Ultra Low Dose Interleukin-2 in Healthy Volunteers

Interleukin 2 (IL-2, aldesleukin) was discovered as a T cell growth factor more than 30 years
ago. IL-2 was the first human cytokine used therapeutically. IL-2 induces antigen specific T
cells, and two important lymphocyte subsets: regulatory T cells (T-regs) and natural killer
cells (NK) cells. T-regs have a critical role in self-tolerance and pathogenesis of
autoimmune disease or graft versus host disease (GVHD), and they have been extensively
studied in solid tumors, hematologic malignancies, viral hepatitis, and HIV infections. NK
cells have a unique role in bridging innate and adaptive immunity. NK cells facilitate
hematopoietic stem cell (HSC) engraftment reduce GVHD and increase graft-versus-leukemia
(GVL) effects. NK cells have important roles on pathogenesis of malignancies, autoimmune
disease and AIDS. Conventional dose IL-2 treatment promotes marked expansion of regulatory T
cells, and NK cells but is associated with significant side effects. However, much lower
doses of interleukin-2 (0.5- 1MIU/m2/day) which lack significant side effects, also induce
expansion of T regs and NK cells. These observations suggest that ultra low dose IL-2 would
be safe and appropriate to give to hematopoietic stem cell donors. The quality of the
transplant would be improved because the higher dose of T-regs would reduce the risk of GVHD
while the higher NK cells would augment the GVL effect. The aim of this study is to evaluate
the safety and the tolerability of ultra low dose IL-2 in healthy volunteer for preferential
expansion of T-regs and NK cells with a view to extending ultra low dose IL-2 administration
to stem cell donors. We anticipate that this study will provide valuable information on the
biology of IL-2 on the human immunome applicable to various human disease conditions,
including cancer, immunodeficiency disease, autoimmune disease, and hematopoietic stem cell
transplantation. The proposed IL-2 dose is 2-3 logs lower than the manufacturer s recommended
dose. We therefore expect that the dose used in this protocol will be well tolerated.
Nevertheless, because there is little information on the tolerability and safety of IL-2 at
these ultra low doses, we have structured this study as a safety protocol with stopping rules
for unacceptable side effects. This is important because we hope to use the safety data
generated to justify a future protocol giving ultra low dose IL-2 to stem cell donors.

- INCLUSION CRITERIA:

- Healthy volunteers confirmed by brief history and physical examination and blood work
through the CHI screening protocol

- Males or females ages 18 years or older

EXCLUSION CRITERIA:

- History of inflammatory or autoimmune disease

- History of inflammatory or autoimmune disease in first degree relatives

- History of malignancies

- Recipients of hematopoietic stem cell transplant or solid organ transplant

- History of seizures

- Positive HIV, hepatitis B surface antigen or hepatitis C antibody

- History or clinical signs of cardiac disease including coronary artery disease,
cardiac arrhythmia, congestive heart failure

- History or clinical signs of of pulmonary disease including obstructive lung disease
and asthma

- Active infections requiring systemic antibiotic therapy or anti-viral therapy

- History of systemic fungal or mycobacterial infections

- Use of immune modifying medications, i.e.- non steroidal anti-inflammatory drugs
(aspirin, ibuprofen, naproxen, celecoxib, ketrolac), steroid (prednisone,
dexamethasone, hydrocortisone), chemotherapy (cisplatin, dacarbazine, interferon
alpha, tamoxifen)

- Persons who are alcoholic or abusers of illicit drugs

- Female subjects who are or may be pregnant or lactating

- Psychiatric diagnoses or symptoms, to include hypomania, bipolar disorder, major
depression, or dysthymia

- Abnormal or marginal peripheral blood count that in the opinion of the PI will cause
Hemoglobin and Hematocrit levels to drop as a result of participation in this study

- Liver function tests above the normal laboratory reference range

- Renal function test above the normal laboratory reference range

- Contraindication to interleukin-2 (i.e. hypersensitivity to IL- 2 products, active
coronary artery disease, patients with organ allograft)

- Recent recipient of any type of vaccination (i.e. rotavirus vaccine, BCG, influenza
virus vaccine, rubella virus vaccine, mumps virus vaccine, measles vaccine, poliovirus
vaccine, smallpox vaccine, typhoid vaccine, varicella virus vaccine, yellow fever
vaccine) in the 4 weeks preceding and during active study participation

- Body mass index greater than 35

- Inability to comprehend the investigational nature of the study or provide informed
consent

- Diabetes mellitus or fasting blood glucose of > 100 mg/dL.

- Any drugs or supplements that interfere with blood clotting such as Vit.E, NSAIDS,
Warfarin (Coumadin), ticlopidine (Ticlid), clopidogrel (Plavix)

- Use of iodinated contrast media in the 4 weeks preceding and during active study
participation.