Differential kidney graft survival associated with interaction between recipient ABO group and pretransplant blood transfusion.

In 1973 we reported significantly superior survival of kidneys transplanted to blood group O recipients compared with recipients of those from blood groups A, B, and AB taken together. In this extended series, the difference between these categories was less prominent and no longer significant. In the present study, blood transfusion significantly improved the survival of kidney grafts in patients of blood group O, but not of combined A, B. and AB groups. The difference between the graft protecting effect of transfusion in group O and combined groups A, B, and AB recipients was also significant. This suggests that the improvement in subsequent graft survival after transfusion is either confined to blood group O recipients, or is much stronger in them than in recipients of other groups. Our previous policy of restriction of blood transfusion is seen as one of the causes of the reduced superiority of group O over other groups in this extended series in comparison with our 1973 series. It seems that transfusion of group O recipients can markedly improve the prognosis of a subsequent first kidney graft.     

Induction of a subpopulation of suppressor cells by a single blood transfusion.

Blood transfusion induces immunosuppression by a mechanism which is probably multifactorial and, in large part, obscure. In this study cellular immune suppression was examined in patients with end-stage renal disease (ESRD) following a single blood transfusion (BT). OKT8+ cells proliferated within four hours, their count increasing significantly, and reached their peak after four days. Since OKT4+ cells tended to decrease, the OKT4/OKT8 ratio declined significantly from the fourth day. Evidence in support of the above results is offered in studies on ability of concanavalin A reagent (ConA)-activated T cells to form autorosettes with human red blood cells (RBC); these T cells have been shown to function as suppressor effector cells. Autorosetting cells (RFC) proliferated in a similar pattern to OKT8+ cells. Moreover, the percentage of rise at one and two weeks of OKT8+ and RFC correlated directly, suggesting that the proliferating OKT8+ cells are in large part a subset of suppressor cells. Functional studies were performed to establish the suppressor activity of T cells before and at various times after blood transfusion. A significant increase in T cell ConA-induced suppressor activity was found one week after BT, peaking at two weeks following BT. Monocytes increased significantly from day 4 following BT, but prostaglandin E2 (PGE2) started to rise immediately, peaking at day 4. PGE2 might induce suppression by induction of suppressor cells or by direct suppression of interleukin-2. Both monocytes and suppressor cells respond immediately, but they probably induce suppression most effectively four days or more after BT.     

Pretransplant dialysis and blood transfusion--correlation with cadaveric kidney graft survival.

Renal graft survival was better for the patients receiving blood transfusions or treated with dialysis before transplantation. Graft survival was more strongly correlated with pretransplant dialysis than with blood transfusion.     

Suppression of antibody response and prolongation of skin graft survival by multiple blood transfusions in the rat

The effect of blood transfusions (BT) on antibody response and skin graft survival was studied in the strongly MHC-incompatible BN and LEW combination. One-to-three BT induced high titer antibodies. Additional BT, however, led to a decrease of antibody titers. After 15 BT the recipients either had no detectable antibodies, or they had very low antibody titers. This suppression of response was shown to be distinct from a simple loss of antibody activity caused by lack of further antigenic challenge. In multiple transfused rats, humoral nonreactivity persisted in spite of rechallenge with antigen; in animals that lost their antibodies as a result of lack of further stimulation, an additional BT boosted strong antibody production. In LEW recipients of multiple BN transfusions, not only the specific anti-BN response but also reactivity to third-party BUF blood was suppressed. However, whereas the donor-specific response (anti-BN) was largely inhibited after a ten-week interval, the response to third-party BUF blood recovered. The state of humoral nonreactivity could be transferred by spleen cells to nontransfused syngeneic animals. In LEW rats that received three injections of 5 X 10(7) "suppressor" spleen cells, the antibody response to BN blood was strongly impaired as compared with animals that received normal spleen cells. BN or (BN X LEW)F1 skin grafts survived significantly better in multiple transfused LEW rats than in nontransfused controls. This was even more pronounced when ALS was given additionally. Third-party grafts (BUF) survived only slightly better than controls. It is concluded that multiple BT (1) result in humoral anti-donor nonreactivity secondary to an initial antibody response, (2) induce strong specific and weak nonspecific suppressor cell activity, and (3) increase skin graft survival.     

Blood transfusions, cytotoxic antibodies, and kidney graft survival. Preliminary results of a systematic transfusion protocol.

Since pretransplant blood transfusions have been shown to prolong the survival of kidney grafts, a new transfusion policy has been started in the frame of Swisstransplant. Before surgery all patients receive at least two and, if possible, five transfusions (whole blood or packed red blood cells). The present study includes 101 recipients of primary cadaver grafts. Of these, 41 were transfused regularly according to the new protocol, 46 had irregular transfusions because of therapeutic necessity, and 14 had no transfusion before grafting. The 1-year survival rate in pretransfused patients was over 70% as compared to 45% in the nontransfused group. There was no significant association with the number of transfusions, but a slight improvement in graft survival was seen in patients deliberately transfused when compared with those transfused because of severe anaemia. A delay of more than 3 months between the last transfusion and transplantation significantly decreased graft survival at 6 months (84 versus 58%; P less than 0.02). The occurrence of cytotoxic antibodies, both antiperipheral blood lymphocytes (PBL) and anti-B cell antibodies, was investigated in relation to the number of transfusions received. Broad-spectrum anti-PBL antibodies (greater than 50% of random panel) were found in 5 of 74 patients transfused according to the protocol (7%) and in 15 of 93 patients transfused for severe anaemia (16% P, not significant). Of 71 recipients followed up for 6 months, 15 (21%) produced anti-PBL antibodies with limited specificity (less than 50%), and 4 (6%) produced broad-spectrum antibodies. Anti-B cell antibodies (less than 50%) were produced in 21 of 64 patients (33%). Six patients (9%) had broad-spectrum activity. The occurrence of these antibodies was not associated with the number of transfusions received and did not significantly influence the graft survival at 6 months. The change in transfusion policy seems to have improved graft survival without producing strong presensitization in a prohibitive proportion of the patients on hemodialysis.     

Immunological studies on renal transplantation in rats. Effects of pretransplant blood transfusion on renal graft survival

An attempt was made to search the mechanism underlying the beneficial effect of blood transfusion effects using the rat renal transplantation model. The mean survival time of (Sprague-Dawley (SD X Wistar)) F1 renal grafts in untreated SD recipients was 11.3 days. Treatment to SD recipients with 1 ml of Wistar whole blood 7 to 21 days prior to transplantation prolonged the mean survival time of (SD X Wistar) F1 renal grafts and maximum effect of prolongation (greater than 81.3 days) was seen when renal transplantation was performed on the 9th day after the treatment. Treatment with Wistar bone marrow cells, red blood cells and platelets 9 days before transplantation prolonged the mean survival time to greater than 41.0 days, greater than 39.3 days and greater than 46.9 days, respectively, whereas no significant effect was observed in the SD recipients pretreated with Wistar thymocytes or with Wistar plasma. Third party blood transfusion also had moderate effects on the prolongation of renal graft survival, but maximum effects of blood transfusion were obtained by donor specific blood transfusion. Sera taken from SD rats at various times after the treatment with Wistar whole blood were assayed for their ability to suppress the mixed leukocyte reaction (MLR) of SD responder and (SD X Wistar) F1 stimulator cells. Suppressor activity rapidly increased with time up to 7 days after blood transfusion. Potent suppression of the MLR was observed with sera obtained between 7 and 15 days after the treatment. Thereafter, suppressor activity gradually decreased but sera obtained even 21 days after the treatment still suppressed the MLR by more than 50%. The experimental results suggest that MLR suppressor factor(s) generated in the recipients by blood transfusion may play an important role in preventing renal graft rejection. Furthermore, not only class II antigens but also class I antigens in the transfusate may be relevant to the immune response which causes a beneficial effect by pretransplant blood transfusion.     

Influence of a single blood transfusion on kidney allograft survival in unrelated rhesus monkeys.

A prospective study was performed in moderately immunosuppressed unrelated rhesus monkeys to investigate the influence of a single transfusion on kidney allograft survival. The recipients received either whole citrated blood or plasma-free transfusates consisting of pure red blood cell or lymphocyte suspensions. Except for one group, in which blood and kidney donors were optimally matched, transfusions and kidney allografts were disparate for two to four A/B locus antigens with the recipients. Transfusions were given 2 to 4 weeks before kidney grafting, except in one experimental group where the recipients were transfused 0 to 12 hr before transplantation. The general trend was that graft prolongation could be obtained with all experimental protocols. However, it was also shown that a single transfusion entails the risk of accelerated rejection. This adverse effect was not observed in the animals receiving blood and kidneys from donors optimally matched for A/B locus antigens and in recipients transfused shortly before or during transplantation. These results may contribute to a further improvement of the current clinical transfusion policy.     

Planned random donor blood transfusion in preparation for transplantation. Sensitization and graft survival

Random donor blood transfusions were used to prepare 183 prospective recipients for one-haplotype living-related donor (LRD) grafts or cadaver donor (CD) grafts. Five units of packed red blood cells were administered over a 7-10 day period, and weekly sera were monitored for six weeks. Sensitization was uncommon in men and nulliparous women (8/153), was of low reactivity, and was not a barrier to transplantation. Multiparous women had a 44% frequency of sensitization on presentation and 11/24 initially lacking cytotoxicity developed reactive serum following transfusion. Single-haplotype LRD recipients had 96% one-year graft survival. CD recipients had one-year graft survival of 72%. The rate of transplantation in surviving candidates exceeded 90%, and supports the hypothesis of a protective immune response.     

Suppression of antibody response to transfusions in rats by preconditioning with antibody-coated cells

In a Lewis-BN rat model, the antibody response to transfused blood cells from strongly histoincompatible donors was suppressed by preincubation of blood with specific antidonor antiserum or broadly reactive heterologous antilymphocyte serum (ALS). Suppression was achieved even when excess antiserum was removed by washing prior to injection. The suppressive effect was dose-dependent. Broadly reactive ALS was even more effective than specific antidonor antiserum in inhibiting the primary antibody response. Lewis animals pretreated three times with ALS-coated BN blood showed no secondary antibody response against subsequent BN-blood booster injections. Our experiments may be relevant for the prevention of undesired sensitization to donor-specific transfusions prior to related donor kidney transplantation.     

The role of macrophage lineage cells in kidney graft rejection and survival

Large numbers of macrophage lineage cells are present in transplants undergoing ischemia-reperfusion injury and rejection, and their presence correlates with a high probability of rejection. However, the extent to which monocytes and macrophages contribute to kidney graft rejection is poorly understood. The heterogeneity of the monocyte/macrophage lineage cells could be one of the reasons why these cells have been neglected up to now. Circulating monocytes can be divided into various subsets, which are able to give rise to tissue macrophages and dendritic cells. Macrophages are believed to be highly plastic cells that can respond to environmental signals by changing their phenotype and function. Macrophages have established roles in early and late kidney graft inflammation, tissue homeostasis, remodeling, and repair. In kidney transplantation, macrophages are believed to play a role in both damage and repair of the graft, depending on the type of macrophages involved, the environmental drive, and the time after transplantation. The heterogeneity and plasticity of monocytes and macrophages are obstacles to translating the functional relevance of this cell lineage to diagnostic and prognostic clinical parameters and to defining specific, macrophage-related, therapeutic targets. Recent evidence has indicated an immunomodulatory role for the so-called regulatory macrophages in induction of tolerance in kidney transplant recipients. In this article, we summarize current views on monocyte/macrophage immunobiology in kidney transplantation. Key issues for ongoing research are discussed.