Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus

Abstract

Macroencapsulation devices provide the dual possibility of immunoprotecting transplanted cells while also being retrievable, the latter bearing importance for safety in future trials with stem cell-derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets into patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155 000-180 000 islet equivalents (ie, 1800-4600 islet equivalents per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited (Clinicaltrials.gov: NCT02064309).

Keywords: cellular biology; clinical research/practice; diabetes: type 1; encapsulation; endocrinology/diabetology; islet transplantation; islets of Langerhans; translational research/science.

© 2018 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

Figures

Figure 1

Accumulation of CD68+ macrophages (A and B) and CD3+ T cells (C and D) varied between devices. CD20+ B cells and CD3+ CD8+ T cells accumulated around small blood vessels in the surrounding subcutaneous tissue (E and F). Only few CD31+ capillaries were found close to the surface of the device and in the area with inflammation; however, capillaries were frequently observed in the surrounding subcutaneous tissue (G and H). Original magnification × 100

Figure 2

Clinical follow‐up data posttransplantation. (A) Fasting plasma C‐peptide concentrations were increased after transplantation and measurable for up to 8 weeks posttransplantation. HbA1c levels (B) and insulin requirements (C) did not change posttransplantation. In A‐C, data are first provided for each individual patient from the day of transplantation up until explantation of the device (indicated by red arrow), and for an additional 6 months. In the graphs to the right in A‐C, means ± standard error of the mean (SEM) for all the 4 patients are provided; the follow‐up visits are labeled 4‐6 PE and 26 PE, meaning 4‐6 and 26 weeks postexplantation, respectively. (D) Data from continuous glucose monitoring (CGM) prior to transplantation, posttransplantation, and 6‐months postexplantation of the device. Data are presented as means ± SEM for all patients with individual values given. Data are expressed as the percentage of time spent in target range of glucose (3.9‐7.8 mmol/L), above target (>7.8 mmol/L), and below target (<3.9 mmol/L). No change in glucose variability was observed posttransplantation. (E) Data from the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were first plotted for each patient with both the positive (a) and negative responses (b) provided in the same graph. In the graph to the right, means ± SEM, separated for DTSQ a and b, for all the 4 patients are provided. *Denotes P < .05 when compared to prior to explantation of the device

Figure 3

Recovered device (A‐B) and device containing slabs (C‐D) were evaluated ex vivo with respect to insulin secretion upon glucose and arginine stimulation. Insulin release was measured in 4 patients for 45 minutes at each condition (A). The dynamic insulin secretion was observed up to 135 minutes after continuous stimulation of device with low (2.8 mmol/L), high (16.7 mmol/L), and finally high glucose supplemented arginine solution (B). Insulin release was measured in slabs, recovered from the device, when stimulated with low, respectively, high glucose (2.8 vs 16.7 mmol/L) with or without arginine for 45 min (C). One slab from each patient was monitored for dynamic insulin secretion when stimulated with different concentrations of glucose (2.8 vs 16.7 mmol/L) with or without arginine (D). Separate slabs were stained with dithizone (red), and islets could easily be detected (E, scale bar 500 μm) and (F, scale bar 200 μm). Islet‐containing slabs were also further processed for immunohistochemistry and stained for insulin (brown). Insulin‐positive cells could be found in slabs from all patients (G), but also areas with fragmented islets and cellular debris were observed (H, scale bar 100 μm). Sections stained with Congo red identified amyloid‐containing islets (I, scale bar 50 μm; amyloid [red] indicated by arrows), and insulin‐positive cells (brown) were verified in consecutive sections (J, scale bar 50 μm). The left islet in (I), where a single deposit occurs, has a markedly reduced number of nucleated cells. The islet to the right contains multiple inclusions occupying almost 20% of the islet area, and the amyloid is surrounded by nucleated cells. The result suggests that amyloid formation proceeded for a long time, which requires functioning beta cells. Sections were counterstained with hematoxylin