ILTS 2012 Report – Regulatory T-cell injection holds promise for inducing tolerance

by Thomas R. Collins – Injection of regulatory T cells could prove to be a powerful method of inducing tolerance among liver transplantation patients, an immunology expert said here at the 18^th International Congress of the International Liver Transplantation Society.

Jeffrey Bluestone, PhD, Professor at the University of California San Francisco Diabetes Center who has worked for 20 years on immune tolerance in autoimmunity and transplantation, said the work of him and his colleagues has centered on FOXP3-positive T-reg cells because they are one of the body’s most crucial defense mechanisms against inappropriate immune responses.

It’s important to attempt to bring about tolerance in transplant recipients — essentially, re-educating the immune system to accept a graft — rather than relying on immunosuppressive drugs because of the many downsides of long-term drug therapy, Dr Bluestone said.

“Life-long immunosuppression results in substantial morbidity and mortality risk for a liver transplantation — including renal insufficiency and end-stage renal disease increasing over time after transplant,” he said. “The current immunosuppressive medications are strongly associated with potent artherosclerosis risk factors such as diabetes.” Infections, post-transplant lymphoproliferative disease and skin cancer are also concerns associated with immunosuppressives.

The liver is a “tolerance-friendly organ,” Dr Bluestone said. He said 20 to 30 percent of selected transplant recipients examined across multiple centers and withdrawal protocols are tolerant and can be taken off drug treatment completely.

The approach by Dr Bluestone and his team has been studied extensively in mouse models but not in humans — although a protocol is being developed for that. The strategy involves more than the injection of regulatory T cells; equally critical is the deletion of donor-reactive T cells. About 70 to 80 percent of deletion of those cells is required to effectively lessen the workload of the regulatory T cells and open a therapeutic window for them.

Dr Bluestone said it is not good enough to simply inject regulatory T cells, though. They have to be donor-specific.

In a study involving islet transplantation in mice, depletion of donor-reactive T cells plus injection of donor-specific T-reg cells led to a survival rate of about 70 percent after 100 days, compared to a rate of less than 20 percent for mice undergoing depletion and injection of the same number of non-specific T-reg cells.

Using an activation process involving donor B cells, researchers have been able to manufacture T-reg cells that are donor specific, Dr Bluestone said.

Although the strategy appears promising, he said care should to be taken.

“Once you put the cells in, it’s not so easy to get them back out,” he said. “You can always stop a drug, it’s hard to get cells out you put in.”

He said stability in an inflammation can be “tricky.”

“If you don’t have a highly specific, donor-specific population, and you put in too many polyclonal cells… these cells are effective at shutting down all kinds of immune responses, some of which you want. And it could lead to long-term non-specific suppression,” Dr Bluestone said. “So I think we need to balance the goal of getting cells in there that are specific enough, but also stable enough to get a selective regulation.”