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

This is an open-label, one-year follow-up study of type 1 diabetic islet allograft recipients who receive FcR non-binding OKT3 antibody hOKT3γ1 (Ala-Ala) plus sirolimus induction immunotherapy combined with sirolimus and delayed tacrolimus maintenance immunosuppression. Six subjects were transplanted.

The premise behind the proposal is that hOKT3γ1(Ala-Ala) corrects the imbalance between autoreactive and regulatory T cells and consequently prevents autoimmune destruction of transplanted islets. To prevent allorejection, hOKT3γ1(Ala-Ala)was combined with sirolimus and delayed tacrolimus. Additionally, the safety and efficacy of the maintenance immunosuppressive regimen of sirolimus combined with tacrolimus was monitored.

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