Autologous Umbilical Cord Blood Transfusion in Young Children With Type 1 Diabetes Fails to Preserve C-Peptide

Haller, Michael J.; Wasserfall, Clive; Hulme, Maigan A.; Cintrón, Miriam; Brusko, Todd M.; McGrail, Kieran; Sumrall, Theresa M.; Wingard, John R.; Theriaque, Douglas W.; Shuster, Jonathan J.; Atkinson, Mark A.; Schatz, Desmond

doi:10.2337/dc11-1406

Cited by 64 publications

(64 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, Haller and colleagues recently reported that i.v. infusion of unfractionated UCB cells induced changes in regulatory T lymphocyte frequency but failed to preserve C-peptide [9]. Although our study did not directly address potential immunomodulatory mechanisms, or the activation of putative islet-derived beta cell precursors that may survive STZ toxicity [10], these experiments establish proof of concept that iPan delivery of purified ALDH hi progenitor cells can formulate a regenerative niche that impacts the behaviour and function of regenerating host islets.…”

Section: Discussionmentioning

confidence: 68%

See 1 more Smart Citation

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 68%

“…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

View full text Add to dashboard Cite

show abstract

“…50 Clinical trials for type 1 diabetes account for 7% of the autologous releases from family banks, but this treatment modality is currently not active because patient response to unmanipulated UCB stem cells was transient. 51 However, donorderived β-cell engraftment has been demonstrated in recipients of UCBT, suggesting that pancreatic cell precursors are present in UCB units. 52 Further exploration of the use of cord blood in these patients will likely need to include immunomodulatory therapies in combination with UCB infusions.…”

Section: Private Ucb Bankingmentioning

confidence: 99%

Umbilical cord blood donation: public or private?

Ballen

Verter²,

Kurtzberg

2015

Bone Marrow Transplant

View full text Add to dashboard Cite

Umbilical cord blood (UCB) is a graft source for patients with malignant or genetic diseases who can be cured by allogeneic hematopoietic cell transplantation (HCT), but who do not have an appropriately HLA-matched family or volunteer unrelated adult donor. Starting in the 1990s, unrelated UCB banks were established, accepting donations from term deliveries and storing UCB units for public use. An estimated 730 000 UCB units have been donated and stored to date and ∼ 35 000 UCB transplants have been performed worldwide. Over the past 20 years, private and family banks have grown rapidly, storing ∼ 4 million UCB units for a particular patient or family, usually charging an up-front and yearly storage fee; therefore, these banks are able to be financially sustainable without releasing UCB units. Private banks are not obligated to fulfill the same regulatory requirements of the public banks. The public banks have released ∼ 30 times more UCB units for therapy. Some countries have transitioned to an integrated banking model, a hybrid of public and family banking. Today, pregnant women, their families, obstetrical providers and pediatricians are faced with multiple choices about the disposition of their newborn's cord blood. In this commentary, we review the progress of UCB banking technology; we also analyze the current data on pediatric and adult unrelated UCB, including the recent expansion of interest in transplantation for hemoglobinopathies, and discuss emerging studies on the use of autologous UCB for neurologic diseases and regenerative medicine. We will review worldwide approaches to UCB banking, ethical considerations, criteria for public and family banking, integrated banking ideas and future strategies for UCB banking.

show abstract

“…Two smaller studies have evaluated the effect of non-expanded autologous umbilical cord blood transfusions into children with recent onset T1D [70,71]. Although well tolerated, neither demonstrated an impact on decline in beta cell function, likely due to an insufficient number of Tregs or loss of function with long-term storage of the cells.…”

Section: Source Of Tregsmentioning

confidence: 99%

Regulatory T cell therapy for type 1 diabetes: May the force be with you

Gitelman

Bluestone

2016

Journal of Autoimmunity

View full text Add to dashboard Cite

a b s t r a c tType 1 diabetes mellitus (T1DM) results from autoimmune destruction of insulin producing beta cells. Regulatory T cells (Tregs) have been shown to be defective in this setting. Immuno-therapies targeting T cells, and resetting the balance between T effectors and Tregs, have had some initial success in preserving beta cell function. With a goal to use Tregs themselves as a novel therapeutic, we developed a technique to isolate and expand Tregs from patients with T1DM. These ex vivo expanded CD4 þ CD127 lo/À CD25 þ cells exhibit improved function and retain their T cell receptor diversity. These cells have subsequently been used in phase I clinical trials in patients with recent onset T1DM. The infusions were well tolerated, with no safety concerns. The studies are too small to assess efficacy definitively, although some individuals exhibit stable beta cell function over intervals as long as 2 years. These efforts set the stage for a larger phase II effort in new onset T1DM, and combination studies with other drugs, as well as efforts in other autoimmune diseases.

show abstract

Autologous Umbilical Cord Blood Transfusion in Young Children With Type 1 Diabetes Fails to Preserve C-Peptide

Cited by 64 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

Umbilical cord blood donation: public or private?

Regulatory T cell therapy for type 1 diabetes: May the force be with you

Contact Info

Product

Resources

About