hOKT3γ1 (Ala-Ala) Combined With Sirolimus and Delayed Tacrolimus in Type 1 Diabetic Islet Allograft Recipients
hOKT3γ1 (Ala-Ala) Combined With Sirolimus and Delayed Tacrolimus in Type 1 Diabetic Islet Allograft Recipients
The collective effects of two-layer pancreas preservation, pretransplant islet culture, day
 -2 pretransplant immunosuppression, and induction immunosuppression with the FcR-nonbinding
 anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala)to facilitate diabetes reversal after
 single-donor islet transplantation.
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:

 1. Primary islet allotransplant

 2. 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:

 1. Metabolic lability/instability;

 2. Reduced awareness of hypoglycemia;

 3. Persistently poor glucose control (as defined by HgbA1c>10% at the end of six
 months of intensive management efforts with the diabetes care team);

 4. Progressive secondary complications.

 3. Age 18 and older

 4. Able to give written informed consent

 Exclusion Criteria:

 1. Age less than 18 years

 2. Body weight greater than75 kg.

 3. BMI greater than 26 kg/m2 for male and females

 4. Waist-to-hip ratio 0.80 (female) and 0.95 (male)

 5. First degree relative with type 2 diabetes

 6. Insulin requirement of greater than 0.7 IU/kg/day

 7. HbA1C greater than 12%

 8. Positive C-peptide response to intravenous arginine stimulation

 9. Untreated proliferative retinopathy

 10. Macroalbuminuria (urinary albumin excretion greater than 300 mg/24hrs)

 11. Creatinine clearance greater than 85 ml/min/1.73 m2 in females, greater than 95
 ml/min/1.73 m2 in males

 12. Serum creatinine greater than 1.2 mg/dl

 13. Previous pancreas or islet transplant

 14. Previous OKT3 antibody therapy

 15. Presence of history of panel-reactive anti-HLA antibodies greater than 10%

 16. Abnormal T4 and TSH despite thyroid replacement therapy

 17. Positive pregnancy test, or presently breast-feeding

 18. Active infection

 19. Negative screen for Epstein-Barr Virus (EBV) by an EBNA method

 20. Invasive aspergillus infection within year prior to study entry

 21. Any history of malignancy

 22. Active alcohol or substance abuse

 23. History of non-adherence to prescribed regimens

 24. Psychiatric disorder making the subject not a suitable candidate for transplantation

 25. Karnofsky performance score greater than 70

 26. 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

 27. Thrombocytopenia greater than 150 x 109/L

 28. Use of warfarin or other anticoagulant therapy (except aspirin) or patient with PT-INR
 greater than 1.5

 29. Severe co-existing cardiac disease

 30. Baseline liver function tests outside of normal range

 31. Presence of gallstones on baseline ultrasound exam

 32. Active peptic ulcer disease

 33. Severe unremitting diarrhea or other gastrointestinal disorders potentially
 interfering with the ability to absorb oral medications

 34. Celiac disease

 35. Hyperlipidemia (fasting LDL cholesterol greater than 130 mg/dl, treated or untreated;
 and/or fasting triglycerides greater than 200 mg/dl)

 36. Addison's disease.

 37. Under treatment for a medical condition requiring chronic use of systemic steroids

 38. Any medical condition that, in the opinion of the investigator, will interfere with
 the safe completion of the trial