Stable alpha- and beta-islet cell function after tolerance induction to pancreatic islet allografts in diabetic primates.
Pancreatic islet transplantation (PIT) is an attractive alternative for type 1 diabetic patients. PIT is not yet an effective clinical reality due in part to early loss of functional islet mass. In addition, current immunosuppressive drugs have toxic effects on islets and increase the risk of morbidity and mortality. Precise and durable alpha- and beta-cell function is essential for the success of PIT. Therefore, it is important to establish whether PIT can produce adequate long-term metabolic control, especially in the absence of chronic immunosuppressive therapy (CIT). In the present study, the stability of functional alpha- and beta-cell mass and metabolic function was assessed in streptozotocin (STZ)-induced diabetic primates following PIT in the absence of CIT. Diabetes was induced in rhesus macaques with STZ, 140 mg/kg. Hyperglycemia was reversed rapidly by PIT coupled with a 14-day tolerance induction protocol based on F(Ab)2-IT and DSG (n = 7). Two diabetic animals received the tolerance induction protocol without PIT. Acute rejection was presented in three animals at 70, 353 and 353 days post transplant in the tolerance induction protocol, whereas the controls [F(Ab)2-IT or DSG alone] showed early 10-day function but all lost islet function by days 15-70. One recipient [F(Ab)2-IT or DSG] died euglycemic after a surgical procedure on day 187. At 2 years, three animals studied had a normal FIM evaluated by oral glucose tolerance test, mixed meal test, acute insulin response to glucose, glucose disposal rate, and hyperinsulinemic hypoglycemic clamp. PIT in STZ-induced diabetic primates resulted in restoration of normal alpha- and beta-cell function. Operational tolerance induction was achieved with only peritransplant administration of F(Ab)2-IT and DSG sparing the animals from chronic exposure of diabetogenic immunosuppressive drugs. These results offer an exciting new potential for treatment of type 1 diabetes mellitus.
Contreras
Juan L
JL
The Transplant Center, Department of Surgery, and Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Jenkins
Stacie
S
Eckhoff
Devin E
DE
Hubbard
William J
WJ
Lobashevsky
Andrew
A
Bilbao
Guadalupe
G
Thomas
Francis T
FT
Neville
David M
DM
Thomas
Judith M
JM
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology* / Q000601:surgery*; D005951:Glucose Tolerance Test; D006084:Graft Rejection / Q000097:blood; D006146:Guanidines / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D008253:Macaca mulatta; D008297:Male; D012016:Reference Values; D023001:Transplantation Tolerance / Q000502:physiology*; D016896:Treatment Outcome
D015415:Biomarkers; D001786:Blood Glucose; D006146:Guanidines; D007166:Immunosuppressive Agents; C037258:gusperimus