B-Lymphocyte Immunotherapy in Islet Transplantation

Inclusion Criteria: * Mentally stable and able to comply with study procedures * Clinical history compatible with type 1 diabetes with onset at less than 40 years of age, insulin dependence for at least 5 years at study entry, and a sum of age and insulin dependent diabetes duration of at least 28 * Absent stimulated C-peptide (less than 0.3 ng/ml) 60 and 90 minutes post-mixed-meal tolerance test * Involvement of intensive diabetes management, defined as: 1. Self-monitoring of glucose values no less than a mean of three times each day averaged over each week 2. Administration of three or more insulin injections each day or insulin pump therapy * Under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least three evaluations the 12 months prior to study enrollment * At least one episode of severe hypoglycemia in the past 12 months, defined as an event with one of the following symptoms: memory loss; confusion; uncontrollable behavior; irrational behavior; unusual difficulty in awakening; suspected seizure; seizure; loss of consciousness; or visual symptoms in which the participant was unable to treat him/herself and which was associated with either a blood glucose (BG) level \< 54 mg/dL \[3.0 mmol/L\] or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, in the past 12 months prior to study enrollment * Reduced awareness of hypoglycemia. More information about this criterion, including specific definition of hypoglycemia unawareness, is in the protocol. Exclusion Criteria: * Body mass index (BMI) greater than 30 kg/m2 or weight less than or equal to 50 kg * Insulin requirement of more than 1.0 IU/kg/day or less than 15 U/day * HbA1c greater than 10% * Untreated proliferative diabetic retinopathy * Systolic blood pressure higher than 160 mmHg or diastolic blood pressure higher than 100 mmHg * Measured glomerular filtration rate using iohexol of less than 80 ml/min/1.73m2. More information about this criterion is in the protocol. * Presence or history of macroalbuminuria (greater than 300 mg/g creatinine) * Presence or history of panel-reactive anti-HLA antibody levels greater than 20% by flow cytometry. More information about this criterion is in the protocol. * Pregnant, breastfeeding, or unwilling to use effective contraception throughout the study and 4 months after study completion * Active infection, including hepatitis B, hepatitis C, HIV, or tuberculosis. More information about this criterion is in the protocol. * Negative for Epstein-Barr virus by IgG determination * Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year prior to study enrollment * History of malignancy except for completely resected squamous or basal cell carcinoma of the skin * Known active alcohol or substance abuse * Baseline Hgb below the lower limits of normal, lymphopenia, neutropenia, or thrombocytopenia * History of Factor V deficiency * Any coagulopathy or medical condition requiring long-term anticoagulant therapy after transplantation or individuals with an INR greater than 1.5 * Severe coexisting cardiac disease, characterized by any one of the following conditions: 1. Heart attack within the last 6 months 2. Evidence of ischemia on functional heart exam within the year prior to study entry 3. Left ventricular ejection fraction less than 30% * Persistent elevation of liver function tests at the time of study entry * Symptomatic cholecystolithiasis * Acute or chronic pancreatitis * Symptomatic peptic ulcer disease * Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders that could interfere with the ability to absorb oral medications * Hyperlipidemia despite medical therapy (fasting LDL cholesterol greater than 130 mg/dl, treated or untreated; and/or fasting triglycerides greater than 200 mg/dl) * Receiving treatment for a medical condition that requires chronic use of systemic steroids, except the use of 5 mg or less of prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only * Treatment with antidiabetic medication other than insulin within the past 4 weeks * Use of any investigational agents within the past 4 weeks * Received a live attenuated vaccine(s) within 2 months of study entry * Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial * Treatment with any immunosuppressive regimen at the time of enrollment * A previous islet transplant * A previous pancreas transplant, unless the graft failed within the first week due to thrombosis, followed by pancreatectomy and transplant occurred more than 6 months prior to enrollment