Islet Cell Transplantation Alone in Patients With Type 1 Diabetes Mellitus: Steroid-Free Immunosuppression

This Phase II trial will have 3 groups: Group A will receive islets from 2 donors and will
not receive infliximab. Group B will receive, in addition to Daclizumab, Sirolimus, and
Tacrolimus, a dose of infliximab and islets from a single donor, as per the Edmonton
protocol. Everything else about the clinical trial will be the same for both groups. The
first 4 patients will be assigned to Group A, the next 4 patients to Group B, the next 4
patients to Group A, and the next 4 patients to Group B (total =16). Patients in Group A will
receive 1-2 transplants with cells from 2 donors. If the second donor pancreas is received
and satisfactory at the same time as the first pancreas, one islet infusion will be used to
infuse cells from both donors. If the second pancreas is not received until after the first
transplantation, a second islet infusion will be done. A second course of five doses of
Daclizumab will be started on the day of the second islet infusion).

In order to determine if prolonged administration of etanercept, in combination with
transplantation of cultured islets, will prevent TNF-α production and enhance engraftment, we
have added Group C to the current protocol. Group C, in addition to Daclizumab, Sirolimus,
and Tacrolimus, will receive Etanercept in the peri-transplant period and islets from one or
more donors. The last 24 patients included in this Protocol will be in Group C if they are
new, or in Group A and B Supplemental Infusion if they had previous transplants. Any Group A
or B participants who are eligible for a supplemental infusion will receive etanercept but no
infliximab.

Inclusion Criteria:

1. Patients between 18 and 65 years of age

2. Patients with type 1 diabetes mellitus for more than 5 years duration

3. One or more of the following:

- Hypoglycemia unawareness - judged by history of blood sugars <54 on glucometer
without symptoms and/or hypoglycemic episodes requiring assistance from either
family, glucagon administration or emergency services

- Poor diabetes control (HbA1c>8% or >2 visits/yr to hospital for treatment of
ketoacidosis) despite intensive insulin therapy

- Progressive complications of type 1 diabetes mellitus

4. Body Mass Index (BMI) ≤26

Exclusion Criteria:

1. c-peptide > 0.3ng/ml basal or stimulated;

2. untreated proliferative diabetic retinopathy;

3. HbA1C >12%;

4. creatinine clearance <60;

5. serum creatinine consistently >1.6 mg/dl;

6. macroalbuminuria >300mg albumin in 24 hours;

7. presence of panel reactive antibodies (PRA) >20%;

8. previous/concurrent organ transplantation (except previous unsuccessful islet cell
transplant;

9. malignancy or previous malignancy (except non-melanomatous skin cancer);

10. x-ray evidence of pulmonary infection;

11. active infections;

12. active peptic ulcer disease, gall stones, hemangioma, or portal hypertension

13. serological evidence of HIV, HbsAg or HCV; serological evidence of active EBV
(IgM>IgG) or EBV negative serology;

14. PPD conversion or positive PPD without historic completion of appropriate prophylactic
treatment;

15. abnormal liver function test;

16. anemia (hemoglobin <12.0);

17. hyperlipidemia (fasting serum triglycerides >200mg/dl and/or fasting serum cholesterol
>240 mg/dl and/or fasting LDL cholesterol >140 mg/dl);

18. BMI above 26;

19. unstable cardiovascular status; prostate specific antigen (PSA) >4;

20. pregnancy or breastfeeding;

21. sexually-active females who are not: a) post-menopausal, b) surgically sterile, or c)
not using an acceptable method of contraception (oral contraceptives, Norplant,
Depo-Provera, and barrier devices are acceptable; condoms used alone are not
acceptable);

22. alcohol abuse, substance abuse or smoking within the previous 6 months; insulin
requirement >1u/kg/day and any condition or any circumstance that makes it unsafe to
undergo an islet cell transplant.