At the time of transplantation, the isolated islets are allowed to embolize the liver after infusion in the portal vein, a procedure that is unique in the area of transplantation. Others and we have demonstrated in a series of reports that an injurious thrombotic/ inflammatory reaction is elicited when islets come in direct contact with ABO-compatible blood. This reaction is termed the instant blood-mediated inflammatory reaction (IBMIR) and is induced as a consequence of the interplay between inflammatory mediators such as tissue factor (TF) and MCP-1 expressed by isolated human Islets and the innate immune system of the recipient. In clinical islet transplantation, the IBMIR is triggered within minutes after islet Infusion Into the portal vein. PET/CT scans performed during clinical islet transplantation with FDG labeled islets show that almost 40% of the islets transplanted were lost within the first few minutes. Based on these studies we hypothesize that the relatively low efficiency of clinical Islet transplantation and the need for Islets from multiple donors in order to obtain normoglycemia is likely to be related to the intravascular transplantation procedure and Initiation of IBMIR, leading to i) initial loss of a large number of islets, and ii) impaired islet engraftment and long-term survival with entrapment by size restriction of islets in the vessel lumen. Consequently only a small fraction of the transplanted islets become functionally incorporated into the liver parenchyma. LMW-DS has in relevant in vitro and in vivo models been shown to: 1) prevent the innate injurious reaction (IBMIR)-induced by the transplanted islets in contact with blood, and 2) markedly stimulate and potentiate the positive biological effects of HGF on islet engraftment and survival after intraportal islet transplantation. An open single centre phase I dose-finding study of LMW-DS was conducted on 34 healthy volunteers. LMW-DS could safely be infused for a period of up to 5 to 6 hours without clinically significant side effects. No signs of increased risks of bleeding were found when infusing LMW-DS at doses that maintain APTT at 150 s for 6h and the pharmacokinetic data were favorable from a safety aspect. Importantly, the phase I trial confirmed in humans that LMW-DS is an extremely potent agent for inducing sustained and high levels of circulating HGF In blood with anticipated beneficial effects on islet survival and engraftment. CIT-01Is designed to test the hypothesis that LMW-DS markedly enhance the efficacy of clinical islet transplantation by reducing the number of islets lost during the first few hours after transplantation and by supporting their engraftment via !he release and potentiation of HGF. The study entails 72 subjects (IA and IAK) randomized to receive either LMW-DS or heparin at the time of islets transplantation. The Nordic Network for clinical islet transplantation provides experienced personnel and expertise in all areas relevant to efficiently conduct CIT-01 In a timely and cost efficient manner, e.g., during the last 12 months 40 islet preparations was released for clinical transplantation.

Public Health Relevance

(provided by applicant): The focus of CIT-01 is to minimize islet loss in the immediate post-transplantation period and to augment islet engraftment. If so, a substantially larger mass would engraft and subsequent specific immune responses would be reduced making it possible to regularly cure patients with T1D with islets from only one donor. If successfully completed the proposed CIT-01 study would allow a widespread application of clinical islet transplantation and make the procedure attractive therapeutic option for people with T1D at an earlier stage before late complications have started to appear.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI065192-08
Application #
8326500
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O1))
Program Officer
Bridges, Nancy D
Project Start
2004-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$1
Indirect Cost
$60,049
Name
Uppsala University
Department
Type
DUNS #
350582201
City
Uppsala
State
Country
Sweden
Zip Code
SE-75-1 05
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Eriksson, Olof; Selvaraju, Ramkumar; Eich, Torsten et al. (2016) Positron Emission Tomography to Assess the Outcome of Intraportal Islet Transplantation. Diabetes 65:2482-9
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