Islet allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720.
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 posttransplant, 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.
Wijkstrom
Martin
M
Diabetes Institute for Immunology and Transplantation, Department of Surgery, University of Minnesota, Minneapolis, 55455, USA.
Kenyon
Norma S
NS
Kirchhof
Nicole
N
Kenyon
Norman M
NM
Mullon
Claudy
C
Lake
Philip
P
Cottens
Sylvain
S
Ricordi
Camillo
C
Hering
Bernhard J
BJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000077552:Basiliximab; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000601:surgery*; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008252:Macaca fascicularis; D011409:Propylene Glycols / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D020123:Sirolimus