is based upon the immunoregulatory properties of HSCs, which may help to rescue peripheral tolerance toward pancreatic b-cells by reshaping the immune response (13,14).…”

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confidence: 99%

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis

et al. 2014

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Type 1 diabetes (T1D) is one of the major autoimmune diseases affecting children and young adults worldwide. To date, the different immunotherapies tested have achieved insulin independence in <5% of treated individuals. Recently, a novel hematopoietic stem cell (HSC)-based strategy has been tested in individuals with new-onset T1D. The aim of this study was to determine the effects of autologous nonmyeloablative HSC transplantation in 65 individuals with new-onset T1D who were enrolled in two Chinese centers and one Polish center, pooled, and followed up for 48 months. A total of 59% of individuals with T1D achieved insulin independence within the first 6 months after receiving conditioning immunosuppression therapy (with antithymocyte globulin and cyclophosphamide) and a single infusion of autologous HSCs, and 32% remained insulin independent at the last time point of their follow-up. All treated subjects showed a decrease in HbA 1c levels and an increase in C-peptide levels compared with pretreatment. Despite a complete immune system recovery (i.e., leukocyte count) after treatment, 52% of treated individuals experienced adverse effects. Our study suggests the following: 1) that remission of T1D is possible by combining HSC transplantation and immunosuppression; 2) that autologous nonmyeloablative HSC transplantation represents an effective treatment for selected individuals with T1D; and 3) that safer HSC-based therapeutic options are required.The incidence of type 1 diabetes (T1D) has been significantly increasing worldwide in the last decade, thus becoming the most common autoimmune disorder in children (1). T1D is characterized by a selective and aggressive destruction of insulin-producing b-cells orchestrated by autoreactive T cells (2,3). Unfortunately, exogenous insulin therapy does not always achieve the necessary metabolic control (4), nor does it prevent the occurrence of disease-associated degenerative macrovascular and microvascular complications (5) or halt b-cell decline (6).The concept of the use of immunotherapeutic strategy to cure T1D has emerged from hallmark data generated using the NOD mouse model and has allowed for a better understanding of the pathogenesis of T1D (7). Several clinical trials-designed based on the preclinical successful targeting of components of innate and adaptive immune responses-performed thus far have failed to cure

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“…HCT has been promoted in polymyositis/dermatomyositis, Sjogren's syndrome, psoriatic arthritis and ankylosing arthritis, chronic inflammatory demyelinating polyneuropathy and autoimmune cytopenias, including hemolytic anemia, ITP, Evans syndrome and other rare combinations [115,116]. Promising preliminary results were registered in small groups of patients with type 1 diabetes (T1D) from Brazil [117,118], China [119,120], and Poland [121]. Preliminary lessons from these small trials suggest that: (i) majority of patients can reach independence of exogenous insulin for a period of few months to years; (ii) according to our knowledge, there were no described transplant-related deaths; and (iii) diabetic ketoacidosis at onset, probably due to a severe depletion of islet cells, can be a poor predicting factor.…”

Section: Hct In Other Autoimmune Diseasesmentioning

confidence: 88%

“…Specific issues vary significantly depending on the country's social and economic climate, differences in medical system or medical insurance barriers, and legislation requiring third-party payers, and as a result, a large portion of patients cannot afford the best, or even equivalent "conventional" lifelong treatment. The majority of failures come in the form of TRM, as well as nonresponsiveness and high relapse rate [121]. The attempts to decrease the treatment toxicity, without sacrificing the efficiency, are directed to balancing the failure-tobenefit ratio.…”

Section: Resultsmentioning

confidence: 99%

Hematopoietic Cell Transplantation for Autoimmune Diseases: A Review of History, Current State, and Future Issues

Resnick¹,

Metodiev²,

Lazarova³

2017

Immunotherapy - Myths, Reality, Ideas, Future

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Autoimmune diseases are characterized by recurrent attacks and remissions, but as a rule they progress and eventually cause a severe disability and death. The present chapter contains general characteristics of autoimmune disease pathogenesis, ways to cause immune tolerance by hematopoietic cell transplantation (HCT), clinical aspects of the treatment for established autoimmune diseases with a special attention to multiple sclerosis (MS) and systemic sclerosis (SSc). A profound analysis of authors' point of view and of the available literature has been performed. The promising results allows to consider HCT as a relevant treatment option for a certain autoimmune diseases.

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Independence of exogenous insulin following immunoablation and stem cell reconstitution in newly diagnosed diabetes type I

Cited by 85 publications

References 9 publications

Intrapancreatic delivery of human umbilical cord blood aldehyde dehydrogenase-producing cells promotes islet regeneration

Intrapancreatic delivery of human umbilical cord blood aldehyde dehydrogenase-producing cells promotes islet regeneration

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis

Hematopoietic Cell Transplantation for Autoimmune Diseases: A Review of History, Current State, and Future Issues

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