We used the Collaborative Transplant Study database to analyze the incidence, risk, and impact of malignant lymphomas in approximately 200 000 organ transplant recipients. Over a 10-year period, the risk in renal transplant recipients was 11.8-fold higher than that in a matched nontransplanted population (p < < 0.0001). The majority of lymphomas were diagnosed after the first post-transplant year. Heart-lung transplants showed the highest relative risk (RR 239.5) among different types of organ transplants. In kidney recipients, immunosuppression with cyclosporine did not confer added risk compared with azathioprine/steroid treatment, whereas treatment with FK506 increased the risk approximately twofold. Induction therapy with OKT3 or ATG, but not with anti-IL2 receptor antibodies, increased the risk of lymphoma during the first year. Antirejection therapy with OKT3 or ATG also increased the risk. First-year mortality in renal and heart transplant patients with lymphoma was approximately 40% and 50%, respectively, and showed no improvement in recent years. A pattern of preferential localization to the vicinity of the transplant was noted, and the prognosis of the patient was related to localization. This study highlights the continuing risk for lymphoma with time post-transplantation, the contribution of immunosuppression to increased risk, and continuing poor outcomes in patients with post-transplant lymphoma.
Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed in certain cells and tissues, particularly in antigen-presenting cells of lymphoid organs and in the placenta. It was shown that IDO prevents rejection of the fetus during pregnancy, probably by inhibiting alloreactive T cells, and it was suggested that IDO-expression in antigen-presenting cells may control autoreactive immune responses. Degradation of tryptophan, an essential amino acid required for cell proliferation, was reported to be the mechanism of IDO-induced T cell suppression. Because we wanted to study the action of IDO-expressing dendritic cells (DCs) on allogeneic T cells, the human IDO gene was inserted into an adenoviral vector and expressed in DCs. Transgenic DCs decreased the concentration of tryptophan, increased the concentration of kynurenine, the main tryptophan metabolite, and suppressed allogeneic T cell proliferation in vitro. Kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, but no other IDO-induced tryptophan metabolites, suppressed the T cell response, the suppressive effects being additive. T cells, once stopped in their proliferation, could not be restimulated. Inhibition of proliferation was likely due to T cell death because suppressive tryptophan catabolites exerted a cytotoxic action on CD3+ cells. This action preferentially affected activated T cells and increased gradually with exposure time. In addition to T cells, B and natural killer (NK) cells were also killed, whereas DCs were not affected. Our findings shed light on suppressive mechanisms mediated by DCs and provide an explanation for important biological processes in which IDO activity apparently is increased, such as protection of the fetus from rejection during pregnancy and possibly T cell death in HIV-infected patients.
A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.
Immunological rejection is the most important cause of kidney transplant failure. Recently, nonimmunological causes of long-term allograft failure have become more widely appreciated. In primary chronic renal disease, blood pressure is of overriding importance for long-term renal function. The role of blood pressure in determining long-term transplant outcome has not yet been established. We studied the influence of blood pressure post-transplantation on long-term kidney graft outcome in 29,751 patients. Outpatient blood pressure measurements were recorded and reported to the Collaborative Transplant Study. Graft and patient survival rates were analyzed over seven years in relation to blood pressure. Increased levels of systolic and diastolic blood pressure post-transplantation were associated with a graded increase of subsequent graft failure (P < 0.0001). Chronic graft failure was significantly associated with blood pressure even when patient death was censored (P < 0.0001). Cox regression analysis established increased blood pressure as an independent risk factor for graft failure. We conclude that post-transplant blood pressure is a highly significant predictor of long-term kidney graft outcome. Whether aggressive lowering of blood pressure improves long-term transplant outcome will have to be studied prospectively.
Presensitization of kidney-transplant recipients against MICA antigens is associated with an increased frequency of graft loss and might contribute to allograft loss among recipients who are well matched for HLA.
ABSTRACT. Differences in actuarial graft survival according to donor gender have been reported for renal allografts and for cardiac and hepatic allografts, but for the latter in small series with limited biostatistical power. Using the large database of the Collaborative Transplant Study (CTS), this study is an evaluation of graft survival according to donor and recipient gender for renal (n = 124,911), cardiac (n = 25,432), and hepatic (n = 16,410) transplants. Confounders, such as calendar year, geographical area, race, donor and recipient age, HLA mismatch, cold ischemia time, and others, as well as interaction terms were taken into consideration. Death-censored actuarial renal allograft survival from female compared with male donors was less in female recipients and even more so in male recipients. The donor gender-associated risk ratio for graft loss was 1.15 in female recipients and 1.22 in male recipients. The age-gender interaction term was statistically significant, the gender effect being more pronounced for younger (16 to 45 yr) compared with older (>45 yr) donors. Serum creatinine concentrations 1 yr after transplantation were also higher for recipients with kidney grafts coming from female donors irrespective of recipient gender. For first cardiac transplants, graft survival was inferior when the donor was female and the recipient male, but no statistical difference according to donor gender was demonstrable in female recipients. For first hepatic transplants overall, no significant differences according to donor gender were noted. The proportion of recipients who had treatment for rejection crisis during the first year was higher for male recipients of kidneys from female donors compared with male donors. No difference according to donor gender was demonstrable in female recipients. For cardiac and hepatic grafts, no significant effect of donor gender on the proportion of patients treated for rejection episodes was noted. The data show that adverse effects of female donor gender for different organs is much less uniform than reported in the past. An important confounder is donor age. A gender effect on graft survival is also observed for cardiac allografts. Therefore, in addition to potential “nephron underdosing,” further pathomechanisms must play a role, possibly differences in immunogenicity according to donor gender. E-mail: martin_zeier@med.uni-heidelberg.de
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