Innovation Spotlight - Cornea Transplant

New Hope for Cornea Transplant Patients

A new oral vaccine being researched at the University of Texas Southwestern University may offer new hope for those who experience corneal graft rejection. Of the 40,000 corneal transplants performed in the United States each year, 10 percent end in continual rejection. These are the patients for whom traditional medications like corticosteroids and cyclosporin have failed and no other preventive treatment exists.

Jerry Y. Niederkorn, Ph.D., a professor of ophthalmology and microbiology at the University of Texas Southwestern is researching and developing this vaccine. He is an expert on eye immunity and corneal transplantation and has received grants from Research to Prevent Blindness. Niederkorn published results of his studies in the British Journal of Ophthalmology last September and at the Association of Research in Vision and Ophthalmology Meeting. Recently he was interviewed for Eyeworld magazine about his research.

"This research focuses on those patients who reject their first corneal transplant, because for these patients, rejection of subsequent transplants skyrockets." Niederkorn's oral vaccine, which is made from processed cells taken from donor corneas or skin, trains the body to accept donor tissue so the body does not reject the new corneas.

Niederkorn has immortalized corneal cells from a donor mouse strain using the human papilloma virus. He fed the mice the cells and the virus through the gastrointestinal tract prior to corneal transplant. Niederkorn found that he did not need to use just corneal cells for enhancing graft survival, but could use the mouse skin cells instead. Using skin cells, being more abundant and easier to obtain from a cadaver will make creation of this vaccine easier. By immortalizing the corneal cells, he has created a constant source of donor cells. He administered 10 doses of the donor cells to a group of mice before corneal transplant and found the incidence of corneal graft rejection was reduced from 100 percent in untreated hosts to 54 percent in those who received the oral vaccine.

To enhance tolerance, Niederkorn added neutralized Cholera Toxin B to the cells. The Cholera toxin B binds tightly to cornea cells and enhances receptors in the tract - so it provides better ingestion of the cells to boost immune response. Niederkorn added the toxin to the skin cells and administered 10 doses of this updated vaccine before the cornea transplant and his results drastically improved. He found that just 9 percent of those mice, who ingested the cholera toxin and cornea cells, rejected their corneal grafts. And even a single dosage of this mix was able to reduce corneal graft rejection by 36 percent.

Niederkorn says the inspiration for his work is based on a series of promising results from the field of autoimmunity. He has followed the research and literature in the field, such as the benefits of oral immunization with autoantigens in animal models of autoimmune diseases such as Multiple Sclerosis.

The next step for him is a randomized single-center double-masked clinical trial. To accomplish this goal, Niederkorn has joined forces with his colleague H. Dwight Cavanagh, M.D., Ph.D., vice chairman and professor of ophthalmology at UT Southwestern Medical Center in Dallas, who has performed 5,000 corneal transplants.

Cavanagh and Neiderkorn are preparing a prospective 3-year pilot clinical grant for submission to the National Institutes of Health to study 20 - 30 patients who are at high risk for corneal graft rejection. If the results are promising, a more extensive multicenter trial will be required to establish final safety and efficacy for this modality.

One of the most important elements of the study is deciding the dosage or amount of donor cellular antigens required to obtain the desired effect. This may require additional pilot testing with increasing dosages, if the initial observations show no improvement in corneal graft survival.

Cavanagh says the need for this vaccine is great because other major studies to help prevent corneal graft rejection have failed. "The Cornea Collaborative Tissue Transplant Studies with 400 patients proved nonconclusive and then the study on Topical Cyclosporin drops failed. So now there are no alternative research studies being done to help these patients."

Niederkorn and Cavanagh hope to begin a pilot human trial by the second quarter of 2000.