EFFECT OF DONOR TREATMENT WITH HEPARINOIDS ON GRAFT FUNCTION AFTER INTRAPORTAL TRANSPLANTATION OF A MARGINAL ISLET MASS

A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin ( N = 8) or placebo ( N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years ( P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group ( n = 7) than in the placebo ( n = 3) group ( P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT ( P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959, clinicaltrials.gov

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DEVELOPMENT OF A NEW STRATEGY FOR MINIMIZING ISLET CELL MASS IN TYPE 1 DIABETIC RECIPIENTS: DIANNEXIN REDUCES PROAPOPTOTIC BID, PROMOTES ANTI-INFLAMMATORY INTERLEUKIN-10 AND IMPROVES EARLY GRAFT FUNCTION IN THE MARGINAL ISLET MASS TRANSPLANTATION MODEL

Transplantation Journal ◽

10.1097/00007890-201007272-00684 ◽

2010 ◽

Vol 90 ◽

pp. 370

Author(s):

E. Cheng ◽

H. Yang ◽

V. Sharma ◽

M. Lagman ◽

D. Leeser ◽

...

Keyword(s):

Islet Cell ◽

Cell Mass ◽

Graft Function ◽

Interleukin 10 ◽

Islet Mass ◽

New Strategy ◽

Early Graft ◽

Anti Inflammatory ◽

Transplantation Model

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Human Hemangioblast-Derived Mesenchymal Stem Cells Promote Islet Engraftment in a Minimal Islet Mass Transplantation Model in Mice

Frontiers in Medicine ◽

10.3389/fmed.2021.660877 ◽

2021 ◽

Vol 8 ◽

Author(s):

Suzanne Bertera ◽

Michael F. Knoll ◽

Carmela Knoll ◽

Hidetaka Hara ◽

Erin A. Kimbrel ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Glycemic Control ◽

Islet Transplantation ◽

Graft Function ◽

Embryonic Stem ◽

Islet Graft ◽

Islet Cell Transplantation ◽

Mass Model ◽

Islet Mass

Islet transplantation can restore glycemic control in patients with type 1 diabetes. Using this procedure, the early stages of engraftment are often crucial to long-term islet function, and outcomes are not always successful. Numerous studies have shown that mesenchymal stem cells (MSCs) facilitate islet graft function. However, experimental data can be inconsistent due to variables associated with MSC generation (including donor characteristics and tissue source), thus, demonstrating the need for a well-characterized and uniform cell product before translation to the clinic. Unlike bone marrow- or adipose tissue-derived MSCs, human embryonic stem cell-derived-MSCs (hESC-MSCs) offer an unlimited source of stable and highly-characterized cells that are easily scalable. Here, we studied the effects of human hemangioblast-derived mesenchymal cells (HMCs), (i.e., MSCs differentiated from hESCs using a hemangioblast intermediate), on islet cell transplantation using a minimal islet mass model. The co-transplantation of the HMCs allowed a mass of islets that was insufficient to correct diabetes on its own to restore glycemic control in all recipients. Our in vitro studies help to elucidate the mechanisms including reduction of cytokine stress by which the HMCs support islet graft protection in vivo. Derivation, stability, and scalability of the HMC source may offer unique advantages for clinical applications, including fewer islets needed for successful islet transplantation.

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Omental Pouch Technique for Combined Site Islet Autotransplantation Following Total Pancreatectomy

Cell Transplantation ◽

10.1177/0963689718798627 ◽

2018 ◽

Vol 27 (10) ◽

pp. 1561-1568 ◽

Cited By ~ 8

Author(s):

Mark J. Stice ◽

Ty B. Dunn ◽

Melena D. Bellin ◽

Mariya E. Skube ◽

Greg J. Beilman

Keyword(s):

Total Pancreatectomy ◽

Graft Function ◽

Mixed Meal ◽

Islet Mass ◽

Novel Technique ◽

Insulin Requirements ◽

Islet Autotransplantation ◽

Intraportal Infusion ◽

Tolerance Testing

Total pancreatectomy and islet autotransplantation (TPIAT) is an effective treatment for selected patients with chronic pancreatitis. The portal circulation is the standard infusion site for islet transplant, but marked elevation of portal pressures may prevent complete islet infusion. Herein we report a novel technique of combined site islet autotransplantation using an omental pouch. This technique may be useful when technical limitations prevent complete intraportal transplantation. In four TPIAT recipients with intraoperative issues precluding the complete intraportal infusion of islets, an omental pouch was created to contain the remaining islet mass. Patients were monitored for complications, and islet graft function was assessed using mixed meal tolerance testing and compared with matched controls who received only intraportally transplanted islets. All patients had decreasing insulin requirements as their recovery progressed. At 3 months follow-up there were no significant differences in glycemic control or graft function for the combined site recipients compared with their matched controls who only received an intraportal islet infusion. The omentum has potentially desirable qualities such as accessibility, capacity, and systemic/portal vascularity comparable to the native pancreas. The omental pouch technique may represent a safe and effective alternate site for islet autotransplantation. Further study is needed to confirm these findings.

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