Biotherapeutic activation of toll-like receptor 5 (TLR5) to treat graft-versus-host disease (GvHD).
- Administration of flagellin reduces both acute and chronic GvHD.
- Contrary to immunosuppressive drugs, flagellin enhances immunity and protects patients from opportunistic infections.
More than 25,000 stem cell transplantations are performed annually worldwide to treat bone marrow diseases. Transplant recipients are prone to rejecting the newly transplanted tissue, and 50% of recipients develop graft-versus-host disease in which the new donor cells destroy tissues in the host body. To prevent GvHD, patients are administered immunosuppressive drugs prophylactically, but patients often experience significant drug-related toxicities as well as increased opportunistic infections due to systemic immunosuppression. While effective for treating GvHD, none of the current treatments increase transplant success rate and simultaneously decrease pathogen susceptibility.
Toll-like receptors recognize molecular structures on bacteria and viruses to launch an innate immune reaction. Activation of Toll-like receptors produces signaling molecules like cytokines and increase antigen presentation. In GvHD, an abundance of proinflammatory cytokines are found along with an up regulation in allo-reactive donor T cells that attack host tissue. Emory researchers have found that administration of a toll-like receptor 5 (TLR5) agonist, flagellin, prior to stem cell transplantation reduces both acute and chronic GvHD in mouse models. All flagellin-treated animals survived without any clinical signs of acute or chronic GvHD whereas 60% of controls exhibited severe GvHD symptoms. Flagellin treated mice were also able to recover from sub lethal doses of the opportunistic infection, mCMV, indicating preservation of host immunity. Toll like receptor ligands are the key to stimulating an immune response and recent clinical trials have successfully administered flagellin as a vaccine adjuvant, demonstrating safety and effectiveness in humans. Flagellin administration offers a safe way to decrease symptoms of GvHD while preserving immunity.
In vivo studies with murine transplant models show reduced GvHD symptoms and increased recovery from opportunistic infections after flagellin treatment.