NEI Clinical Studies
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Collaborative Corneal Transplantation Studies (CCTS)
To determine whether histocompatibility matching of corneal transplant donors and recipients can reduce the incidence of graft rejection in high-risk patients.
Approximately 20 percent of corneal transplant patients, about 6,000 per year, face donor tissue rejection at rates of up to 60 percent because of corneal vascularization or prior graft rejection. Histocompatibility antigen matching and/or crossmatching may have offered these patients an improved chance for successful outcome.
The Collaborative Corneal Transplantation Studies Group conducted two controlled, double-masked studies addressing distinct scientific questions about donor-recipient histocompatibility matching. The Crossmatch Study was a randomized study assessing the effectiveness of crossmatching in preventing graft rejection among high-risk patients with lymphocytotoxic antibodies. The Antigen Matching Study was a prospective, double-masked, observational study of the effectiveness of HLA-A, -B, and -DR donor-recipient matching in high-risk patients who had no lymphocytotoxic antibodies.
Six clinical centers recruited high-risk patients and collaborated with their local eye banking and organ procurement agencies in procuring donor corneal tissue. For each of the two studies, a total of 400 patients were sought. Blood samples from each enrolled patient were sent to the local CCTS tissue typing laboratory for HLA typing, and serum samples were sent to the Central Laboratory to be screened for preformed lymphocytotoxic antibodies. Depending on the results of the testing, patients were entered into the Crossmatch Study or the Antigen Matching Study.
As corneal donors became available, donor blood samples were HLA typed at the local laboratories and crossmatched against all CCTS patients who awaited transplantation. Results of the testing were entered in a national, 24-hour computerized allocation system operated by the United Network for Organ Sharing (UNOS). Patients in the Crossmatch Study received a cornea from either a positively crossmatched donor or a negatively crossmatched donor. Patients in the Antigen Matching Study received a cornea with 0 to 6 matched antigens.
Transplant patients were followed intensively during the first months after surgery. The number of clinic visits was tapered to 2 during the third and final year of followup, resulting in a total of 17 postoperative visits. Irreversible failure of the corneal allograft due to all causes was the primary outcome variable in both studies. Allograft reaction episodes, irreversible failure due to rejection, and visual acuity were secondary outcome variables.
Males and females age 10 years or older with two to four quadrants of corneal stroma vascularization or a history of allograft rejection in the eye considered for surgery were eligible for both studies in the CCTS.
Patients must have been willing to participate in 3 years of followup. No one was eligible for the CCTS who had a condition that would greatly increase the risk of nonrejection graft failure, such as xerophthalmia or severe exposure keratopathy. Also excluded were patients with systemic diseases or with medication usage that might alter their immune response.
Patient Recruitment Status
Recruitment began in May 1986 and was completed September 30, 1989.
Current Status of Study
Researchers report that donor-recipient tissue typing had no significant long-term effect on the success of corneal transplantation in more than 400 patients at high risk for rejection.
The Collaborative Corneal Transplantation Studies (CCTS) suggested instead that matching patient and donor blood types (ABO compatibility), a test that is not currently standard practice in corneal transplantation, might be effective in improving patient outcome. Treating patients with high-dose topical steroid therapy for several months after surgery may have improved transplant survival in this study.
After 3 years of patient followup, CCTS researchers found that people who received corneal transplants with well-matched antigens did not fare significantly better than those with a poor match. Each patient group had similar rates of initial immune reactions, graft rejection, and graft failure due to rejection or other causes. The researchers also noted that CCTS patients who were compatible with the donor's blood type had a better outcome than unmatched patients.
The CCTS also reported a 65 percent rate of graft survival at its 3-year mark--higher than the usual average of about 50 percent in high-risk patients. The study's high success rate might be due to rigorous high-dose steroid therapy given to control the patients' immune reaction to the donor cornea several months after surgery.
The most important conclusion to be drawn from the CCTS is that high-dose, postoperative topical steroids, good patient compliance with a self-administered steroid regimen, and close patient followup are the keys to successful corneal transplantation in high-risk individuals.
Data from the CCTS indicate that matching patient and donor blood types combined with treating patients with high-dose topical steroids after surgery may be potentially more effective in improving high-risk corneal transplantation. These two inexpensive strategies are considerably more economical than the more expensive donor-recipient tissue typing. These findings provide clinicians with solid information on managing patients at high-risk for graft failure, while keeping health care costs to a minimum.
Hahn AB, Foulks GN, Enger C, Fink N, Stark WJ, Hopkins KA, Sanfilippo F: The association of lymphocytotoxic antibodies with corneal allograft rejection in high risk patients. The Collaborative Corneal Transplantation Studies Research Group. Transplantation 59(1): 21-27, 1995.
Kamp MT, Fink NE, Enger C, Maguire MG, Stark WJ, Stulting RD: Patient-reported symptoms associated with graft reactions in high-risk patients in the Collaborative Corneal Transplantation Studies. Collaborative Corneal Transplantation Studies Research Group. Cornea 14(1): 43-48, 1995.
Fink N, Stark WJ, Maguire MG, Stulting D, Meyer R, Foulks G, Smith RE, Rapoza P: Effectiveness of histocompatibility matching in high-risk corneal transplantation: A summary of results from the Collaborative Corneal Transplantation Studies. Cesk Oftalmol 50(1): 3-12, 1994.
Maguire MG, Stark WJ, Gottsch JD, Stulting RD, Sugar A, Fink NE, Schwartz A: Risk factors for corneal graft failure and rejection in the Collaborative Corneal Transplantation Studies. Collaborative Corneal Transplantation Studies Research Group. Ophthalmology 101(9): 1536-1547, 1994.
McDonnell PJ, Enger C, Stark WJ, Stulting RD: Corneal thickness changes after high-risk penetrating keratoplasty. Collaborative Corneal Transplantation Study Group. Arch Ophthalmol 111(10): 1374-1381, 1993.
The Collaborative Corneal Transplantation Studies Research Group: Effectiveness of histocompatibility matching in high-risk corneal transplantation. Arch Ophthalmol 110: 1392-1403, 1992.
Stark WJ, Stulting RD, Collaborative Corneal Transplantation Research Group: Sharing tissue typing information from the Collaborative Corneal Transplantation Studies. Arch Ophthalmol 107: 633, 1989.
Klein PK, Stark WJ, Maguire MG, Stulting RD, Collaborative Corneal Transplantation Research Group: Donor-recipient crossmatching and typing to avoid corneal allograft rejection, in Cavanaugh HD (ed). The Cornea: The World Congress on the Cornea III, New York, Raven Press, 395-398, 1988.
Maguire MG (for the Collaborative Corneal Transplantation Studies Group): Cytomegalovirus (CMV) transmission and corneal transplantation. Arch Ophthalmol 106: 877, 1988.
Stark WJ, Stulting RD, Thoft R: HLA matching and corneal transplantation. N Engl J Med 316: 1476-1477, 1987.
Walter J. Stark, M.D.
Wilmer Eye Institute
The Johns Hopkins Medical Institutions
600 North Wolfe Street
Baltimore, MD 21205
Telephone: (410) 614-4340
Fax: (410) 955-0867
Maureen G. Maguire, Ph.D.
Scheie Eye Institute
51 North 39th Street
Philadelphia, PA 19104
Telephone: (215) 662-8139
Fax: (215) 662-0133
Nancy E. Fink, M.P.H.
The Johns Hopkins Medical Institutions
2024 East Monument Street
Baltimore, MD 21205
Telephone: (410) 614-3994
Natalie Kurinij, Ph.D.
National Eye Institute
National Institutes of Health
6120 Executive Boulevard, MSC 7164
Bethesda, MD 20892-7164
Telephone: (301) 496-5983
Fax: (301) 402-0528
Last Updated: 10/21/99