Long-term islet graft survival in streptozotocin- and autoimmune-induced diabetes models by immunosuppressive and potential insulinotropic agent FTY720.
BACKGROUND
Toxicity of current immunosuppressive agents to islet grafts is one of the major obstacles to clinical islet transplantation (Tx). This study was designed to assess the efficacy of FTY720, a novel immunomodulator with a unique mechanism of action, on islet graft survival and function in streptozotocin (STZ)- and autoimmune-induced diabetic recipients.


METHODS
Islet allograft from BALB/C mice or islet isografts were transplanted into STZ-induced diabetic CBA mice and autoimmune nonobese diabetic (NOD) mice. FTY720 was administered orally at 0.5 mg/kg per day in STZ diabetic recipients or 3 mg/kg per day in NOD recipients after Tx. Functional status of the islet graft was monitored by measuring blood glucose daily. Insulin secretion from mouse islets was measured with an insulin scintillation proximity assay.


RESULTS
Under the treatment of FTY720, long-term normoglycemia (>100 days) was achieved in 100% of STZ diabetic recipients and 50% of diabetic NOD recipients compared with a respective 11 and 7 days in untreated animals after allogeneic islet Tx. Normoglycemia persisted only temporarily (<4 weeks) in untreated NOD recipients of NOD islets, but was maintained for >100days with FTY720 treatment. Histologically, leukocyte infiltration observed in untreated animals was largely inhibited in FTY720-treated ones. Additionally, FTY720 stimulated insulin secretion from isolated islets by approximately twofold under both normoglycemic and hyperglycemic conditions.


CONCLUSIONS
FTY720 is highly effective in protecting allo- and autoimmune response-mediated islet graft destruction without direct toxicity to the islets. The effect is likely attributable to its action in preventing effector lymphocyte infiltration into the grafted tissue.
Fu
Fumin
F
Novartis Institute for Biomedical Research, Summit, New Jersey; Novartis Pharma AG, Basel, Switzerland.
Hu
Shiling
S
Deleo
Jeffrey
J
Li
Shu
S
Hopf
Christine
C
Hoover
Jennifer
J
Wang
Shuya
S
Brinkmann
Volker
V
Lake
Philip
P
Shi
Victor C
VC
D000818:Animals; D001327:Autoimmune Diseases / Q000601:surgery*; D001786:Blood Glucose / Q000032:analysis; D003920:Diabetes Mellitus / Q000378:metabolism / Q000601:surgery*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery*; D000068876:Fingolimod Hydrochloride; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives; D013997:Time Factors
D001786:Blood Glucose; D007166:Immunosuppressive Agents; D007328:Insulin; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine