Chronic Rejection Registry. HLA Alloantibodies and Organ Transplant Rejection

Paul I. Terasaki, Co-Chair
Dan Cook, Co-Chair

Background and Rationale.

Over the years, an association between HLA antibodies present at the time of transplant and graft loss has been well established. It is somewhat less clear as to actual involvement of alloantibodies developing fol-lowing transplantation. The antibody status of 5,000 long-term surviving organ transplant recipients will be determined for the 13th International Histocompatibility Workshop in the coming 5 months. Since the expected rate of attrition of all organ grafts is about 5% per year, the answer to the question of whether antibodies cause chronic rejection can only be obtained (in a reasonable length of time), by a large scale collaborative study.

This hypothesis is supported by the following observations:

In a recent study, 96% of 825 patients who had rejected a kidney transplant and were waiting for a regraft had HLA antibodies. This confirms earlier studies showing that 95% of 100 patients who had rejected a kidney had antibodies detectable by flow cytometry.
Association of HLA antibodies with rejection and survival was shown in 23 papers reviewed last year. During the past year, 7 more publications have confirmed these findings.

References

Harmer AW, Koffman CG, Heads AJ, Vaughan RW. Sensitization to HLA antigens occurs in 95% of primary renal transplant rejections. Transplant Proc. 27(1): 666, 1995. (95% of 100 patients who rejected a kidney graft had antibodies detected by flow cytomertry)

El-Awar. Transplant Proc. In press. (96% of 825 patients recently studied who are waiting for a regraft had antibodies)

Worthington, Al-Husseini, Dyer, Martin. Post-transplant production of donor HLA specific antibodies as a predictor of renal transplant outcome. Human Immuno. 62:39, 2001 (recent finding that 60 out of 117 patients who rejected a graft (51%) had donor specific antibodies prior to rejection, as compared to 2 out of 120 controls (0.2%): p<0.0001)

Theruvath et al, Transplantation 72:77, 2001; (evidence that chronic rejection can be stopped by reducing antibodies)

Overview. We will test the hypothesis that alloantibodies are the cause of chronic rejection in a prospective study. Patients with a functioning graft for at least one year post-transplant will be enrolled, their antibody status will be evaluated and then followed for subsequent development of chronic rejection. Because prior studies have suggested that essentially all organs have the common association, all solid organ transplants will be included. As an ancillary objective, the frequency of antibody formation with respect to type of immunosuppression will be obtained.

     Phase I. Workshop participants are requested to enroll eligible patients with a functioning graft at least one year from transplant. Serum should be tested for alloantibodies by any established method preferred by the local lab. It is suggested that typing labs calculate the number of patients they will be able to test by examining the number of patients who had re-turned to the follow up clinic in the past 3 months. Then collect and test sera left over from other tests (such as creatinine tests) during the next 3-4 months. It is essential to get the testing and data submitted early so that some analysis can start. The deadline for pre-IHWS data submission will be April 1. Data submitted by this date will be included in the 13th IHWS analysis and discussed at the Workshop meeting in Victoria BC in May 2002.

Data Analysis. Participants will be assigned to different segments of the analysis depending upon the extent of their participation in submitting data, and asked to present and discuss findings at the Workshop meeting.

     Phase II (post-13th IHWS). It is anticipated that interesting questions will emerge out of the basic study, such as com-parisons of methods, specificities of antibodies produced, antibodies to Class I or II or DP, antibodies to 'minor' antigens, new types of antibodies, significant antibody immunoglobulin subtypes, organ specific responses, effect of duration and strength of antibodies, possible enhancing or anti idiotypic antibodies, etc.

Methods

Phase I. participants are requested to test any long term (>1 year) allograft recipient for antibodies by any of their own preferred method.

Phase II. To be determined.

Work Plan

     Phase I. The initial stages of the first study will involve the following:

Identify transplant centers and laboratories interested in participation.
Individual laboratories begin testing available post-transplant sera (suggest initial testing at one year or longer post-transplant).
As soon as sera are tested, submit Chronic Rejection data entry form. Data forms should be submitted to the central database (via email) together with the registration form (including patient ID, demographics and clinical data).
The last forms that will be processed before the workshop meeting must be received by April 1, 2002 (for inclusion in the pre-IHWS Victoria analysis). The initial phase will involve the examination of anti-HLA class I & II PRA's obtained using a local method.

Phase II. It is anticipated that the next stage of this project, post-13th IHWS, will require prospective collection of serial post-transplant samples and the cryopreservation of donor lymphocytes. Details will be determined at the 13th IHWS meeting in Victoria BC, May 12-16, 2002.

Dr. Terasaki may be reached at:
11570 Olympic Blvd
Los Angeles CA 90064
310-479-6101 (phone)
310 477-0926 (fax)
terasaki@terasakilab.org (e-mail)