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Background: Preexisting IgG antibodies to donor human leukocyte antigens (HLA) are a risk factor for rapid allograft rejection. However, non-HLA antibodies, of the IgM class, also called autoreactive antibodies, are not believed to affect graft survival. The aim of this study was to determine the incidence and clinical relevance of pretransplant lymphocytotoxic non-HLA IgM antibodies on long-term cardiac allograft survival., Methods: A retrospective study of 616 adult recipients of cardiac allografts, transplanted at this center between 1991 and 2003, has been performed. Antibodies in pretransplant sera were initially defined using complement-dependent cytotoxicity assays, and subsequently analyzed for HLA specificities using solid phase assays., Results: HLA antibodies were present in 69 of 616 heart recipients (58 IgG, 11 IgM); in 22 of these, the antibodies were donor-specific. Non-HLA IgM antibodies were detected in 59 of 616 recipients who did not have HLA-specific antibodies; these patients had a 1, 2, 5, and 10 year survival of 55.9%, 54.2%, 49.9%, and 43.3% compared with 75.8%, 73.7%, 66.6%, and 52.8% for those without antibodies (P=0.0085 log-rank test). Multivariate analysis demonstrated pretransplant non-HLA IgM antibodies to be an independent risk factor for mortality (P=0.0001). Myocardial histology of postmortem heart and cardiac biopsies suggested an association with ischemic damage and "primary" allograft failure., Conclusions: We propose the hypothesis that the presence of cytotoxic IgM antibodies to non-HLAs before heart transplantation maybe a risk factor for early allograft failure.

Background: Surveillance endomyocardial biopsies (EMBs) are used for the early diagnosis of acute cardiac allograft rejection. Protocols became standardized in an earlier era and their utility with contemporary immunosuppression has not been investigated., Methods: We studied 258 patients after orthotopic heart transplantation comparing 135 patients immunosuppressed by mycophenolate mofetil (MMF) with 123 patients treated by azathioprine (AZA); both with cyclosporine and corticosteroids after induction therapy with rabbit antithymocyte globulin. Fifteen EMBs were scheduled in the first year. Additional EMBs were performed for suspected rejection, after treatment, or for inadequate samples. The MMF group had 1875 EMBs vs. 1854 in the AZA group., Results: The yield of International Society for Heart and Lung Transplantation (ISHLT) grade> or =3A biopsy-proven acute rejection (BPAR) was 1.87% per biopsy (35 of 1875) with MMF vs. 3.13% (58 of 1854) with AZA P=0.024. The number of clinically silent BPAR ISHLT grade > or =3A (the true yield of surveillance EMBs) was 1.39% (26 of 1875) of biopsies MMF vs. 2.1% (39 of 1854) AZA, P=0.48. There were five serious complications requiring intervention or causing long-term sequelae; 0.13% (5 of 3729) per biopsy and 1.94% (5 of 258) per patient. The incidence of all definite and potential complications was 1.42% (53 of 3729) per biopsy and 20.5% (53 of 258) per patient. There was no biopsy-related mortality., Conclusion: The yield of BPAR was low in the AZA group and very low in the MMF group. The incidence of complications was also low, but repeated biopsies led to a higher rate per patient. Routine surveillance EMBs and the frequency of such biopsies should be reevaluated in the light of their low yield with current immunosuppression.

Background: Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation., Method: In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction., Results: By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133+/-45 vs. 155+/-46 micromol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74+/-32 mL/min vs. AZA 62+/-24 mL/min, P=0.004)., Conclusion: Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.

Background: It has been known for more than 20 years that there is an increased risk of lymphoid neoplasia after cardiothoracic transplantation. Recent studies have demonstrated the importance of primary Epstein-Barr virus (EBV) infection and type of immunosuppressive therapy to the cause of these neoplasms, but the contribution of other factors remains equivocal., Methods: The authors followed 1,562 patients undergoing cardiothoracic transplantation at Harefield Hospital, United Kingdom, and used standard cohort methods of analysis to examine whether posttransplant lymphoma risk was related to the underlying disease requiring transplantation or the human leukocyte antigen (HLA) type and matching. Lymphomas were categorized into EBV-associated lymphoproliferative disease (LPD) and EBV-negative non-Hodgkin's lymphoma (NHL), and the authors carried out separate analyses of these., Results: The authors found no significant association between the underlying disease necessitating transplantation and the risk of lymphoid neoplasia. There was also no evidence of a relation of lymphoma risk with the presence or absence of any particular HLA antigen, although significant protective effects of HLA-B14 and -B57 were found when analyses were conducted without adjustment for multiple testing. Risk of LPD was not associated with degree of HLA mismatching, but there was a significant effect of mismatching on risk of EBV-negative tumors., Conclusions: The differential effect of HLA mismatching on the risks of LPD and EBV-negative NHL provides further evidence that these two tumors are distinct etiologic entities. The authors' results suggest that the immunologic cause of EBV-negative NHL may be different from that of LPD. Investigation of the relation of risk of EBV-negative NHL to degree of immunosuppression is needed.

Background: Organ transplantation is associated with a greatly increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD), which is often fatal. There has been little epidemiological analysis, however, of the risk factors for LPD in transplant patients and none on whether the risks of non-EBV-associated lymphoid neoplasms are also increased., Methods: The risk of lymphoid neoplasia was assessed in a cohort of 1563 patients who underwent cardiothoracic transplantation at Harefield Hospital, UK from 1980 to 1994 and were followed until December 1995. EBV antibody was assessed in the patients before transplantation, and lymphoid neoplasms were assessed for EBV RNA and latent EBV gene expression., Results: Thirty cases of LPD occurred during follow-up. One lymphoma of unknown EBV status occurred. There were also six cases of EBV-negative non-Hodgkin's lymphoma (EBV-negative NHL), a highly significant excess over expectations from the general population rates of NHL (standardized incidence ratio 10.2 [95% confidence interval, 4.6-22.8]). The risk of LPD was significantly 10-fold raised in individuals who were EBV seronegative before transplantation; independently of this, it decreased steeply with age at transplantation and was greatest in the first year after transplantation. The risk was significantly raised in young seronegative recipients if the donor was older than the recipient. EBV-negative NHL occurred entirely in men 45 years old and older who were EBV seropositive before transplantation, and risk was not related to duration since transplantation., Conclusions: The risk factors found for LPD accord with EBV etiology and with greater hazard from primary infection than from reactivation. A second non-Hodgkin's lymphoid neoplasm, not related to EBV, seems also to be a consequence of transplantation and immunosuppression but is unlikely to be due to first infection by a ubiquitous agent. Its etiology and prevention need investigation separately from LPD.

The frequency of donor-reactive cytolytic T lymphocytes was measured in the peripheral blood mononuclear cell population of a group of 12 cardiac allograft recipients immediately before and at various time points after transplantation. At each of the time points after transplantation the donor heart was biopsied and the rejection status of the graft was determined by applying standard histological criteria. The results of this study showed that the preoperative frequency of donor-reactive cytolytic T lymphocytes in the blood was not predictive of a future tendency toward graft rejection. However, when all the data were examined it was apparent that the frequency of donor-reactive cytolytic T lymphocytes was significantly higher (P less than 0.05) in blood samples from patients whose simultaneous biopsy showed histological evidence of acute cardiac allograft rejection than in blood samples from transplant patients showing no evidence of rejection.