INTRODUCTION: A large proportion of clinical islet transplant recipients fail to initially achieve or sustain meaningful independence from exogenous insulin use. We hypothesized that immediate allograft injury is a key constraint on independence from exogenous insulin use. METHODS: Standard human leukocyte antigen genotyping was reviewed to identify nonshared polymorphisms between 21 prospectively recruited islet transplant recipients from a single institution and their respective donors. Human leukocyte antigen polymorphism-specific quantitative polymerase chain reaction was used to quantify donor DNA shed into blood by injured islets from serial sera acquired over the first 10 days postprocedure and examined for correlation with achievement of insulin independence. RESULTS: Nearly fourfold higher serum concentrations of donor DNA were detected in subjects whose grafts failed to generate insulin independence. The median for the average area under the curve in recipients who did and did not achieve insulin independence was 12 (range, 1-61) and 45 (range, 14-255) donor genome equivalents (gEq)-day/mL (p=0.03), respectively. CONCLUSIONS: These findings represent the first direct testing of allograft injury in humans undergoing islet cell transplantation. Injury to donor islets very soon after transplantation may represent an important barrier to achieving insulin independence other than adaptive immune responses targeting allografts at later times. In addition, soluble donor DNA merits further development as a quantifiable biomarker to evaluate new interventions aimed at mitigating immediate islet injury.
INTRODUCTION: A large proportion of clinical islet transplant recipients fail to initially achieve or sustain meaningful independence from exogenous insulin use. We hypothesized that immediate allograft injury is a key constraint on independence from exogenous insulin use. METHODS: Standard human leukocyte antigen genotyping was reviewed to identify nonshared polymorphisms between 21 prospectively recruited islet transplant recipients from a single institution and their respective donors. Human leukocyte antigen polymorphism-specific quantitative polymerase chain reaction was used to quantify donor DNA shed into blood by injured islets from serial sera acquired over the first 10 days postprocedure and examined for correlation with achievement of insulin independence. RESULTS: Nearly fourfold higher serum concentrations of donor DNA were detected in subjects whose grafts failed to generate insulin independence. The median for the average area under the curve in recipients who did and did not achieve insulin independence was 12 (range, 1-61) and 45 (range, 14-255) donor genome equivalents (gEq)-day/mL (p=0.03), respectively. CONCLUSIONS: These findings represent the first direct testing of allograft injury in humans undergoing islet cell transplantation. Injury to donor islets very soon after transplantation may represent an important barrier to achieving insulin independence other than adaptive immune responses targeting allografts at later times. In addition, soluble donor DNA merits further development as a quantifiable biomarker to evaluate new interventions aimed at mitigating immediate islet injury.
Authors: Jun Zou; Brian Duffy; Michael Slade; Andrew Lee Young; Nancy Steward; Ramsey Hachem; T Mohanakumar Journal: Hum Immunol Date: 2017-03-04 Impact factor: 2.850
Authors: V J Auer; E Janas; V Ninichuk; E Eppler; T S Weiss; S Kirchner; A M Otto; M J Stangl Journal: Clin Exp Immunol Date: 2012-11 Impact factor: 4.330