Long-term Function of Beta Cell Allografts in Non-uremic Type 1 Diabetic Patients

The present proof of concept study addresses the following specific aims:

The general objectives of this work are:

1. To increase and maintain the functional beta-cell mass after islet transplantation under a condition of low-dose tacrolimus
2. To co-investigate the potential of alternative sites for encapsulated beta-cells

1. Aim 1: To increase functional beta cell mass by adding rituximab at first implantation
2. Aim 2: To increase functional beta cell mass by adding basilixumab at second implantation
3. Aim 3: To assess the influence of down-tapering the tacrolimus dose during posttransplant years 2-5 on these data, on metabolic control, on the prevalence of hypoglycemia and on safety parameters.
4. Aim 4: To investigate the potential of the peritoneum and omentum as an alternative site for encapsulated beta-cells.
5. Aim 5: To investigate the potential of the brachioradial muscle as an alternative site for encapsulated beta-cells.

Eligibility Criteria:
Inclusion Criteria:

* Age 18-65 years, male or female, Caucasian or not; only subjects \< 50 yrs will be allocated to the rituximab treatment arm
* Body weight \< 100 kg; patients with a bodyweight of \< 80kg, will receive priority
* Patients with a BMI ≤ 27 kg/m2 will receive priority
* Type 1 insulin-dependent diabetes
* C-peptide \< 0.07 nmol/l (\<0.2 µg/l) 6 min. after glucagon IV (1mg) (glycemia \> 180 mg/dl)
* Intensive insulin therapy for more than two years, patients with insulin pump during at least 2 months before inclusion will receive priority
* Patients should have at least one of the following chronic complications of diabetes:

  * Plasma creatinine \<2 mg/dl and albuminuria 30-1000 mg/ 24hrs on 3 separate determinations (\>1 month) outside an episode of illness, despite intake of ACE inhibitors; mean systolic blood pressure should be under 130 mmHg and mean diastolic blood pressure under 85 mmHg, when measured at home with ambulatory BP monitoring
  * Moderate or severe non-proliferative or proliferative retinopathy
  * Hypoglycemic unawareness
* Cooperative and reliable patient giving informed consent by signature

Exclusion Criteria:

* Smoker
* EBV antibody negativity
* HIV 1 \& 2 antibody positivity
* CMV IgM positivity
* Plasma creatinine ≥ 2 mg/dl and/or albuminuria ≥1000 mg/24 hrs
* History of thrombosis or pulmonary embolism
* History of malignancy, tuberculosis or chronic viral hepatitis
* History of any other serious illness which could be relevant for the protocol
* Presence of HLA antibodies
* Blood donation within one month prior to screening or during the study
* Symptoms and/or signs of infection, particularly (present or past) endocarditis, osteomyelitis, past tuberculosis with requirement for therapy
* Any history of hepatic or neoplastic disease
* Any history of renal disease (except diabetes)
* Abnormal liver function tests and /or NMR of liver
* Hemoglobinopathy
* History of any illness that, in the opinion of the investigator, might confound the results of the study or pose additional risks to the patient
* Pregnancy or use of inadequate contraception by female patients of childbearing potential
* Use of illicit drugs or overconsumption of alcohol (\> 3 beers/day) or history of drug or alcohol abuse
* Being legally incapacitated, having significant emotional problems at the time of the study, or having a history of psychiatric disorders
* Having received antidepressant medications during the last 6 months
* Having participated the last 12 months or participating in another clinical study