Differences in baseline lymphocyte counts and autoreactivity are associated with differences in outcome of islet cell transplantation in type 1 diabetic patients

Robert Hilbrands, Volkert A L Huurman, Pieter Gillard, Jurjen H L Velthuis, Marc De Waele, Chantal Mathieu, Leonard Kaufman, Miriam Pipeleers-Marichal, Zhidong Ling, Babak Movahedi, Daniel Jacobs-Tulleneers-Thevissen, Diethard Monbaliu, Dirk Ysebaert, Frans K Gorus, Bart O Roep, Daniel G Pipeleers, Bart Keymeulen, Robert Hilbrands, Volkert A L Huurman, Pieter Gillard, Jurjen H L Velthuis, Marc De Waele, Chantal Mathieu, Leonard Kaufman, Miriam Pipeleers-Marichal, Zhidong Ling, Babak Movahedi, Daniel Jacobs-Tulleneers-Thevissen, Diethard Monbaliu, Dirk Ysebaert, Frans K Gorus, Bart O Roep, Daniel G Pipeleers, Bart Keymeulen

Abstract

Objective: The metabolic outcome of islet cell transplants in type 1 diabetic patients is variable. This retrospective analysis examines whether differences in recipient characteristics at the time of transplantation are correlated with inadequate graft function.

Research design and methods: Thirty nonuremic C-peptide-negative type 1 diabetic patients had received an intraportal islet cell graft of comparable size under an ATG-tacrolimus-mycophenolate mofetil regimen. Baseline patient characteristics were compared with outcome parameters during the first 6 posttransplant months (i.e., plasma C-peptide, glycemic variability, and gain of insulin independence). Correlations in univariate analysis were further examined in a multivariate model.

Results: Patients that did not become insulin independent exhibited significantly higher counts of B-cells as well as a T-cell autoreactivity against insulinoma-associated protein 2 (IA2) and/or GAD. In one of them, a liver biopsy during posttransplant year 2 showed B-cell accumulations near insulin-positive beta-cell aggregates. Higher baseline total lymphocytes and T-cell autoreactivity were also correlated with lower plasma C-peptide levels and higher glycemic variability.

Conclusions: Higher total and B-cell counts and presence of T-cell autoreactivity at baseline are independently associated with lower graft function in type 1 diabetic patients receiving intraportal islet cells under ATG-tacrolimus-mycophenolate mofetil therapy. Prospective studies are needed to assess whether control of these characteristics can help increase the function of islet cell grafts during the first year posttransplantation.

Figures

FIG. 1.
FIG. 1.
T- and B-cell count at baseline and during 6 months after transplantation (A) in islet graft recipients gaining insulin independence (solid line) and remaining insulin independent (dotted line). Data represent means ± SE; *P < 0.05. B: Gain of insulin independence according to baseline in vitro T-cell reactivity against islet autoantigens. The lower panel shows gain of insulin independence in three different groups according to both T-cell autoreactivity and baseline B-cell count.
FIG. 2.
FIG. 2.
The effect of baseline total lymphocyte count (A), in vitro T-cell reactivity against islet autoantigens or both (B) on glycemic stability and C-peptide release.
FIG. 3.
FIG. 3.
Two islets were identified in the portal tract. Semiconsecutive sections of islet two show inflammatory cells located around the graft, which are dominated by CD20+ B-cells. (A high-quality digital representation of this figure is available in the online issue.)

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