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Despite the introduction of new immunosuppressive agents, a steady decline of functioning renal allografts after living donation is observed. Thus nonpharmacological strategies to prevent graft loss have to be reconsidered, including donor-specific transfusions (DST). We introduced a cyclosporine-based DST protocol for renal allograft recipients from living-related/unrelated donation. From 1993 to 2003, 200 ml of whole blood, or the respective mononuclear cells from the potential living donor were administered twice to all of our 61 recipient candidates. The transplanted subjects were compared with three groups of patients without DST from the Collaborative Transplant Study (Heidelberg, Germany) during a 6-year period. Six patients were sensitized without delay for a subsequent cadaveric kidney. DST patients had less often treatment for rejection and graft survival was superior compared with subjects from the other Swiss transplant centers (n = 513) or from Western Europe (n = 7024). To diminish the probability that superior results reflect patient selection rather than effects of DST, a 'matched-pair' analysis controlling for relevant factors of transplant outcome was performed. Again, this analysis indicated that recipients with DST had better outcome. Thus, our observation suggests that DST improve the outcome of living kidney transplants even when modern immunosuppressive drugs are prescribed.

Background: A beneficial effect of pretransplant transfusions on graft survival was demonstrated in the early 1970s. In the mid-1980s, however, retrospective studies showed that transfusions had lost their graft-protective effect in the cyclosporine era. During the last 10 years, deliberate transfusion pretreatment of transplant patients has been discontinued., Methods: Within a collaborative project of 14 transplant centers, prospective recipients of cadaver kidney grafts were randomized to receive either three pretransplant transfusions or transplants without transfusions. RESULTS; The graft survival rate was significantly higher in the 205 transfusion recipients than in the 218 patients who did not receive transfusions (at 1 year: 90+/-2% vs. 82+/-3%, P=0.020; at 5 years: 79+/-3% vs. 70+/-4%, P=0.025). Cox regression analysis showed that this effect was independent of age, gender, underlying disease, prophylaxis with antilymphocyte antibodies, and preformed lymphocytotoxins. CONCLUSIONS; Transfusion pretreatment improves the outcome of cadaver kidney transplants even with the use of modern immunosuppressive regimens.

To assess the effect of pretransplant blood transfusions on the outcome of cadaveric kidney transplantation, a single-centre analysis was performed of 171 patients randomly assigned to receive no pretransplant transfusion (n = 85) or to receive at least three random blood transfusions (n = 86). After transfusion 18 of the latter patients developed circulating lymphocytotoxic T-cell antibodies, but the sensitization was only transient. At the time of transplantation, none was still sensitized. In both groups 60 patients have been transplanted. Patient and graft survival rates were significantly higher in the transfused group than in the non-transfused group. In the non-transfused patients the higher mortality was due to complications related to repeated anti-rejection therapy. Non-transfused patients had more repeated acute rejection episodes than the transfused patients. The present study indicates that pretransplant blood transfusions still facilitate graft acceptance even in the setting of good HLA matching and with cyclosporine as the basic immunosuppressant. The risk of sensitization is very low.

Our previous studies showed that a broadly reactive immunoglobulin G (IgG) anti-immunoglobulin (IgG-anti-Ig) autoantibody is induced during the immune response of LEW rats to BN blood cells. The present experiments analyze the immunoregulatory effect of this physiological autoantibody on antigen receptor-activated B cells in cell cultures. The results show that: (a) At 0.9 pg IgG-anti-Ig/10(6) B cells, an almost complete suppression of the antibody response is induced: we calculated that a few IgG-anti-Ig molecules are sufficient to suppress the antibody response of one B cell; (b) IgG-anti-Ig-induced B-cell suppression is dose-dependent; (c) IgG-anti-Ig suppresses B cells contained in their natural environment (mixed spleen cell population). These data demonstrate that the IgG-anti-Ig autoantibody is an extremely efficient regulatory molecule of the alloimmune response.

The prevalence of anti-HCV in patients after kidney transplantation was tested by HCV-Antibody-ELISA (Ortho Diagnostics). In addition, reactive samples were tested by HCV-EIA (Abbott Laboratories), neutralization, anti-HBc (Corzyme, Abbott) and by HBs-Ag (Auszyme, Abbott). 27 of 271 patients (10%) were anti-HCV positive. Receiving more than one kidney graft (TPL) or the transfusion of more than four blood units (BU) increases the risk of HCV infection four times (OR: 4.1; p less than 0.01) or 2.5 times (OR: 2.5; p less than 0.05), respectively, compared with one TPL or less than 4 BU. Receiving more than one kidney graft and transfusion of more than four BU raises the risk of HCV infection 6.8 times. 52% of anti-HCV positive patients were anti-HBc positive, 48% were anti-HBc negative as well as HBs-Ag negative.

The outcome of 684 cadaver kidney transplants in recipients who had never been transfused was compared to that in 371 recipients who had been transfused only preoperatively. No significant difference in graft survival was observed. Peroperative transfusions were ineffective regardless of their number or the type of blood product. These results contradict a recent report on the benefits of peroperative transfusions. Transfusions given before transplantation continued to show a striking graft improvement effect in a new series of 538 transplants performed in 1979.

In order to select MLC incompatible one-haplotype related donor-recipient pairs that would achieve better graft survival and in an effort to alter the recipient immune response, 45 patients received three fresh blood transfuions from their prospective kidney donors. Recipient sensitization was evaluated by cross-match testing weekly sera obtained during and after the blood transfusions against donor T- and B-lymphocytes at 5 C (cold) and 37 C (warm). Thirteen (29%) of the 45 potential related recipients developed a positive warm T-cell cross-match or a persistent warm B-cell cross-match to their blood donor and related transplantation was not performed. Thirty-two (71%) patients had an appropriate negative cross-match to their blood donor. Thirty of these patients subsequently received kidneys from their blood donor. Ninety-seven per cent of the kidneys are functioning from one to 25 months with a single graft failure due to a patient discontinuing immunosuppressive medication. In addition to the excellent graft survival there was an unusually low incidence of rejection episodes in the recipients of kidneys from their blood donor so that the posttransplant course paralleled that of HLA-identical siblings. This approach may have future application with two-haplotype mismatched donor-recipient pairs, both related and unrelated.

The benefits of successful kidney transplants for patients with end stage renal disease associated with insulin-dependent diabetes mellitus are well known, and the potential advantages of earlier transplantation have been emphasized in other reports. Cadaver transplants, which are not always available for these patients, have not provided a high degree of success in many centers. This has discouraged the use of transplants unless well matched related donors are available. Most patients do not have well matched family members who are able to donate. We have attempted to increase the availability of related transplants for diabetic patients by using a new protocol in which related donors who are poorly matched by mixed lymphocyte culture (MLC) testing (stimulation index (SI) greater than or equal to 7) can often serve as the source of the transplant. This protocol of pretransplant donor-specific transfusions (DSTs) has been applied to 20 diabetic patients. Sixteen transplants have been performed after serial immunological studies following the DSTs detected no specific evidence of recipient sensitization to the respective transfusion donors. Only one of the transplants has been rejected, and this occurred in a patient who intentionally terminated immunosuppressive therapy. Graft survival for the group of 16 patients is 93 and 84% at 1 and 3 years, respectively. The quality of renal function for most of the patients is very good, with a mean serum creatinine of 1.9 and 1.5 ml/dl for those transplants at risk for 12 and 24 months. This new method has given encouraging results for poorly matched related transplants in diabetic patients and makes earlier transplantation possible by providing an alternative to cadaver transplants.

In 33 centres that adopted a policy of liberal preoperative blood transfusion 174 recipients of cadaver donor transplants were followed up. Those who received no pretransplant transfusions had a 23% 1-year graft survival rate whereas those who had greater than 10 transfusions had an 87% survival rate (p less than 0.000001). 3% of those transfused acquired highly reactive cytotoxic antibodies and greater than 70% had no antibodies, so transfusions do not exert their beneficial effect by excluding strong immune responders. Since transplant survival rates improved with the number of transfusions, they probably produce their beneficial effect by inducing a state of unresponsiveness. Multiple transfusion seems a simple and effective way of improving kidney transplant survival rates. Moreover, the immunosuppressive effect is specific in that it does not alter the immune response to infectious agents.

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.

A series of 737 hemodialysis patients were studied for the relationship between lymphocytotoxic antibody formation and blood transfusions; 331 thereof were studied prospectively. With up to 20 transfusions, highly reactive (greater than 90% reactivity against random panel) antibodies were not found in any of the prospectively studied males or females without previous pregnancies. Nearly 90% of the males failed to form antibodies against greater than 10% of the panel donors. Patients with previous pregnancies developed antibodies at a much higher rate. Among 316 patients tested, antibodies against B cells were found more frequently than antibodies against T cells. Both T and B cell antibody levels often decreased in spite of additional transfusions. It is concluded that the risk of rendering a patient untransplantable because of sensitization as a result of transfusions is very small.

Transfusion with antibody-coated allogeneic blood cells suppresses the cytotoxic antidonor antibody response in a strongly incompatible rat combination (BN----LEW). Cell coating with homologous recipient antidonor antiserum, rat monoclonal antibodies against MHC class I donor antigens, or rabbit antirat lymphocyte serum all were effective. The suppression was not abrogated by repeated booster transfusions with untreated donor blood. Moreover, the suppression extended to antibody-uncoated antigens present on the same donor cell. Not only the antibody response but also the Graft-versus-host reaction against donor antigens was suppressed. The serum of pretreated animals contained suppressive activity. It suppressed the cytotoxic antibody response as well as the cellular immune response (GVH) when transferred into syngeneic recipients. A weaker suppression of antibody response was obtained by transferring spleen cells of pretreated animals into syngeneic recipients. The transfer data suggest that broadly reactive serum factor(s) were mainly responsible for the suppressive effect. Transfusion with LEW-anti-BN-coated donor cells before transplantation induced markedly prolonged kidney graft survival in the BN----LEW combination without additional immunosuppression (untreated controls: 8.4 +/- 0.4, pretreated recipients: 124 +/- 36 days, P less than 10(-4)).

Pre-transplant blood transfusions (BT) improve the survival of kidney grafts. Apart from specific immunoregulation by T suppressor cells or anti-idiotypic antibodies, the role of non-specific immunoregulatory factors, such as prostaglandins is being discussed as a possible mechanism for this effect. We studied the in vitro prostanoid release from peripheral mononuclear cells following three deliberate blood transfusions. Twenty-five previously non-transfused dialysis patients were studied. Spontaneous and LPS-induced prostaglandin E (PGE) and thromboxane B2 (TXB2) were determined in cell-free culture supernatants by fluid phase RIA. Transfused patients exhibited a more rapid onset and steeper increase of prostanoid production. After 24 hours incubation, the spontaneous and LPS-induced PGE release of pre- and post-BT cells was significantly different (pre-BT: 2.1 and 5.1 ng/ml; post-3-BT: 5.0 and 7.9 ng/ml; p less than 0.01). Pre-BT cells released considerably lower amounts of TXB2 than post-BT cells (spontaneous release: 39 vs 88 ng/ml; LPS-induced release: 62 ng/ml vs 129 ng/ml; p less than 0.05). After correction for monocytes as defined by monoclonal antibodies, post-BT cells again showed increased prostanoid release as compared to pre-BT cells. Therefore, the enhanced PGE and TXB2 release of post-BT cells is not caused by an increase merely in the number of monocytes. Rather, BT appear to induce an enhanced release of prostanoids by activation of monocytes. We also found a correlation between the number of BT and the amount of prostanoid release.

In this study, pretransplant transfusions significantly improved the survival of first cadaver kidney transplants. Large numbers of transfusions had the same influence on graft survival as small number of transfusions. Graft survival was not influenced by pretransplant antibody levels, and the beneficial effect of transfusions was also independent of highest pretransplant antibody levels. The positive relationship between transfusions and cytotoxic antibodies was shown to be highly significant. B-warm and T-warm antibodies were both increased by transfusions and tended to occur together. B-cold antibodies occurred independent of transfusions, B-warm and T-warm antibodies. The results of this study suggest, but do not confirm, that B-cold antibodies benefit graft survival, while T-warm antibodies adversely influence graft survival. Transfusions and B-cold antibodies appear to influence graft survival by different mechanisms.

The number of pretransplant blood transfusions influences the graft survival of cadaver kidney transplants more than HLA-A and B matching, preformed lymphocytotoxic antibodies, or center variation. At 1 year the graft survival rate in patients with more than 20 packed cells transfusions was over 30% higher than that in nontransfused recipients (75 +/- 5% versus 41 +/- 2%, P less than 0.0001). Recipients with on packed cell transfusion had a 59 +/- 5% 1-year graft survival rate. Frozen blood and any transfusions given at the time of surgery were relatively ineffective. Pretransplant pregnancies had no significant effect on graft outcome. The improvement effect of transfusions was significant in each of the last four calendar years (1975, P less than 0.001; 1976, P less than 0.01; 1977, P less than 0.0001; 1978, P less than 0.0001). Yet, the percentage of nontransfused recipients has remained almost unchanged over the years. A preliminary survey of transplants done from January to April 1979 showed that one-third of the recipients had not been transfused. A change in transfusion policy is indicated to improve the results of cadaver kidney transplantation.

Transfusion data were collected during a 3-year period on 382 hemodialysis patients with the aid of a computerized followup system. Thirty-seven per cent of the patients did not receive any blood transfusions prior to transplantation. The graft survival in nontransfused patients was statistically significantly lower than that in transfused patients. These results confirm our previous findings in an independent series of patients.

It has been shown that kidney transplant graft survival rates were lower among nontransfused patients than among those receiving transfusions. In a relatively small series of 49 patients who received frozen blood only the 1 year transplant survival rate was 42+/-7% as compared to 49+/-5% in 190 patients with whole blood transfusions and 31+/-4 in 143 patients with no transfusions. We conclude that frozen blood transfusions appear to be better than no transfusions, but may be inferior to whole blood in prolonging graft survival.

In a study of 1360 cadaver-donor kidney transplants we found a striking correlation of increased numbers of pretransplant blood transfusions with improved transplant survival (P less than 0.0001). Graft survival rate in recipients with greater than 20 transfusions was 71 p5 per cent at one year as compared with 42p2 per cent for recipients with no transfusions; at four years the survival rates were 65p5 per cent and 30p3 per cent (P less than 10(-6). Frozen blood was less effective than nonfrozen blood in producing this effect. In contrast to previous reports based on fewer numbers of transplants, a single pretransplant transfusion of transfusions given during transplantation had no statistically significant influence on graft outcome. The beneficial effect of pretransplant transfusions was apparent at transplant centers with high or low overall success rates. Deliberate transfusion trials in prospective transplant recipients should consider this strong dose dependence of graft prolongation by transfusions.

Pretreatment with deliberate DST has not resulted in hyperacute or irreversible rejection in patients receiving kidneys after negative donor-specific crossmatches, but has afforded immunologically disparate related recipients enhanced opportunity at successful transplantation. Additionally, with a post-transplant course paralleling that of HLA-identical siblings, high-dose immunosuppressive therapy for rejection has been spared in many recipients. Transplantation, however, proved unsuccessful in a patient receiving a kidney from his positive B-warm crossmatch blood donor in a protocol departure. This case experience and subsequent antibody studies have reconfirmed our initially established criterion of not proceeding with transplantation against a persistently positive B-warm donor-specific crossmatch. By pursuing the initially established DST protocol, it appears that a potentially unsuccessful living related transplant can be avoided, while the transplants actually performed have enhanced prospects of success. The nature of the various immunologic responses in this patient population remain to be more clearly defined.

In 50% of recurrent miscarriages (RM) the cause remains unknown and standardized immunological diagnosis and treatment of idiopathic RM (iRM) is yet not established. In this prospective case-control study, out of 220 RM patients screened, 97 iRM patients were identified and compared to 26 healthy controls without a previous pregnancy or blood transfusion in order to identify deregulated immunological parameters. Blood levels of lymphocyte subpopulations, cytokines and neopterin were determined by FACS, ELISA, and Luminex technique. Lymphocyte function was studied by in-vitro lympocyte proliferation tests. As compared to controls, patients had significantly higher proportions of activated CD3+DR+, CD4+DR+ and CD8+DR+ lymphocytes, elevated levels of neopterin and a lower in-vitro proliferation of lymphocytes (all p < 0.05). Within the iRM patients higher proportions of CD3+DR+ T-lymphocytes correlated with higher proportions and absolute numbers of CD4+DR+ and CD8+DR+ T-lymphocytes and lower CD16+CD56+ NK-cells. Further, it was associated with lower absolute numbers of CD19+ B-lymphocytes, CD3+CD25+ T-lymphocytes and CD45+ total lymphocytes (all p < 0.05). In addition we found decreased in-vitro lymphocyte proliferation in iRM patients with high CD3+DR+ T-lymphocytes ( p < 0.05). In summary patients with iRM showed increased activated T-cells that are less responsive to mitogens in-vitro. The inverse relationship of increased DR but decreased CD25 expression on CD3+ T-cells and the decreased in-vitro proliferation characterize an immunological disorder with similarities to T-cell exhaustion in patients with HIV and cancer. These abnormalities potentially contribute to the pathogenesis of iRM and might be a target for future immunomodulatory therapies. [ABSTRACT FROM AUTHOR]