Positron Emission Tomography to Assess the Outcome of Intraportal Islet Transplantation

Olof Eriksson, Ramkumar Selvaraju, Torsten Eich, Mariam Willny, Torkel B Brismar, Lina Carlbom, Håkan Ahlström, Gunnar Tufvesson, Torbjörn Lundgren, Olle Korsgren, Olof Eriksson, Ramkumar Selvaraju, Torsten Eich, Mariam Willny, Torkel B Brismar, Lina Carlbom, Håkan Ahlström, Gunnar Tufvesson, Torbjörn Lundgren, Olle Korsgren

Abstract

No imaging methodology currently exists to monitor viable islet mass after clinical intraportal islet transplantation. We investigated the potential of the endocrine positron emission tomography (PET) marker [(11)C]5-hydroxytryptophan ([(11)C]5-HTP) for this purpose. In a preclinical proof-of-concept study, the ex vivo and in vivo [(11)C]5-HTP signal was compared with the number of islets transplanted in rats. In a clinical study, human subjects with an intraportal islet graft (n = 8) underwent two [(11)C]5-HTP PET and MRI examinations 8 months apart. The tracer concentration in the liver as a whole, or in defined hotspots, was correlated to measurements of islet graft function. In rat, hepatic uptake of [(11)C]5-HTP correlated with the number of transplanted islets. In human subjects, uptake in hepatic hotspots showed a correlation with metabolic assessments of islet function. Change in hotspot standardized uptake value (SUV) predicted loss of graft function in one subject, whereas hotspot SUV was unchanged in subjects with stable graft function. The endocrine marker [(11)C]5-HTP thus shows a correlation between hepatic uptake and transplanted islet function and promise as a tool for noninvasive detection of viable islets. The evaluation procedure described can be used as a benchmark for novel agents targeting intraportally transplanted islets.

Trial registration: ClinicalTrials.gov NCT02689479.

© 2016 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Preclinical evaluation of [11C]5-HTP in a rat model of intraportal islet allotransplantation. A progressive increase in hepatic SUV was observed in rats transplanted with 300, 600, and 1,200 islets (A) when measured ex vivo 30 min (B) or 60 min (C) after tracer administration. PET imaging in representative subjects demonstrates low hepatic background in a nontransplanted subject (D). In an animal transplanted with 1,200 islets, there was an increased hepatic retention (E). adm, administration; IEQ, islet equivalent.
Figure 2
Figure 2
Comparison of hepatic uptake of [11C]5-HTP between nontransplanted subjects with T1D (A) and subjects with IPX with good function (B) and low function (C). The renal [11C]5-HTP uptake is absent in B due to renal failure (subject IPX2 was transplanted with islets after receiving a kidney transplant). The renal uptake, although high in comparison, does not affect the liver measurement due to spillover effects. The average hepatic background uptake was SUV = 1.68 in nontransplanted subjects, which was lower than the average SUV = 2.14 in subjects with a hepatic islet graft (D). K, kidney; L, liver; P, pancreas.
Figure 3
Figure 3
Mean SUV in whole liver and in hepatic hotspots as measured by [11C]5-HTP PET and their correlation to the metabolic function of intraportally transplanted islets. PET output was measured either as whole-liver mean SUV (A) or as mean SUV in hotspots 2 × SD above the expected hepatic background in subjects with T1D (B). Whole-liver mean SUV correlated weakly with graft function as assessed by AUC C-peptide and C-peptide response after first B-glucose >8 mmol/L (C and E). Using tracer uptake concentration in hotspots to remove noise caused by background uptake (mean SUV in all hotspots in aggregate in each subject) improved correlation with graft function (D and F). gluc, glucose.
Figure 4
Figure 4
A: Change in graft function as assessed by immediate C-peptide response after first B-glucose >8 mmol/L after administration of an MMTT. Graft function was largely unchanged in five subjects with IPX. Two subjects (IPX2 and IPX3) unexpectedly exhibited a marked decrease in graft function at the second examination. B: The PET output, measured as hotspot SUV, was unchanged in the five subjects with stable graft function (average coefficient of variation 7.8%) (circled). The change in hotspot SUV was also markedly decreased in subject IPX2, who had the largest loss in graft function. However, the loss in graft function for subject IPX3 was not reflected in the PET output.

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