Original Article
Pretransplantation Blood Transfusion Revisited
N Engl J Med 1991; 325:1210-1213October 24, 1991
- Abstract
- Abstract
Background.
Blood transfusion before organ transplantation has a beneficial effect on allograft survival; the mechanism of this effect has remained a mystery. In murine models, the presence of common histocompatibility antigens in the blood donor and the recipient favors the induction of allograft tolerance.
Methods.
To investigate the effect of HLA compatibility between blood donor and recipient on the induction of allograft tolerance, we determined the relative frequency of cytotoxic T-lymphocyte precursors specific for donor cells before and at several times after blood transfusion in 23 patients awaiting a first renal transplant. We correlated the results with the presence of shared HLA antigens.
Results.
T-cell nonresponsiveness against donor cells developed after blood transfusion in 10 of the 23 patients. Tolerance developed only if the blood donor and the recipient had one HLA haplotype or at least one HLA-B and one HLA-DR antigen in common (as was observed in 9 of these 10 patients). Tolerance developed relatively late after blood transfusion (one to two months) and was longlasting. No decline in the T-cell response against donor alloantigens was observed in any of the 13 patients who received transfusions without having HLA-antigen compatibility with the donor.
Conclusions.
Blood transfusion in which there is a common HLA haplotype or shared HLA-B and HLA-DR antigens induces tolerance to donor antigens. This finding may lead to the development of new strategies with which to induce tolerance for transplantation after blood transfusion. Perhaps transplant donors will be selected not only by HLA-antigen matching, but also on the basis of acceptable HLA-antigen mismatches associated with T-cell nonresponsiveness induced by selected blood transfusion. (N Engl J Med 1991;325:1210–3.)
Media in This Article
Figure 1
Relative Frequencies of Cytotoxic T-Lymphocyte Precursors after Incubation of Donor Cells with Peripheral-Blood Cells from 13 Patients Receiving Blood Transfusions from HLA-Incompatible Donors.Figure 2
Estimates of Precursor Frequency in 10 Patients Receiving Blood Transfusions from Donors with Whom They Had HLA Antigens in Common.Article Activity
- Article
THE beneficial effect of a blood transfusion before transplantation on allograft survival has been well documented both in humans and in animal models.1 , 2 However, the mechanisms involved are still largely unknown. Recently, as a result of improved patient care and immunosuppression, the clinical importance of the transfusion effect has declined because of improved graft survival in patients who do not receive transfusions.3 The risk of sensitization and the availability of erythropoietin cast further doubt on the usefulness of blood transfusion. As a result, the practice of giving blood transfusions to patients awaiting organ transplantation may change, unless the beneficial effect of such transfusions on allograft survival is better understood and allows the induction of specific and reproducible allograft tolerance.4
We have demonstrated in a murine model that blood transfusion induces a functional clonal deletion of donor-specific cytotoxic T-lymphocyte precursors within the allograft that correlates with skin-allograft tolerance. This tolerance-inducing effect of blood transfusion depends on the presence of shared histocompatibility antigens in the blood donor and the recipient.5 6 7 In humans, it has been shown that blood transfusion can improve allograft survival only when the transfusion recipients have at least one HLA-DR antigen in common with the blood donors. The transfusion of blood mismatched for two HLA-DR antigens appears to be contraindicated, because of the increased sensitization rate and the lack of improvement in graft survival.8
We demonstrate here that blood transfusion can induce a marked donor-specific reduction in the frequency of cytotoxic T-lymphocyte precursors (expressed as the number of precursors per 106 cultured cells), provided that the blood donor and the recipient have one HLA haplotype in common, or at least one HLA-B and one HLA-DR antigen.
Methods
Patients
Twenty-three patients awaiting a first renal transplant received transfusions of HLA-typed buffy-coat—depleted packed cells. Each transfusion contained on average 7.7±3.5×108 leukocytes and was given within 36 hours of its donation. The relative frequency of cytotoxic T-lymphocyte precursors before transfusion and 1, 4, 8, and 16 weeks afterward was determined when peripheral-blood cells from the transfusion recipient were incubated with cells from the donor and with cells from a third-party blood donor. The transfusion history of three patients was unknown; only one had previously received a transfusion of packed cells.
Measurement of Frequency of Cytotoxic T-Lymphocyte Precursors
The frequency of cytotoxic T-lymphocyte precursors in limiting dilution cultures was analyzed as described elsewhere.9 In brief, varying numbers of responding peripheral-blood mononuclear cells from the recipient were cultured with 5×104 stimulating peripheral-blood mononuclear cells, irradiated at 20 Gy, from either the blood donor or a third-party donor. The cultures were started in round-bottomed microtiter plates in 0.1 ml of culture medium. The control cultures contained stimulator cells only. Twenty-four replicate cultures were analyzed for each concentration of responder cells (range, 312 to 2×104 per well). The culture medium used was Iscove's modified Dulbecco's medium supplemented with 20 percent heat-inactivated pooled human serum and 5 to 10 percent lectin-free culture supernatant, with a final concentration of 25 IU of interleukin-2, 100 IU of penicillin, and 100 μg of streptomycin per milliliter.
After two days of culture at 37°C in humidified air with 5 percent carbon dioxide, 50 μl of fresh culture medium was placed in each well. After another six days of culture, 3×103 51Cr-labeled target cells (peripheral-blood lymphocytes cultured for six days) were added to the wells. The plates were centrifuged for five minutes at 1000 rpm, and after eight hours of incubation at 37°C, supernatants were harvested with a harvesting system (Skatron) and radioactivity was measured in a Packard gamma counter. Cultures were considered positive if the release of 51Cr was more than 3 SD above that of control cultures containing stimulator and target cells only.
Statistical Analysis
Frequencies of cytotoxic T-lymphocyte precursors (expressed as the number of precursor cells per 106 cultured cells) and P values were calculated by the jackknife procedure for maximum likelihood, as described elsewhere.5 P values for differences between frequency estimates were derived by Student's t-test. Frequencies were considered significantly different at a P value below 0.01.5
Results
The frequency of cytotoxic T-lymphocyte precursors was determined before and several times after blood transfusion in patients awaiting renal transplantation. In 13 recipients of an HLA-typed blood transfusion, the frequency of cytotoxic T-lymphocyte precursors against the donor cells either remained at the pretransfusion level or increased (Fig. 1Figure 1
Relative Frequencies of Cytotoxic T-Lymphocyte Precursors after Incubation of Donor Cells with Peripheral-Blood Cells from 13 Patients Receiving Blood Transfusions from HLA-Incompatible Donors.A). No significant changes occurred in the frequency of precursors against the third-party controls (Fig. 1B). In 10 patients, a marked decrease in the frequency of donor-specific precursors was observed (Fig. 2Figure 2Estimates of Precursor Frequency in 10 Patients Receiving Blood Transfusions from Donors with Whom They Had HLA Antigens in Common.A). This effect was specific, since the frequency of cytotoxic T-lymphocyte precursors against third-party control cells was unaffected (Fig. 2B). The decrease in the T-cell response against donor alloantigens developed relatively late, between one and two months after blood transfusion (Fig. 2A). In two patients the T-cell response could be measured one year after transfusion. At that time the T-cell response against donor alloantigens was still absent (data not shown).Analysis of the results of HLA typing revealed that an absence of the T-cell response against donor alloantigens was observed only if the blood donor and recipient had one HLA-A, one HLA-B, and one HLA-DR antigen in common (or at least one HLA-B and one HLA-DR antigen) (Table 1Table 1
HLA-Antigen Status of Blood Donors and 23 Transfusion Recipients and the Development of Tolerance after Transfusion.). No such combinations were present among the recipients who did not show the tolerance-inducing effect of blood transfusion. For the donor and the recipient to have in common only HLA-DR antigens was not sufficient to influence the T-cell response in these patients (Table 1). The optimal requirement for the induction of T-cell tolerance after blood transfusion seems to be the presence of one common HLA haplotype.Discussion
Our findings show that blood transfusion results in the elimination of the T-cell response against donor alloantigens if the blood donor and the recipient have in common at least one HLA-B and one HLA-DR antigen. The HLA phenotypes of patients and blood donors indicate that the presence of one common HLA haplotype is optimal for the induction of T-cell tolerance. Disappearance of the T-cell response against donor alloantigens occurs relatively late (4 to 16 weeks) after blood transfusion and seems to be long-lasting.
Recently, in a selected population of previously nonimmunized patients, the transfusion of blood from donors who had only one HLA-DR antigen in common with the recipients resulted in optimal survival of heart and kidney allografts.8 From the combined results of these studies it appears that whether or not the donor and the recipient have a number of HLA antigens in common determines whether specific T-cell tolerance is induced and whether allograft survival is optimal. The clinical relevance of a decreased T-cell response against alloantigens was emphasized in studies of patients receiving either renal or corneal transplants; in these patients, low frequencies of donorspecific cytotoxic T-lymphocyte precursors correlated with beneficial graft outcomes, and the occurrence of graft-versus-host disease after the transplantation of HLA-identical bone marrow from an unrelated donor was found to depend on the frequency of cytotoxic T-lymphocyte precursors.10 11 12 13
At first glance, a recent report indicating that blood transfusion induced an increased frequency of donorspecific precursors in 10 patients seems at variance with our findings.14 However, the measurement of frequency was made soon (two weeks) after transfusion, and only one of the patients studied had the combination of at least one HLA-B and one HLA-DR antigen in common with the blood donor. Therefore, the results of both, studies are compatible.
How does the presence of some of the same HLA antigens in both donors and recipients result in the elimination of the T-cell response? In mice, it has been shown that the induction of a low grade of mixed chimerism results in stable allograft survival across different barriers at the H-2 locus.15 16 17 Accordingly, Qin et al.16 elegantly demonstrated that in this situation, tolerance for transplantation was not caused by a clonal deletion of T cells reactive to the donor cells, but rather by their inactivation (clonal anergy). We have previously shown that the intravenous injection of allogeneic lymphocytes in the presence of a donorrecipient disparity in either H-2 Class I or H-2 Class II results in tolerance for transplantation.5 6 7 At least in the first of these situations, it has recently been demonstrated that mixed chimerism is induced.18 Our current hypothesis is that under certain conditions donor lymphocytes can home in on privileged sites after transfusion and induce low-grade mixed chimerism, and that the induction of such chimerism depends on the HLA match or mismatch between the donor and the recipient. On the one hand, a state of permanent chimerism could result from the transfusion of stem cells, which are present in peripheral blood, though in low quantity (10 to 100 times less than in bone marrow).19 , 20 The level of mixed chimerism needed to induce tolerance for transplantation is probably extremely low.15 16 17 On the other hand, blood transfusion in which the donor and the recipient have HLA antigens in common may create a temporary state of chimerism. In this case, it can be envisaged that the interaction between the transfused cells and the recipient's specific T cells leads to inappropriate T-cell signaling, ultimately resulting in T-cell inactivation.21 The hypothesis of either permanent or temporary chimerism explains our finding that the T-cell response against donor alloantigens disappears relatively late after blood transfusion; it also explains the clinical findings that viable leukocytes are needed for the transfusion effect and that the effect is long-lasting. In addition, it would explain the extremely beneficial effect of donor-specific transfusion in renal transplantation involving a haploidentical living related donor and the reduced donor-specific T-cell response associated with such transfusion.22 , 23
In contrast with this hypothesis, Lazda et al.24 reported that the induction of renal-allograft enhancement by donor-specific transfusion depends on the presence of a disparity between the donor and the recipient with respect to HLA Class II antigens. However, the protocol for donor-specific transfusion in their study required simultaneous treatment with azathioprine. This protocol could affect the function of proliferating T cells directed against the mismatched HLA-DR antigen, eventually resulting in enhanced graft survival.
The apparent nonspecificity of the clinical transfusion effect can be explained if one assumes that mixed chimerism induces tolerance not only of the chimeric foreign HLA antigens themselves, but also of a wide variety of different peptides (both those in the recipient and those derived from the donor) presented by the chimeric foreign HLA antigens, leading to broadly specific tolerance of antigens received in transplantation.
If the mechanism of low-grade mixed chimerism has a role in clinical transplantation, one should use HLA-typed blood donors prospectively to induce specific T-cell tolerance against transplantation antigens. Indeed, the induction of tolerance through blood transfusion that involves shared HLA antigens may improve the selection of transplant donors, thus increasing graft survival.
Supported by a grant (C86.613) from the Dutch Kidney Foundation.
We are indebted to C. van der Poel for providing us with buffy-coat cells from the blood donors.
Source Information
From the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and the Laboratory for Experimental and Clinical Immunology, University of Amsterdam (E.v.T., R.J.D.M., A. R. v. d.H., L.P.d.W.); the Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center (I.J.M.t.B., J.M.W.), University of Amsterdam; and the Department of Immunohematology and the Blood Bank, University Hospital Leiden, Leiden (W.M.K., C.J.M.M.); all in the Netherlands. Address reprint requests to Dr. de Waal at the Publication Secretariat, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, P.O. Box 9406, 1006 AK Amsterdam, the Netherlands.
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