Islet allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720

Martin Wijkstrom, Norma S Kenyon, Nicole Kirchhof, Norman M. Kenyon, Claudy Mullon, Philip Lake, Sylvain Cottens, Camillo Ricordi, Bernhard J. Hering

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Objective. In a preclinical, nonhuman primate islet allotransplant model, the authors evaluated a novel immunosuppressive combination of basiliximab for induction and of RAD and FTY720 for maintenance. Methods. Five ABO-compatible and mixed lymphocyte reactivity-mismatched streptozotocin-induced diabetic juvenile cynomolgus monkeys underwent transplantation intraportally with 48-hr cultured 10,000 islet equivalents per kilogram. Induction immunosuppression was with intravenous basiliximab (10 mg on postoperative days 0 and 4). Maintenance immunosuppression was with RAD (everolimus) (0.075 mg/kg per day administered subcutaneously) and FTY720 (0.3 mg/kg per day administered orally), both administered on day -2 through day 180 posttransplant. Results. All five recipients tolerated their transplants and immunosuppressive therapy well, without adverse events or infectious complications. Insulin requirements pretransplant were 2.6 to 4.0 U/kg per day. All recipients became normoglycemic and insulin-independent posttransplant. Posttransplant serum C-peptide levels averaged 2.7 ng/mL (range, 0.6-6.2 ng/mL). Morning blood glucose levels ranged from less than 100 mg/dL to 150 mg/dL. Posttransplant acute C-peptide response to intravenous arginine averaged 1.3 ng/mL (range, 0.23-2.72 ng/mL). In one recipient with subtherapeutic RAD blood levels on day 7 post-transplant, exogenous insulin was resumed 100 days posttransplant; basal C-peptide levels remained positive in this recipient and averaged 2.6 ng/mL. The other four recipients remained insulin-independent for more than 6 months. Conclusions. This study provides preliminary evidence of the safety and efficacy of corticosteroid- and calcineurin inhibitor-free immunosuppression in a relevant preclinical transplant model. These findings provide a strong rationale for evaluating this nondiabetogenic regimen in a clinical trial of islet transplants in type 1 diabetic recipients.

Original languageEnglish
Pages (from-to)827-835
Number of pages9
JournalTransplantation
Volume77
Issue number6
DOIs
StatePublished - Mar 27 2004

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Primates
Allografts
C-Peptide
Immunosuppression
Insulin
Transplants
Immunosuppressive Agents
Maintenance
Macaca fascicularis
Streptozocin
Arginine
Blood Glucose
Adrenal Cortex Hormones
Transplantation
Clinical Trials
Lymphocytes
Safety
Fingolimod Hydrochloride
basiliximab
Serum

ASJC Scopus subject areas

  • Transplantation
  • Immunology

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Islet allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720. / Wijkstrom, Martin; Kenyon, Norma S; Kirchhof, Nicole; Kenyon, Norman M.; Mullon, Claudy; Lake, Philip; Cottens, Sylvain; Ricordi, Camillo; Hering, Bernhard J.

In: Transplantation, Vol. 77, No. 6, 27.03.2004, p. 827-835.

Research output: Contribution to journalArticle

Wijkstrom, M, Kenyon, NS, Kirchhof, N, Kenyon, NM, Mullon, C, Lake, P, Cottens, S, Ricordi, C & Hering, BJ 2004, 'Islet allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720', Transplantation, vol. 77, no. 6, pp. 827-835. https://doi.org/10.1097/01.TP.0000116390.76425.20
Wijkstrom, Martin ; Kenyon, Norma S ; Kirchhof, Nicole ; Kenyon, Norman M. ; Mullon, Claudy ; Lake, Philip ; Cottens, Sylvain ; Ricordi, Camillo ; Hering, Bernhard J. / Islet allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720. In: Transplantation. 2004 ; Vol. 77, No. 6. pp. 827-835.
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abstract = "Objective. In a preclinical, nonhuman primate islet allotransplant model, the authors evaluated a novel immunosuppressive combination of basiliximab for induction and of RAD and FTY720 for maintenance. Methods. Five ABO-compatible and mixed lymphocyte reactivity-mismatched streptozotocin-induced diabetic juvenile cynomolgus monkeys underwent transplantation intraportally with 48-hr cultured 10,000 islet equivalents per kilogram. Induction immunosuppression was with intravenous basiliximab (10 mg on postoperative days 0 and 4). Maintenance immunosuppression was with RAD (everolimus) (0.075 mg/kg per day administered subcutaneously) and FTY720 (0.3 mg/kg per day administered orally), both administered on day -2 through day 180 posttransplant. Results. All five recipients tolerated their transplants and immunosuppressive therapy well, without adverse events or infectious complications. Insulin requirements pretransplant were 2.6 to 4.0 U/kg per day. All recipients became normoglycemic and insulin-independent posttransplant. Posttransplant serum C-peptide levels averaged 2.7 ng/mL (range, 0.6-6.2 ng/mL). Morning blood glucose levels ranged from less than 100 mg/dL to 150 mg/dL. Posttransplant acute C-peptide response to intravenous arginine averaged 1.3 ng/mL (range, 0.23-2.72 ng/mL). In one recipient with subtherapeutic RAD blood levels on day 7 post-transplant, exogenous insulin was resumed 100 days posttransplant; basal C-peptide levels remained positive in this recipient and averaged 2.6 ng/mL. The other four recipients remained insulin-independent for more than 6 months. Conclusions. This study provides preliminary evidence of the safety and efficacy of corticosteroid- and calcineurin inhibitor-free immunosuppression in a relevant preclinical transplant model. These findings provide a strong rationale for evaluating this nondiabetogenic regimen in a clinical trial of islet transplants in type 1 diabetic recipients.",
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AU - Wijkstrom, Martin

AU - Kenyon, Norma S

AU - Kirchhof, Nicole

AU - Kenyon, Norman M.

AU - Mullon, Claudy

AU - Lake, Philip

AU - Cottens, Sylvain

AU - Ricordi, Camillo

AU - Hering, Bernhard J.

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N2 - Objective. In a preclinical, nonhuman primate islet allotransplant model, the authors evaluated a novel immunosuppressive combination of basiliximab for induction and of RAD and FTY720 for maintenance. Methods. Five ABO-compatible and mixed lymphocyte reactivity-mismatched streptozotocin-induced diabetic juvenile cynomolgus monkeys underwent transplantation intraportally with 48-hr cultured 10,000 islet equivalents per kilogram. Induction immunosuppression was with intravenous basiliximab (10 mg on postoperative days 0 and 4). Maintenance immunosuppression was with RAD (everolimus) (0.075 mg/kg per day administered subcutaneously) and FTY720 (0.3 mg/kg per day administered orally), both administered on day -2 through day 180 posttransplant. Results. All five recipients tolerated their transplants and immunosuppressive therapy well, without adverse events or infectious complications. Insulin requirements pretransplant were 2.6 to 4.0 U/kg per day. All recipients became normoglycemic and insulin-independent posttransplant. Posttransplant serum C-peptide levels averaged 2.7 ng/mL (range, 0.6-6.2 ng/mL). Morning blood glucose levels ranged from less than 100 mg/dL to 150 mg/dL. Posttransplant acute C-peptide response to intravenous arginine averaged 1.3 ng/mL (range, 0.23-2.72 ng/mL). In one recipient with subtherapeutic RAD blood levels on day 7 post-transplant, exogenous insulin was resumed 100 days posttransplant; basal C-peptide levels remained positive in this recipient and averaged 2.6 ng/mL. The other four recipients remained insulin-independent for more than 6 months. Conclusions. This study provides preliminary evidence of the safety and efficacy of corticosteroid- and calcineurin inhibitor-free immunosuppression in a relevant preclinical transplant model. These findings provide a strong rationale for evaluating this nondiabetogenic regimen in a clinical trial of islet transplants in type 1 diabetic recipients.

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