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Current expansion of the recipient population and increased utilization of left ventricular assist devices as a bridge-to-transplantation have resulted in HLA sensitization becoming an increasingly important clinical problem in cardiac transplantation. We evaluated the impact of HLA sensitization and donor cause of death on survival in 500 cardiac transplant recipients. Donor cause of death was grouped into two categories, trauma and nontrauma. Panel reactive antibodies at the time of transplant were assayed and used as a marker for sensitization if more than 10%. Sensitized recipients had a poorer 1-year survival than those not sensitized (76 vs. 89%, respectively, P=0.2). Donor cause of death had an overall significant impact on survival with 1-year survival for recipients of trauma organs of 92 and 82% for recipients of nontrauma hearts (P=0.02). Trauma hearts transplanted into sensitized recipients yielded a survival of 93% at 1 year whereas if nontrauma donor hearts were transplanted into these recipients, survival was only 52% at 1 year, P<0.001. These intriguing results suggest that graft survival in HLA-sensitized recipients could be significantly improved through the use of hearts from trauma death donors.

Background: We attempted to minimize the undesired side effects and maximize the benefit of OKT3 induction therapy in renal transplantation., Methods: One hundred and one recipients of kidney-only transplants were randomized to three groups. Each received low-dose 2.5-mg OKT3 induction for 7-14 days, but different premedication on days 0, 1, and 2. Group I was given 250 mg i.v. methylprednisolone at 1 and 6 hr, and group II received another 500 mg at 1 hr before initial OKT3. Group III received Atgam 15 mg/kg on day 0 and began OKT3 on day 1. A CD3+ T-cell cut-off of 50/mm3 was used to guide therapy. Maintenance therapy included cyclosporine and steroids for each patient. However, groups I and II were also given mycophenolate mofetil, and group III received azathioprine as a third agent. All rejections were biopsy confirmed and Banff scored., Results: No differences in demographic or transplant characteristics were noted between groups I, II, and III, and mean follow-up was 25.7 (1-38) months. There was no significant difference in actuarial patient (90%, 91%, 94%) or graft survival (83%, 88%, 84%) at 3 years between the respective groups. Mean creatinine values and infectious complications were similar for each group. No patient experienced acute rejection during induction, and eight patients required dose escalation to sustain suppression of CD3 counts. The incidence of acute rejection at 6 and 12 months was significantly (P=0.004) greater in group III (38.2, 44.1%) than in either group I (15.1, 18.1%) or group II (14.7, 17.6%); relative risk 1.988 (95% CI 1.012-3.906). Formation of anti-OKT3 antibody was significantly (P=0.006) greater in group III (26.5%) than in group I (6%) or group II (2.9%). Group I recipients enjoyed significantly (P=0.001) fewer (2.17) OKT3 side effects on days 0, 1, and 2 than group II (3.03) or group III (2.49), and contained the largest number (61%) of recipients who experienced no side effects. Group I also exhibited the most suppressed profile of OKT3-induced release of tumor necrosis factor-alpha (P=0.006), interferon-gamma (P=NS), and interleukin-6 (P=0.01) on days 0 and 1., Conclusions: Low-dose 2.5-mg OKT3 with pretreatment of split-dose steroids on days 0, 1, and 2 provides the most effective method for OKT3 induction, which minimizes side effects for most patients. Subsequent maintenance therapy with cyclosporine, mycophenolate mofetil, and steroids provides effective rejection prophylaxis without increased complications for up to 3 years. Predepletion of T cells before exposure to OKT3 does not prevent cytokine release.

Background: The performance characteristics and interlaboratory comparisons of the T-cell flow cytometry crossmatch remain largely unknown., Methods: This study was performed using data from the ASHI-CAP proficiency testing program. Four unknown sera and two unknown cells were sent to participating laboratories twice a year for 4 years., Results: In one survey in which different crossmatch techniques were compared, flow cytometry was slightly more sensitive than the antiglobulin method and considerably more sensitive than direct cytotoxicity. However, the proportion of participants in any given survey detecting antibodies in all sera expected to be positive was 50-60% and has not changed over the years. Failure to detect antibodies correlated with low antibody concentration, diluting the unknown serum by the testing laboratory, and with the instrument used. False positive results with normal sera were infrequent. Fluorescence intensity values were not standardized and were highly variable, but when fluorescence units reported by individual laboratories were divided by their own positive-negative cutoff values, results from different centers were more comparable. In general, fluorescence-to-cutoff ratios >5 correlated with complement binding activity, whereas values <5 denoted concentrations below those required to fix complement., Conclusions: Flow cytometry, as used by most centers, is highly sensitive and allows relative antibody quantitation. Furthermore, the data define objective parameters that may help to standardize the test and improve its predictive value in clinical transplantation.

Using actuarial methods, factors influencing long-term graft survival were examined in 33,594 recent (since 1974) kidney transplants reported to the University of California, Los Angeles, Transplant Registry. One- and 10-year graft-survival rates as well as late (from 3 through 10 years) graft-loss rates (half-lives) were determined. The donor-recipient relationship had the greatest influence on long-term graft survival. Transplants between HLA-identical siblings had graft-survival rates of 89% at 1 year and 68% at 10 years, compared with 76% and 43% for parental donors, and 58% and 26% for cadaver donor transplants, respectively. These differences were also evident from the graft half-lives, which were 22 years for HLA-identical sibling, 12 years for parental, and 8 years for cadaver donor allografts. In cadaver donor transplants, matching for HLA-A,B antigens had the greatest influence on long-term graft survival, with a 15% 10-year graft survival (39% vs. 24%) and 7-year half-life (14 vs. 7 years) advantage seen with the best (zero HLA-A,B mismatches) compared with the worst (4 HLA-A,B) cases, respectively. Some of the factors studied, such as transplant number and pretransplant transfusions, tended to influence the short- rather than long-term graft-survival rates. Others, including HLA-A,B matching, early graft function and the recipient's original disease, influenced both early and late graft survival. Over all, histocompatibility between donor and recipient had by far the greatest influence on the long-term success of renal allografts.

The sera of 45 hypersensitized patients with more than 90% panel reactive antibodies were tested for reactivity against peripheral blood T lymphocytes from 7 donors matched for HLA-A,B antigens. The target cells were phenotypically homozygous HLA-A1,B8 or A2,B44. Tests for lymphocytotoxic antibodies were essentially negative except for one target cell in which 10 of 25 sera were positive. More positive reactions were detected by flow cytometry, and the proportion of positive specimens ranged from 15% to 48% with the different target cells. Most positive reactions involved the HLA-A2 and B44 antigens, in which heterogeneity within the serologically defined specificities has been described. The positive reactions were further evaluated by testing the effect of purified soluble HLA molecules on the binding of antibodies to the HLA-marched targets. Purified HLA produced a detectable inhibition of antibody binding in the majority of the serum-target combinations studied. These results document that anti-HLA antibodies can still react with HLA-matched lymphocytes, which may be due to the recognition of subtypes of the known serologically defined specificities.