Study examines why second corneal transplants are rejected

Corneal transplantations are successful in 90 percent of first-time procedures, but second allografts are rejected at three times the rate of the first surgeries. A new study published online by the American Journal of Transplantation sought to elucidate the reasons for these rejections.

“In the future, ophthalmologists may be able to implement processes, and eventually prescribe medications, that can lower the rates of rejection,” said the study’s senior author, Jerry Niederkorn, PhD. He is a professor and vice chairman of research of ophthalmology, as well as professor of microbiology, at the University of Texas Southwestern Medical Center, Dallas.

Surgeons perform more than 40,000 transplants annually to replace the cornea with donor tissue-most of them to correct severe visual impairments caused by keratoconus. Immune privilege is thought to be responsible for the high success rate of first-time corneal allografts. The process allows the procedures to be successfully performed without the human leukocyte antigen matching between donor and recipient tissue necessary for organ transplants. Immune privilege occasionally can fail, however, leading to the rejection of corneal transplants in about 10 percent of patients. In patients requiring a second allograft, the incidence of immune rejection is almost 70 percent.

“We believe that this loss of immune privilege is similar to an alarm that signals the immune system of potential infection, which results in a full-blown immune response at the expense of the corneal transplant,” said Niederkorn, who also holds the Royal C. Miller Chair in Age-Related Macular Degeneration Research and the George A. and Nancy P. Shutt Professorship in Medical Science.

The researchers studied mouse models of penetrating keratoplasty and discovered that after the body accepts the first corneal transplant, T regulatory cells prevent other types of immune cells from attacking and rejecting it. The necessary severing of corneal nerves during the first transplantation procedure, however, releases high levels of the neuropeptide substance P. The resulting high substance P levels disable the T regulatory cells needed for acceptance of subsequent corneal transplants. This inactivation results in the rejection of more than 90 percent of second corneal allografts in mice and helps explain the high risk for corneal graft rejection in patients who receive a second corneal transplant, the investigators say.

Next: Findings, future research

The scientists found that the high substance P levels can be blocked with drugs to restore the eye’s immune privilege and promote acceptance of a second corneal transplant. Their future research will examine pharmacologic strategies for restoring T regulatory cell function and promoting the survival of second corneal transplants. Additional studies will determine whether these findings can be extended to enhancing the body’s immune response to cancer.