Effect Of Donor-specific Blood Transfusion Research Articles

Combination of Donor-Specific Blood Transfusion With Anti-CD28 Antibody Synergizes to Prolong Graft Survival in Rat Liver Transplantation

Donor-specific blood transfusion (DST) has been shown to effectively induce tolerance to certain allografts. In addition, it is well known that blockade of costimulatory signals reduces the ability of T cells to respond to alloantigens, prolonging allograft survival in some transplant models. We assessed the effects of single or multiple DSTs in the absence or presence of anti-CD28 monoclonal antibodies (mAbs) on graft function and host survival in rat liver transplantation (LTx). Fully MHC-mismatched adult male Dark Agouti (DA) and Lewis (LEW) rats were used as donors and recipients, respectively. Heparinized DA blood was administered to naïve LEW rats 7 days before LTx [DST(−7d)], 14 and 7 days before LTx [DST(1×2)], twice a week for 2 weeks prior to LTx [DST(2×2)] and once a week for 4 weeks prior to LTx [DST(1×4)]. For some experiments, two different monoclonal antibodies (mAb) to rat CD28 (JJ316 and JJ319) were administered in combination with some DST treatments. We found that DST administration induced a time- and dose-dependent increase in host survival. Treatment of LEW rats with JJ316 or JJ319 mAb alone failed to prolong graft survival over untreated rats; however, the combination of DST(1×2) with JJ316 or JJ319 mAb induced indefinite survival at 100 days following surgery. We found that this protective effect was associated with increased numbers of splenic CD4 +CD45RC − but not CD4 +CD25 +foxp3 + T-cells in long-term survivors. Our data suggest that the combination of suboptimal DST with CD28 mAb induces donor-specific tolerance that correlates with enhanced numbers of regulatory T-cells.

Role of Blood Transfusion in Transplantation: A Review

The ultimate goal of transplantation immunology is induction of donor-specific tolerance without the need for chronic immunosuppression. A number of strategies have been used to induce tolerance, including donor-specific blood transfusion (DST). A large number of experimental and clinical studies have evaluated the ability of DST to induce tolerance in solid organ transplantation. In contrast, a limited number of experimental studies have been reported evaluating the effect of DST in induction of tolerance in composite tissue allograft transplants. DST applications include cadaveric and living-related graft recipients in humans, leading to achievement of microchimerism. Although the mechanism of action is still uncertain, microchimerism with the concomitant persistence of soluble donor HLA antigen is considered to be the most significant contributing factor. In this article, the experimental and clinical applications, as well as the immunomodulatory mechanism of DST, are reviewed.

Deoxyspergualin Prophylaxis With Tacrolimus Further Improves Long-Term Graft Survival in Living-Related Renal-Transplant Recipients Transfused With Donor-Specific Blood

Background We examined whether deoxyspergualin (DSG) prophylaxis in combination with cyclosporine (CsA)- or tacrolimus (Tac)-based immunosuppression augments the effect of donor-specific blood transfusions (DSTs) to improve long-term survival of living-related renal-transplants. Methods From May 1985 to January 1998, 176 patients received DST from one-haplotype-identical donors prior to kidney transplantation. Group A (n = 64, 1985 to 1989) received CsA, prednisolone (PSL), antilymphocyte globulin (ALG), and azathioprine (AZA). Group B (n = 89, 1989 to 1996) received CsA, PSL, ALG, and DSG. Group C (n = 23, 1996 to 1998) received Tac, PSL, ALG, and DSG, with DSG followed by AZA. Rejection episodes were classified as acute rejection (AR, within the first 3 months) or late acute rejection (LAR, from 4 months to 1 year). Results Five-year graft survivals were 73.4%, 88.8%, and 91.3% for groups A, B, and C, respectively. The incidence of AR was 34%, 30%, and 13%, and that of LAR was 23%, 26%, and 30% for groups A, B, and C, respectively. There was no significant difference in the incidence of AR or LAR among the three groups. However, an elevated serum creatinine (sCr) ≥1 mg/dL was observed in 73%, 15%, and 0% of patients during AR, and in 53%, 30%, and 14% during LAR for groups A, B, and C, respectively. These results suggest that the severity of AR or LAR was lowest among group C, contributing to the improved long-term graft survival in these patients. Conclusions DSG prophylaxis with Tac-based immunosuppression further improves long-term graft survival among living-related renal-transplant recipients treated with DST by decreasing the severity of acute rejection episodes.

DEOXYSPERGUALIN PROPHYLAXIS WITH TACROLIMUS FURTHER IMPROVES LONG-TERM GRAFT SURVIVAL IN LIVING-RELATED RENAL-TRANSPLANT RECIPIENTS TRANSFUSED WITH DONOR-SPECIFIC BLOOD

Abstract Background We examined whether deoxyspergualin (DSG) prophylaxis in combination with cyclosporine (CsA)- or tacrolimus (Tac)-based immunosuppression augments the effect of donor-specific blood transfusions (DSTs) to improve long-term survival of living-related renal-transplants. Methods From May 1985 to January 1998, 176 patients received DST from one-haplotype-identical donors prior to kidney transplantation. Group A (n = 64, 1985 to 1989) received CsA, prednisolone (PSL), antilymphocyte globulin (ALG), and azathioprine (AZA). Group B (n = 89, 1989 to 1996) received CsA, PSL, ALG, and DSG. Group C (n = 23, 1996 to 1998) received Tac, PSL, ALG, and DSG, with DSG followed by AZA. Rejection episodes were classified as acute rejection (AR, within the first 3 months) or late acute rejection (LAR, from 4 months to 1 year). Results Five-year graft survivals were 73.4%, 88.8%, and 91.3% for groups A, B, and C, respectively. The incidence of AR was 34%, 30%, and 13%, and that of LAR was 23%, 26%, and 30% for groups A, B, and C, respectively. There was no significant difference in the incidence of AR or LAR among the three groups. However, an elevated serum creatinine (sCr) ≥1 mg/dL was observed in 73%, 15%, and 0% of patients during AR, and in 53%, 30%, and 14% during LAR for groups A, B, and C, respectively. These results suggest that the severity of AR or LAR was lowest among group C, contributing to the improved long-term graft survival in these patients. Conclusions DSG prophylaxis with Tac-based immunosuppression further improves long-term graft survival among living-related renal-transplant recipients treated with DST by decreasing the severity of acute rejection episodes.

Long-Term Results of Donor-Specific Blood Transfusion with Cyclosporine in Living Related Kidney Transplantation

Donor-specific blood transfusion (DST) was introduced to achieve better graft survival. However, its benefits are controversial considering the immunosuppression of cyclosporine (CYA) or tacrolimus (Tac), and its long-term effects have not been well discussed. Of the 40 patients who received DST with CYA, 3 (7.5%) became cross-match positive. Of the 37 patients with negative cross-match, 34 patients received a one-haplotype-matched kidney and were compared to patients with one-haplotype-matched kidney transplant without preoperative DST (n = 13). Acute rejection within 3 months after transplant was 29.4% in the DST group, and 15.4% in the non-DST group. All rejection episodes were steroid resistant in the non-DST group. If the graft survival rates were calculated excluding non-immunological graft loss, graft survival rate was 91.0 and 72.8% at 5 and 10 years in the DST group, and 83.3% at 5 and 10 years in the non-DST group, respectively. The two graft survival lines converged 7 years and 7 months after transplantation. No beneficial effect of DST was statistically evident under CYA immunosuppression. In terms of the severity of acute rejection or the onset of chronic rejection, DST induced a small benefit, however, which seemed to disappear within 8 years after transplantation.

Posttransplant infusion of donor-specific blood induces immunological unresponsiveness in rat hepatic allografts.

We previously reported that pretransplant donor-specific blood transfusion (DST) induces CD45RC-CD4+ T cells, Th2-like effector cells, and prolongs rat hepatic allograft survival. Our study investigated the effects of posttransplant DST on rat hepatic allograft survival. Three days after transplantation, LEW (RT1(1)) recipient rats with ACI (RT1a) livers were injected i.v. with freshly heparinized donor-specific blood. The time kinetics of CD45RC-CD4+ and CD45RC+CD4+ T cell subsets in hepatic infiltrates were examined. Posttransplant DST significantly prolonged rat hepatic allograft survival. Interferon (IFN)-gamma, interleukin (IL)-12, and IL-18 mRNA levels in hepatic allografts of untreated recipients were significantly greater than in recipients treated with posttransplant DST. However, hepatic allografts of recipients treated with posttransplant DST showed significantly higher IL-4, IL-10, and transforming growth factor (TGF)-beta mRNA levels than untreated recipients. The ratio of CD45RC-CD4+ T cells to CD45RC+CD4+ T cells was significantly higher in hepatic allografts treated with posttransplant DST than in untreated animals. Immunostaining with anti-rat dendritic cell (OX-62) monoclonal antibody revealed that OX-62+ cells were distributed to the splenic red pulp of animals treated with posttransplant DST and to the splenic white pulp in untreated animals. Most OX62+ cells isolated from the spleen of recipients treated with posttransplant DST expressed donor RT1Ba class II major histocompatibility complex antigens, suggesting that OX-62+ cells were of donor origin. Posttransplant DST was associated with persistent infiltration of CD45RC-CD4+ T cells, Th2-like effector cells, in rat hepatic allografts, causing immunologic unresponsiveness and establishment of microchimerism in the spleen.

Differential effect of donor‐specific blood transfusions after kidney, heart, pancreas, and skin transplantation in major histocompatibility complex‐incompatible rats

Donor-specific blood transfusion prior to transplantation has been demonstrated to prolong allograft survival. This study compared the effect of donor-specific blood transfusion after kidney, heart, pancreas, and skin allotransplantation in congenic rats of reciprocal strain combinations across a major histocompatibility complex barrier. Whole donor-specific and third-party blood was administered to the prospective graft recipients 14 and 7 days before the transplantation of kidney, heart, pancreas, and skin. Rejection was defined by cessation of organ-specific function (i.e., uremia, cessation of heartbeat, and recurrence of diabetes). The survival of skin grafts was monitored visually. All allografts were histologically assessed immediately after rejection or at the end of a 100-day observation period. Donor-specific blood transfusion leads to permanent acceptance of all renal allografts. LEW.1U heart allografts were accepted by LEW.1A recipients, but they were rejected in the reciprocal situation. Survival of pancreas and skin allografts was not significantly prolonged. Third-party blood had no effect on allograft survival. The beneficial effect of donor-specific blood transfusion depends on both the kind of transplanted organ and the genetic incompatibility involved. The precise mechanisms responsible for the remarkable organ-specific differences remain unknown.

Synergistic effect of donor-specific blood transfusion and a short course of deoxyspergualin in rat kidney transplantation

Abstract Abstract Deoxyspergualin (DSG), an analogue of spergualin produced by B. larerosporus, has a strong im-munosuppressive effect in various transplantation models. We have in vestigated the mechanism of donor-specific prolongation of survival time in rat kidney grafting by donor-specific blood transfusion (DST) and a short course of DSG. Lewis (LEW) kidney allografts were transplanted into fully allogeneic BN rats. Fresh, whole LEW blood 1.0 ml, was injected iv. into BN rats 2 days prior to transplantation. Then, DSG, 6 mg/kg per day, was administered by in. injection on days 0,1, and 2 after transplantation. The recipients were divided into five groups: group 1 (n = 6) no treatment: group 2 (n = 6) DST only; group 3 (n= 7) DSG only: group 4 (n = 7) DST and DSG: and group 5 (n= 6), third party (ACI rats) blood transfusion and DSG. Lymphocytes (cervical lymph nodes) and serum were harvested from BN recipients on day 7 postgrafting. For suppressor cell assays, lymphocytes from BN recipients in each group were added as a third cell to the mixed lymphocyte reaction (MLC) between nontransplanted BN lympho cytes (responder) and LEW or other third party (PVGC, ACI, WKA rats) lymphocytes (stimulator). An-tidonor lymphocytotoxic antibody (ADLA) was checked by microcy-totoxicity assays. Median survival times (MST) for each group were: group 1, 10 days; group 2, 10 days; group 3,13 days; group 4, 75 days; and group 5,13 days. Remarkable prolongation of MST was only noted in group 4. In the suppressor cell as say, group 4 showed significant sup pression (40 %: P < 0.05); the other groups did not show any suppression. This suppressive activity in group 4 was effective only during the MLC between BN and LEW, not during the MLC of third party-BN combinations. Thus, suppressor cells from DST/DSG-treated BN recipients appear to be donor-specific. In the microcytotoxicity assay, the only group that showed any ADLA was group 2, which was not treated with DSG. These results clearly show that both induction of donor-specific suppressor cells and inhibition of ADLA production are associated with the remarkable donor-specific prolongation of kidney allograft survival in DST/DSG-treated recipients.

The association of enhancement of renal allograft survival by donor-specific blood transfusion with host MHC-linked inhibition of IgG anti-donor class I alloantibody responses.

Donor-specific blood transfusion (DSBT) in animals and humans can either promote subsequent renal graft survival or lead to sensitization and graft rejection. Using a rat renal allograft model, we have examined whether the effects of DSBT on renal allograft outcome and IgG alloantibody responses are linked to the host MHC. In F1 rats produced by mating PVG (RT1c), a low IgG alloantibody responder to transfused ACI (RT1a) blood, with 3 different high-IgG responders [W/F (RT1u), LOU (RT1u), and LEW (RT1l)], high IgG alloantibody production was found to be inherited as a dominant trait and associated with acute rejection of ACI renal allografts. DSBT given to offspring of (PVG x W/F)F1 rats backcrossed to W/F with either RT1u/c (u/c) or RT1u/u) (u/u) phenotype induced high-IgG-alloantibody responses that were associated with acute renal allograft rejection. Likewise, offspring of (PVG x W/F)F1 rats backcrossed to PVG expressing the u/c phenotype had high IgG responses to ACI DSBT associated with acute renal allograft rejection. In contrast, DSBT given to backcrossed recipients expressing the RT1c/c (c/c) phenotype elicited a transient IgM response that switched to a very low IgG response and was associated with renal allograft acceptance. Analysis of IgG isotypes demonstrated that DSBT prevented production of IgG1 and IgG2a, and to a lesser extent IgG2b and IgG2c alloantibodies in c/c but not u/c renal allograft recipients. The differences in the level and isotype of IgG alloantibody responses found in sera of DSBT-pretreated backcross rats of u/c and c/c phenotypes were also present in allograft eluates and splenocyte cultures. Likewise, DSBT-pretreated renal allograft recipients of the c/c phenotype produced lower levels of alloantibodies directed to class I RT1.Aa antigens compared with their u/c counterparts; in contrast, no difference was found in alloantibody responses to class II RT1.Ba antigens. These findings demonstrate that the variable ability of DSBT to enhance renal allograft survival correlates with the inhibition of antidonor class I alloantibody responses of all IgG subclasses by a mechanism that is linked to host MHC.

Renal transplantation from HLA-haploidentical living-related donors: the effects of donor-specific blood transfusions and different immunosuppressive regimens.

One-hundred-nine HLA-haploidentical living related renal transplants have been retrospectively analysed to compare the effect of donor-specific blood transfusion (DST) and different immunosuppressive regimens on graft survival and acute rejection. The recipients were divided into four groups according to the immunosuppressive therapy. Group 1 (n = 44): conventional therapy with posttransplant azathioprine (AZP) + methylprednisolone (MP). Group 2 (n = 25): pretransplant DST + posttransplant AZP + MP. Group 3 (n = 12): triple-drug therapy with posttransplant AZP + MP + cyclosporine (CS). Group 4 (n = 25): pretransplant DST + posttransplant AZP + MP + CS. The five-year actuarial survival rates for groups 1, 2, 3 and 4 were 48%, 73%, 79%, and 89%, respectively. The graft survival rate in group 3 was significantly (p less than 0.01) better than that in group 1. The transfusion effect was reduced, and appears as a 10% improvement in the graft survival in the cyclosporin era compared with a 25% improvement at pre-cyclosporin era. Furthermore, the incidence of the first rejection episode was decreased in recipients that received DST. The present study revealed that DST, as pretransplant conditioning has a definite impact on rejection-free long-term graft survival in HLA-haploidentical living-related kidney recipients and the most favorable outcome in such patients could be achieved by DST pretreatment in conjunction with posttransplant triple-drug therapy including cyclosporine.

SUPPRESSOR CELLS INDUCED BY DONOR-SPECIFIC TRANSFUSION AND DEOXYSPERGUALIN IN RAT CARDIAC XENOGRAFTS

The effect of donor-specific blood transfusion (DST), in combination with pretransplant immunosuppression with deoxyspergualin (DSG), on hamster-to-Wistar rat cardiac xenograft survival was assessed. While DST given on day -6 sensitized the recipients, resulting in hyperacute xenograft rejection, the addition of 5 mg/kg/k/day DSG from the day of transfusion to the day of grafting not only prevented hyperacute rejection but resulted in prolongation of graft survival from 3.4 +/- 0.5 days in untreated controls to 7.0 +/- 0.7 days (P less than 0.01). In contrast, DSG alone as pretransplant immunosuppression had no beneficial effect and rejection occurred in 4.0 +/- 0.7 days. This effect appears to be at least donor species-specific, in the sense that ACI cardiac allograft survival was not prolonged when transplanted into xenotransfused and DSG-treated Wistar recipients. DST alone resulted in marked increase in antibody titers, showing the value of 1:512 or more on transplantation day. On the other hand, combined treatment suppressed the titers to 1:1-1:4 on that day. An adoptive cell transfer system was used to analyze the mechanisms underlying this effect. When sublethally irradiated secondary hosts were transferred with 5 x 10(7) lymph node cells (LNCs) harvested on day 0 from xenotransfused and DSG-treated rats, the test heart xenograft survived longer than the irradiated and nontransferred controls, suggesting the presence of suppressor cells. Further in vitro studies demonstrate that LNCs from DST+DSG-treated rats response less in a mixed lymphocyte reaction to hamster LNCs (41% on day 0 [P less than 0.01]), compared with the controls. In coculture experiments, the LNCs from treated recipients suppressed the response of unmodified Wistar LNCs to hamster LNCs by 76% on day 0 compared with the positive controls (P less than 0.01). On the other hand, the transfer of serum taken from treated rats on day 0 did not lead to prolongation of test heart xenografts in syngeneic naive hosts. These findings suggest that the mechanisms underlying the hyporesponsiveness induced by pretreatment with DST and DSG include the induction of suppressor cells, although a degree of clonal deletion can not be ruled out. The generation of serum suppressor factors seems to have no role in this phenomenon.

生体腎移植における donor specific blood transfusion の効果

Donor specific blood transfusion (DST), given prior to living related kidney transplantation has resulted in significant improvement in graft survival. This improvement, however, has been accomplished with a high rate of adverse sensitization against the donor. In an attempt to reduce the incidence of sensitization, we have employed DST with intermittent coverage of cyclophosphamide. A comparative study was done between 2 methods of DST with or without the coverage of immunosuppressant for prospective kidney transplant recipients from living related donors. In addition, the beneficial effect of DST on graft survival was evaluated in our recent series of living related transplantation using cyclosporine A (CsA) as postoperative immunosuppression. Twenty-nine prospective kidney transplant patients received 200 ml of fresh whole blood 3 times at 2 week intervals from HLA one-haploidentical living related donors. The first 13 patients received DST alone, while the remaining 16 were given cyclophosphamide (CPM 1.5 mg/kg/day) for 3 days prior to each DST. In patients with CPM coverage, 6.3% (1 of 16) developed positive T-warm antibody against donor and 15% of patients (2 of 13) with DST alone developed it. Like-wise 19% (3 of 16) of the former and 38% (5 of 13) of the latter became positive B-warm crossmatch. The difference in sensitization rates between these 2 groups was not statistically significant. Nineteen patients receiving DST were compared to 21 non-DST patients in incidence of acute rejection, graft function and graft survival with the same immunosuppressive regimen, such as CsA, prednisolone, and mizoribine.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of donor-specific blood transfusion, cyclosporine, and dietary prostaglandin precursors on rat cardiac allograft survival. II. Effectiveness of a 24-hour induction period with DST and CsA in inducing long-term graft survival.

We investigated the effect of donor-specific transfusion given 24 hours pretransplant, a short course of low-dose cyclosporine, and dietary enrichment with the prostaglandin precursor linoleic acid (LA) to see which of the modalities could act synergistically on cardiac allograft survival in a stringent animal model. ACI male rats (RT1a) were used as blood and heart donors, and Lewis male rats (RT1l) were used as recipients. DST alone (1 ml) given 24 hr pretransplant or LA alone started 24 hr pretransplant and given daily p.o. until rejection prolonged cardiac allograft survival slightly but significantly, from 6 to 8 days. CsA alone started at the time of transplant at a dose of 5 mg/kg/day s.c. and given daily for 14 days prolonged cardiac survival to 11.8 days. However, when CsA was started 24 hr pretransplant and continued for two weeks, there was a significantly prolonged allograft survival to 55 days. CsA given together with DST 24 hr pretransplant and continued for two weeks posttransplant significantly prolonged cardiac allograft survival to 80 days and resulted in permanent tolerance in some animals. The addition of LA to a DST and CSA treatment regimen did not further improve allograft survival. CsA blood levels were determined in a separate group of Lewis rats. Three dosages of CsA were administered s.c. for 2 weeks: 2.5 mg/kg/day, 5 mg/kg/day, and 10 mg/kg/day. One injection of the three CsA doses did not achieve what are considered therapeutic levels in man. After 5 days, all three doses of CsA achieved significant blood levels. Significant blood levels were still present one week, but not 3 weeks after CsA was stopped. We conclude that DST given 24 hr before transplant and a 2-week course of low-dose CsA started one day pretransplant have strong synergism in inducing long-term graft survival in this rat model. Linoleic acid started 24 hr pretransplant, together with DST and CsA, did not contribute significantly to graft survival compared with the group given CsA and DST alone. Prolonged heart allograft survival was not due to persistently high CsA levels after the drug was discontinued.

Failure to prolong pancreatic islet allograft survival in rats with donor-specific blood transfusions and immunosuppression.

The effects on pancreatic islet allograft survival of donor-specific blood transfusions (DST) in combination with pre- and posttransplant immunosuppression were studied. A total of 12 groups of rats (n = 105) with chemically induced diabetes underwent islet allotransplantation. Multiple DST or third-party blood transfusions (TPT) were given prior to transplantation. Pretransplant immunosuppression consisted of azathioprine and prednisolone, and low-dose cyclosporin A was used for posttransplant immunosuppression. TPT, as well as separate or combined pre- and posttransplant immunosuppression without blood transfusions, did not prolong islet allograft survival. DST resulted in either primary nonfunction of the islet allografts or a markedly decreased islet allograft survival. These findings contrast with the beneficial effect of DST on whole-organ allograft survival in rats previously described by others.

Failure to prolong pancreatic islet allograft survival in rats with donor-specific blood transfusions and immunosuppression

Abstract. The effects on pancreatic islet allograft survival of donor-specific blood transfusions (DST) in combination with pre-and posttransplant immunosuppression were studied. A total of 12 groups of rats (n= 105) with chemically induced diabetes underwent islet allotransplantation. Multiple DST or third-party blood transfusions (TPT) were given prior to transplantation. Pretransplant immunosuppression consisted of azathioprine and prednisolone, and low-dose cyclosporin A was used for posttransplant immunosuppression. TPT, as well as separate or combined pre-and posttransplant immunosuppression without blood transfusions, did not prolong islet allograft survival. DST resulted in either primary nonfunction of the islet allografts or a markedly decreased islet allograft survival. These findings contrast with the beneficial effect of DST on whole-organ allograft survival in rats previously described by others.

Donor-Specific Transfusions in Living-Related Transplantation

Two-hundred thirty-nine transplants have been performed following donor-specific blood transfusions (DSTs) from 1978 through 1984 at the University of California, San Francisco (UCSF). The results of this experience show that DST provides excellent long-term graft survival in 1-haplotype mismatched pairs. Excellent graft survival has also been obtained in a limited 0-haplotype matched experience. These results are comparable to those achieved with concurrent HLA-identical sibling transplants. Azathioprine coverage during DST administration does appear to decrease DST sensitization to the blood donor in unsensitized patients undergoing a first transplant, encouraging early DST and transplantation in this group. The majority of patients formerly excluded from transplantation because of a post-DST positive B-warm crossmatch can now be successfully transplanted with the use of flow cytometry analysis to rule out previously undetectable low levels of anti-class I antigen activity. The DST protocol by itself does not appear to preclude subsequent cadaveric transplantation in patients sensitized to their blood donor by the DST procedure. Preliminary results of cyclosporin treatment in 1-haplotype matched living-related donor-recipient pairs is reported with a 1-year graft survival rate that is similar to that obtained following cadaveric transplantation at this same center. In summary, the long-term immunologic effect of DST has been confirmed, and the indications and considerations for the optimum use of the DST protocol appear to be more clearly defined.

Role of MLC serum inhibitory factors in high MLC-reactive kidney transplant recipients pretreated with donor-specific blood transfusion (DST).

In order to clarify the beneficial effect of donor-specific blood transfusions (DST) on kidney allograft survival, sera from 16 patients treated with DST were studied using the mixed lymphocyte culture (MLC) serum inhibition test. The results demonstrate that MLC inhibitory factors could be induced in the serum of the recipients after the completion of DST, and that these factors are directed against cells of the recipient but not against cell from the donor. Regarding the correlation with rejection episodes and clinical outcome, a significant improvement in renal transplant survival and reduction in rejection episodes was observed when MLC inhibitory factors were present in post-DST sera. These data suggest that such factors may contain antibodies directed against recognition sites on T lymphocytes, e.g., anti-idiotypic antibodies, and be associated with prolonged graft survival of living-related, high MLC-reactive one-haplotype-mismatched kidney.

Donor-specific transfusions in living-related transplantation.

AbstractTwo‐hundred thirty‐nine transplants have been performed following donor‐specific blood transfusions (DSTs) from 1978 through 1984 at the University of California, San Francisco (UCSF). The results of this experience show that DST provides excellent long‐term graft survival in 1‐haplotype mismatched pairs. Excellent graft survival has also been obtained in a limited 0‐haplotype matched experience. These results are comparable to those achieved with concurrent HLA‐identical sibling transplants. Azathioprine coverage during DST administration does appear to decrease DST sensitization to the blood donor in unsensitized patients undergoing a first transplant, encouraging early DST and transplantation in this group. The majority of patients formerly excluded from transplantation because of a post‐DST positive B‐warm crossmatch can now be successfully transplanted with the use of flow cytometry analysis to rule out previously undetectable low levels of anti‐class I antigen activity. The DST protocol by itself does not appear to preclude subsequent cadaveric transplantation in patients sensitized to their blood donor by the DST procedure. Preliminary results of cyclosporin treatment in 1‐haplotype matched living‐related donor‐recipient pairs is reported with a 1‐year graft survival rate that is similar to that obtained following cadaveric transplantation at this same center. In summary, the long‐term immunologic effect of DST has been confirmed, and the indications and considerations for the optimum use of the DST protocol appear to be more clearly defined.

A seven-year experience with donor-specific blood transfusions. Results and considerations for maximum efficacy.

Two hundred thirty-nine transplants have been performed following donor-specific blood transfusions (DSTs) since 1978. Graft and patient survival in 1- and 0-haplotype-matched transplants with DST pretreatment is comparable to HLA-identical results through 4 years. Graft survival in 174 consecutive nondiabetic, non-HLA-identical DST recipients shows that the transfusion effect persists for at least 4 years, with graft survival of 88 +/- 3% at that time, compared with 83 +/- 4% in the concurrent HLA-identical group. Graft function, as determined by serum creatinine, was the same in both groups. Graft and patient survival in 20 0-haplotype matched pairs with DST pretreatment is 100% at 2 years. Low-dose Imuran coverage during DST administration (n = 91) was compared with a concurrent group with no Imuran (n = 93). Imuran had its maximum effect in patients undergoing their first transplant and with a pre-DST PRA less than 10% (12% vs. 21% sensitization rate in the no-Imuran group). Imuran did not appear to confer any beneficial effect in primary transplants with high PRAs and in patients undergoing a second or third transplant. The majority of patients formally excluded from transplantation because of a post-DST positive B-warm crossmatch can now be successfully transplanted with the use of flow cytometry analysis to rule out previously undetectable low levels of anti-T-lymphocyte antibodies. Of 62 patients with a positive B-warm crossmatch alone since 1982, 73% had a subsequent negative fluorescence-activated cell sorter (FACS) crossmatch permitting transplantation. Preliminary results of a DST and cyclosporine treatment study are described. In conclusion, a long-term immunologic effect of DST has been confirmed and the indications and considerations for optimum use of the DST protocol have been more clearly defined.

Role of IA-positive cells in the beneficial effect of donor blood transfusion and induction of suppressor cells in cardiac allotransplantation of rats.

An attempt was made to reveal the role of Ia-positive cells in the beneficial effect of pretransplant donor-specific blood transfusion (DST) and induction of suppressor cells in the cardiac allotransplantation of rats. Mean graft survival time (MST) of F344 (RT1 1v1) hearts transplanted in WKA (RT1k) rats was 6.5 +/- 0.8 days. Pretreatment of recipients with 1 ml DST 10 days before grafting prolonged it to 56.5 +/- 38.1 days. Plasma or erythrocytes did not prolong MST at all, whereas pretreatment with 1 X 10(7) lymphocytes prolonged MST significantly. B enriched cells separated on a nylon-wool column prolonged MST, but T-enriched cells did not. Treatment of lymphocytes with interspecies crossreactive monoclonal anti-Ia antibody and complement eliminated the ability of lymphocytes to prolong MST, suggesting an important role of Ia-positive cells in the beneficial effect of DST. The role of Ia-positive cells in prolonging graft survival, was analyzed by a cell and serum transfer experiment. MST of F344 heart allografts transplanted in sublethally irradiated (500 rads) WKA rats was 17.4 +/- 4.0 days. MSTs of allografts in rats irradiated and treated with serum or spleen cells of blood-conditioned rats were 23.2 +/- 1.6 (P less than 0.05) and 5.2 +/- 0.7 (NS) days, respectively. On the other hand, MSTs of the grafts in rats irradiated and treated with serum or spleen cells harvested from rats that had accepted grafts for 30 days were 18.7 +/- 1.9 (NS) and 63.8 +/- 29.9 (P less than 0.01) days, respectively. The results indicate that the initial role of a serum factor in prolonging graft survival induced by DST containing Ia-positive cells was followed by activating suppressor cells by the presence of the allograft.