JULY 2009

Post-Transplant Combo Could Replace Toxic Immune-Suppressing Drugs

Allan Kirk, MD, PhD, scientific director of the Emory Transplant Center and a Georgia Research Alliance Eminent Scholar, was the PI of a study published in the July 2009 issue of Nature Medicine, "Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates," that found that a combination of treatments could effectively replace calcineurin inhibitors in preventing graft rejection following kidney transplants in rhesus macaques. The study concluded that development of a human clinical trial in the regimen was warranted, perhaps opening the door to less-toxic post-transplant treatment that could be administered once a week rather than an overwhelming mound of pills every day.

"Both of the drugs used in this regimen are already used separately in humans, thus a clinical trial could be developed quickly," Dr. Kirk notes.

Transplant patients rely on drugs to prevent graft rejection, but at the cost of serious side effects. The class of immunosuppressive drugs known as calcineurin inhibitors (examples are cyclosporine and tacrolimus) can damage patients' kidneys and lead to high blood pressure, among other problems.

One key ingredient in the combination is an experimental therapy called a costimulation blocker, designed to interfere with the T cells that cause graft rejection without affecting other organs. Costimulation refers to one of two signals T cells need from other cells (antigen presenting cells) to become fully activated. The other prime ingredient — a protein called alefacept — subdues memory T cells, a variety of T cells that allow the immune system to respond faster and stronger to an infectious agent or vaccine upon second exposure.

Costimulation blockers are sufficient for allowing mice to tolerate a transplanted kidney, but not monkeys or people, Kirk says. Memory cells appear to prevent costimulation blockers from working as well in monkeys as they do in mice.

"One of the big differences we've found between mice and both monkeys and people is that we primates have more exposure to infections that require us to develop immunological memory," he says. "Memory cells are quicker to become activated and don't need costimulation as much, so blocking costimulation doesn't slow them down."

By themselves, neither costimulation blockers (in this case, a molecule called CTLA4-Ig) or alefacept could prevent rejection in monkeys after the eight week treatment period, Dr. Kirk and his colleagues found. They had more success by combining costimulation blockers, alefacept and the transplant drug sirolimus. Under this regimen, monkeys could last for months after treatment ended without developing rejection or self-reactive antibodies.

CTLA4-Ig mimics a molecule found on T cells (CTLA4) and acts as a decoy. CTLA4-Ig is now used as an FDA-approved therapy for rheumatoid arthritis. A similar drug called belatacept is now in phase III kidney transplant clinical trials, but current studies use it in combination with conventional immunosuppressive drugs.

Dr. Kirk and his team found that alefacept targets memory T cells via a molecule on their surfaces called CD2. Alefacept was approved by the FDA for treatment of psoriasis in 2003 and is also being tested in a kidney transplant clinical trial in combination with conventional drugs.

The paper's first author was Tim A. Weaver, and the other co-authors were Ali H. Charafeddine, Avinash Agarwal, Alexandra P. Turner, Maria Russel, Frank V. Leopardi, Robert L. Kampen, Linda Stempora, Mingging Song, and Christian P. Larsen. The research was supported by the National Institutes of Health.

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