M.H. Yamani

The use and misuse of immunologic monitoring after transplantation: approaches that have proved useful.

Current practice in the monitoring of cardiac transplants revolves around the use of the endomyocardial biopsy. While this is effective for the identification of an ongoing immune response in the graft, for years investigators have explored less invasive approaches in the hope of achieving the same goal by examining the patient’s immune response. For a number of years, lymphocytes, their subsets, and their level of activation in the periphery were investigated. To a large degree, it was a lack of specificity in these approaches that led to their falling out of favor. Examination of donor-specific reactivity by means of lymphocyte proliferation assays has also been used; however, these approaches have been impeded by the time and effort required to accomplish them. During the last few years, flow cytometric cross-matching during the posttransplant period has been used at our institution. While this cross-matching focuses on the humoral immune responses, we have found it to be of value in identifying patients at risk of rejection and in allowing the assessment of treatment modalities used to treat ongoing rejection. While the perfect approach remains to be found, the potential advantages of immunologic monitoring would seem to justify continued study.

The role of vitronectin receptor and tissue factor in the pathogenesis of transplant coronary vasculopathy

OBJECTIVES This study was undertaken to test the hypothesis that transplant coronary vasculopathy (CV) is associated with increased myocardial protein expression of both tissue factor (TF) and integrin v 3. BACKGROUND The vitronectin receptor (integrin v 3) and TF have recently been found to play a key role in apoptotic cell death and vascular endothelial cell injury. METHODS A total of 77 heart transplant recipients underwent simultaneous endomyocardial biopsy and intravascular ultrasound (IVUS) at one year of transplant. Patients with pre-existing donor coronary atherosclerosis (n 35) or with acute rejection (grade 1A, n 10) at the time of the IVUS were excluded from the analysis. The remaining 32 patients constitute the cohort of the present study. A computerized biopsy score was derived based on the duration and severity of cellular rejection. Both TF and v 3 expression in the heart biopsy specimens were evaluated by immunoperoxidase histochemistry and Western blot analysis. RESULTS Patients with CV (n 24) had increased expression of v 3 (2.7-fold, p 0.003) and TF (7.9-fold, p 0.04) compared with patients without evidence of vasculopathy (n 8). In the absence of myocardial fibrosis, v 3 expression correlated significantly with the cellular rejection score (r 0.58, p 0.02). CONCLUSIONS Transplant vasculopathy is associated with increased expression of both TF and v 3. The significant correlation of v 3 with cellular rejection suggests an important role for this integrin in serving as a mechanistic link between cellular rejection and vasculopathy. (J Am Coll Cardiol 2002;39:804–10)

HLA alloantibodies and time of death in cardiac transplantation

For some time now it has become clear at our program that a positive flow cytometry crossmatch (FCXM) is associated with a degree of morbidity and mortality. Here we have examined this issue again to determine what impact these anti-donor HLA antibodies might have on the time of death in failed transplants. Of 876 total transplants available for analysis, 637 continue to survive (72.7%), 63 (7.2%) were lost within 90 days, 76 (8.7%) were lost between 90 days and 3 years, and 100 (11.4%) greater than 3 years post-transplant. As seen in the table, when 584 patients with FCXM results were stratified by FCXM as negative, HLA class I positive (T&B reactive) and class II positive (T negative, B cell positive), there was a significant difference observed with class I and class II reactions associated with increased early and intermediate losses when compared to the negatives. We have also previously observed that hearts from donors who died due to a cerebrovascular accident (CVA) seem particularily sensitive to these antibodies. With these donors, almost 30% of the class I positive transplants were lost within the first 90 days. The amount of antibody reactivity of the FCXM measured in molecules of fluorescence binding to the donor cells also differed among these groups. The mean increase in fluorescence over controls was 562 for survivors, 3491 for 90 day deaths, 1102 for intermediate (90 days-3 years), and 10,562 molecules for late deaths (p 0.0001). It seems that HLA antibodies identified at the time of transplant may be assoicated not only with early but also late death in cardiac transplantation.