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Transplant protocol induces immune cells to switch sides

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Holly Korschun

Transplant surgeons want to convince a transplant recipient’s immune cells to “switch sides”: convert cells that would normally recognize and attack the transplanted organ to cells that control the immune response instead.

This could mean a better chance of avoiding rejection of the transplanted organ, and may help the recipient wean off anti-rejection drugs over time, reducing the rate of long-term complications.

Now Emory Transplant Center researchers have shown that an experimental combination of treatments can induce turncoat behavior among immune cells in mice with skin grafts. The combination involves transfusion of spleen cells from the donor, as well as a limited course of a drug that blocks immune cell signals.

The results are published this week in the Proceedings of the National Academy of Sciences Early Edition.

The senior author is Mandy Ford, PhD, assistant professor of surgery at Emory University School of Medicine. First author Ivana Ferrer is a student in Emory’s Immunology & Molecular Pathogenesis graduate program.

“Using this treatment protocol, we found that a subset of cells that would normally attack the graft instead turn on a gene that instructs them to become graft-protective,” Ford says. “These protective cells are called regulatory T cells – they are present in everyone’s immune system and normally prevent us from developing autoimmunity. Previously we didn’t know whether the treatment was simply enhancing regulatory T cells that were already there, or whether it actually induces the emergence of a new group of graft-specific regulatory T cells.”

The drug used by Ferrer, Ford and their co-workers blocks signals from a molecule called CD154. Several studies have shown that blocking CD154, combined with transfusion of spleen cells from the donor, can help transplants of various types (heart, skin, kidney) last longer in both mice and monkeys.

Besides the drug that blocks CD154, the animals don’t receive any anti-rejection drugs after the transplant as part of the combination protocol. Even so, the skin grafts survived for months, the Emory team found. If one part of the combination is missing, the grafts don’t last more than a few weeks.

An opportunity to alter the course of an immune response exists when cells that would normally attack the transplanted organ are activated, which occurs when they come into contact with donor cells. If this happens while CD154 is blocked, the cells either die or convert into regulatory T cells, the Emory team showed.

One obstacle to using drugs that block CD154 clinically is that in humans, they have been shown to induce blood clots. Ford says Emory researchers have been investigating the possibility of blocking CD154 signals in a different way, avoiding the blood clotting mechanism.

Transplant surgeons have used “donor-specific transfusion” as a tactic to control the immune system for several decades, but it is not part of standard transplant practice. The Emory Transplant Center is currently studying donor-specific transfusion (but with different drugs, not anti-CD154 drugs) as part of an experimental kidney transplant protocol.

The research was supported by the National Institute of Allergy and Infectious Diseases.  

Reference: I.R. Ferrer. M.E. Wagener, M. Song, A.D. Kirk, C.P. Larsen and M.L. Ford. Antigen-specific induced Foxp3+ regulatory T cells are generated following CD40/CD154 blockade. PNAS Early Edition (2011).

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