hOKT3γ1 (Ala-Ala) Combined With Sirolimus and Delayed Tacrolimus in Type 1 Diabetic Islet Allograft Recipients

Inclusion Criteria: Primary islet allotransplant Type 1 diabetes mellitus, complicated by at least one of the following situations that persist despite intensive efforts in close cooperation with their diabetes care team: Metabolic lability/instability; Reduced awareness of hypoglycemia; Persistently poor glucose control (as defined by HgbA1c>10% at the end of six months of intensive management efforts with the diabetes care team); Progressive secondary complications. Age 18 and older Able to give written informed consent Exclusion Criteria: Age less than 18 years Body weight greater than75 kg. BMI greater than 26 kg/m2 for male and females Waist-to-hip ratio 0.80 (female) and 0.95 (male) First degree relative with type 2 diabetes Insulin requirement of greater than 0.7 IU/kg/day HbA1C greater than 12% Positive C-peptide response to intravenous arginine stimulation Untreated proliferative retinopathy Macroalbuminuria (urinary albumin excretion greater than 300 mg/24hrs) Creatinine clearance greater than 85 ml/min/1.73 m2 in females, greater than 95 ml/min/1.73 m2 in males Serum creatinine greater than 1.2 mg/dl Previous pancreas or islet transplant Previous OKT3 antibody therapy Presence of history of panel-reactive anti-HLA antibodies greater than 10% Abnormal T4 and TSH despite thyroid replacement therapy Positive pregnancy test, or presently breast-feeding Active infection Negative screen for Epstein-Barr Virus (EBV) by an EBNA method Invasive aspergillus infection within year prior to study entry Any history of malignancy Active alcohol or substance abuse History of non-adherence to prescribed regimens Psychiatric disorder making the subject not a suitable candidate for transplantation Karnofsky performance score greater than 70 Baseline Hgb greater than 11.7 g/dl; lymphopenia (greater than 1,000/L), or leukopenia (greater than 4,000 total leukocytes/L), or an absolute CD4+ count <500/L Thrombocytopenia greater than 150 x 109/L Use of warfarin or other anticoagulant therapy (except aspirin) or patient with PT-INR greater than 1.5 Severe co-existing cardiac disease Baseline liver function tests outside of normal range Presence of gallstones on baseline ultrasound exam Active peptic ulcer disease Severe unremitting diarrhea or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications Celiac disease Hyperlipidemia (fasting LDL cholesterol greater than 130 mg/dl, treated or untreated; and/or fasting triglycerides greater than 200 mg/dl) Addison's disease. Under treatment for a medical condition requiring chronic use of systemic steroids Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial