Islet transplantation: outcome
Human islet graft function in NOD-SCID mice predicts clinical response in islet transplant recipients

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Abstract

The purpose of this study was to evaluate the utility of nondiabetic immune-deficient NOD-SCID mouse model in assessing the functional capacity of isolated human islets. We transplanted 2000 islet equivalents obtained from six preparations used for human islet transplantation in three patients under the kidney capsule of groups of 10 mice. Human (Hu) C-peptide and insulin levels were determined following intraperitoneal (IP) glucose challenge at days 0, 7, 14, 21, 30, 60, 90, and 120. The Hu C-peptide level >1.5 ng/mL was the threshold for islet function in this model. The first patient did not achieve insulin independence and had minimal (0.5 ng/mL) fasting C-peptide levels that mirrored the low C-peptide levels observed in the mice. After the first infusion, the insulin requirements were reduced by 50% in the second patient. She became insulin free 10 days after her second infusion with a C-peptide level of 3.0 ng/mL, which corresponded to the peak C-peptide level (3.9 ng/mL) observed in the mice. By 150 days' posttransplant, the decline in C-peptide level paralleled the decline observed in mice. Within 2 weeks after the first transplant, insulin dose was reduced by 75% in the third patient, which corresponded to the robust C-peptide production in mice (7.3 ng/mL). Both patient and mice had a delay in islet function following the second infusion. She remained with a C-peptide level of 1.8 ng/mL and insulin free until suffering a rejection episode 3 months later. We observed that human islet graft function in NOD-SCID mice correlated with clinical response in islet transplant recipients.

Section snippets

Methods

Pancreata were obtained from heart-beating, cadaveric, multiorgan donors. Isolations were performed using our modification of the Ricordi technique, which was previously published.6 To test the islet function and the viability in three human islet transplants performed using the Edmonton protocol,7 we transplanted an aliquot of 2000 IEQ from each islet preparation under each kidney capsule of groups of 10 NOD-SCID mice. Following an overnight fast, NOD-SCID mice were injected intraperitoneally

Results

The IEQ of each human islet transplantation is listed in Table 1. Both C-peptide and insulin production patterns in the mice as shown in Fig 1 correlated with the clinical course of the patients.

Conclusion

The in vivo mouse assay is a good surrogate marker for islet potency and function in humans. Thus, the assay can be used to screen preparations for their suitability for transplantation after being cultured.

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This work is supported in part by USPHS/NIH Grant DK57700, USPHS/NCRR Grant RR16602, Assisi Foundation, and Juvenile Diabetes Research Foundation Grant 1-2000-416 to Dr A.O. Gaber.

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