IMMUNOSUPPRESANT DRUGS

Administration of immunosuppressant drugs is the most widely used treatment to prevent graft rejection. The immunosuppressive effects of the drug cyclosporine was first discovered in 1972, and approved by the FDA in 1983. Since then, it continues to be one of the most widely used immunosuppressants, but more refined drugs are in use today.

Immunosuppressant drugs can be classified based on their mechanism of blocking lymphocyte proliferation. Generally, they fall into four categories: glucocorticoids, cytostatics, antibodies, or immunophilins. Others include interferons, opioids, TNF binding proteins, and mycophenolate. However, they all share a common limitation-- immunosuppressant drugs are nonselective and frequently result in immunodeficiency.

Thus, patients suffer from increased susceptibility to infection, and decreased cancer immunosurveillance. The issue is evident in the 10-15% of recipients who die from infection. Other side effects include liver and kidney damage, peptic ulcers, and hyperglycemia (high blood sugar). Hypertension (high blood pressure) develops in more than 70 percent of heart transplant patients within a year and in nearly 95 percent within 5 years; dyslipidemia (high levels of lipids in the blood) develop in more than 50 percent of heart transplant patients within a year and in 84 percent within 5 years. These complications, which are not specific to heart recipients, contribute to the large population who die from heart failure, heart attack, or arrhythmia.

IMMUNOTOLERANCE INDUCTION THERAPY

The phenomenon of immunological tolerance was not recognized until 1945, when it was described by Ray D. Owen. Validated in 1953 by the experiments of Rupert E. Billingham and Peter Medawar, who demonstrated that fetal/neonatal mice who were injected with foreign cells could accept future grafts from the same donor, these observations inspired the future field of immunological tolerance induction. Sir Frank MacFarlane Burnet and Frank Fenner first proposed the deletion of self-reactive lymphocytes to establish tolerance (clonal deletion) in 1957.

Today, tolerance induction is being applied in treatments for autoimmune diseases, hemophilia, and graft rejection. Methods include mixed hematopoietic chimerism, costimulation blockades, peripheral T-cell depletion, and induction/expansion of regulatory T-cells. Unfortunately, these therapies require myeloablation, a severe reduction of bone marrow activity to reduce white blood cells but also red blood cells and platelets, and/or blocking antibodies with significant toxicities to target various T-cell signaling components. Induction methods also generally require long-term exposure since fetal development/birth, which is not possible for most transplant patients. Operational tolerance, where patients are able to cede immunosuppressive therapy without consequences, is also rare.