title: Reversal of naturally occuring diabetes in primates by unmodified islet xenografts without chronic immunosuppression.
abstract: BACKGROUND
  Isolated pancreatic islet transplantation (IPITx) is an attractive alternative for treatment of insulin-dependent diabetes mellitus (IDDM). However, IPITx has been difficult to implement clinically because islets frequently fail to function, have a high incidence of rejection, and are susceptible to autoimmune recurrence and damage by chronic immunosuppressive therapy. Tolerance induction may be a rational approach to resolve several of these limitations. Because anti-CD3 immunotoxin (IT) has been successful in promoting stable primate kidney transplant tolerance in our experience, we considered that tolerance induction with IT might be duplicated in IPITx.
  
  
  METHODS
  Three monkeys with spontaneous IDDM (two Macaca fascicularis and one Ceropithecus aethiops) were treated with xenogeneic pancreatic islets (Macaca mulatta). Intrahepatic islet transplantation was performed at a mean of 13136+/-3860 islet equivalents/kg. Islet xenograft acceptance was accomplished by tolerance induction with two injections of IT given on day 0 at 2 hr before transplantation and on day +1, respectively. IT treatment was supplemented with cyclosporine and steroids administered on days 0 through 4. No additional immunosuppression was given thereafter. Two additional control macaques with spontaneous IDDM received the immunosuppressive protocol without islet infusion.
  
  
  RESULTS
  All recipients were restored to stable euglycemia, off exogenous insulin, within 1-2 weeks after transplantation. Glucose tolerance, C-peptide, and glycosylated hemoglobin tests confirmed the restoration of normal glucose homeostasis after islet transplantation. All three islet recipients have remained euglycemic at 410, 255, and 100 days of follow-up despite recovery of peripheral T cells to normal levels. In contrast, none of the controls presented changes in the diabetic status 4 and 8 months after treatment.
  
  
  CONCLUSIONS
  These results represent the first demonstration in nonhuman primates of stable, long-term acceptance of nonencapsulated xenogeneic islets off all immunosuppression, suggesting operational tolerance. The findings have potential implications for islet transplantation as well as improved and more cost-effective therapy for IDDM.
authors: Department of Surgery, University of Alabama at Birmingham, 35294, USA.
authors: F T
authors: FT
authors: Thomas
authors: C
authors: C
authors: Ricordi
authors: J L
authors: JL
authors: Contreras
authors: W J
authors: WJ
authors: Hubbard
authors: X L
authors: XL
authors: Jiang
authors: D E
authors: DE
authors: Eckhoff
authors: S
authors: S
authors: Cartner
authors: G
authors: G
authors: Bilbao
authors: D M
authors: DM
authors: Neville
authors: J M
authors: JM
authors: Thomas
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D016381:Islets of Langerhans Transplantation; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D014183:Transplantation, Heterologous
chemical_list: D007328:Insulin