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BACKGROUND: The beneficial effect on graft survival achieved by pretransplant blood transfusions is well established. Previous studies have shown that the degree of major histocompatibility complex (MHC) (mis)-match between the transfusion donor and the recipient plays a determining role. However, other factors are also involved. In this study, we explored the hypothesis that, in addition to sharing of MHC antigens between the transfusion donor and the recipient, the MHC type of the organ donor is also of importance. METHODS: To mimic the human situation, F1 mice, rather than inbred strains, were pretreated with haplotype-shared allogeneic whole blood transfusions and transplanted with hearts of organ donors with different matched or mismatched H2 haplotypes. RESULTS: When a heart was transplanted 1 week after donor-specific transfusion (DST; blood transfusion donor=organ donor), an excellent prolongation of graft survival was obtained (median survival time: 77 days vs. 9 days in untreated mice). However, this was only the case when a haplotype was shared with the recipient; a DST given with no match between organ donor (=BT donor) and recipient did not induce any prolongation. Furthermore, in order to obtain the optimal beneficial effect of a haplotype-shared blood transfusion, the other haplotype of the transfusion donor had to be mismatched with the recipient. The immunogenetic studies showed that haplotype-shared blood transfusions in combinations where the H2 type of the organ donor differed from that of the transfusion donor are less efficient in inducing prolongation of graft survival. CONCLUSIONS: These results demonstrate that haplotype-shared blood transfusions can induce a significantly prolonged survival of cardiac allografts in F1 mice. The immunogenetic studies suggest that presentation of alloantigen-derived peptides in the context of self MHC (the indirect pathway of allorecognition) is essential for the beneficial effect of haplotype-shared blood transfusions.

We examined the graft survival of 12,883 first unrelated kidney grafts from nonliving donors, transplanted between 1 January 1971 and 31 December 1987 within 52 renal transplantation centers participating in the Eurotransplant organization. The 5-year graft survival increased from 38.8% for the period 1971-1975 to 66.0% for the period 1981-1987 for patients treated with cyclosporine, whereas the half-life increased by only 2 years, from 9.7 years to 11.6 years over the same period, based on grafts functioning at 1 year posttransplantation. Results per HLA locus showed considerable improvements within mismatch groups over the entire period. Large differences between mismatch groups for the early years were observed, but within the cyclosporine era only HLA-B showed a statistically significant difference in half-lives (13.2 versus 9.0 years, for 0 and 2 mismatches respectively, P = 0.013). When other prognostic factors were taken into account, it was revealed by means of an exponential model that number of HLA-B mismatches, donor and recipient age and sex, and recipient diagnosis of diabetes had significant effects on the long-term outcome of the grafts. Depending on the combination of these parameters, estimates of half-life varied from 4.9 to 14.5 years. These results show that matching for HLA-B is still of benefit in the longer term and that other prognostic factors play an important role in predicting the late outcome of renal allografts.

The effect of matching for the HLA antigens has been well established as important in the prognosis of kidney grafts. By analyzing the effect of matching on first transplants from unrelated donors in specific intervals up to 3 years posttransplantation, we show that the effect of HLA-DR matching is strongest in the first 5 months following transplantation (relative risks of graft failure 1.31 and 1.77 for 1 and 2 HLA-DR mismatches, respectively, compared with no mismatches). For patients whose grafts remained functioning after 5 months, there was no significant further improvement in graft survival to 3 years (relative risks 1.16 and 0.98 for 1 and 2 HLA-DR mismatches, respectively, compared with no mismatches)--i.e., the gain in graft survival by matching for HLA-DR appears to be due to its influence in the first 5 months following transplantation. For HLA-B, the matching effect was evident both before and after 5 months (relative risks 1.11 and 1.27 for 1 and 2 HLA-B mismatches, respectively, compared with no mismatches and modelled as constant over the 3-year period), whereas no effect of HLA-A matching was evident in the period up to 3 years.

In order to determine whether the donor-specific T cell allorepertoire evaluated in patients before transplantation can be predictive for kidney graft survival, a study has been set up in which the number and activation state of donor-specific T lymphocytes before transplantation were correlated to transplant survival time. Limiting dilution analysis assays were carried out to determine precursor frequencies of both T helper and cytotoxic T lymphocytes. The activation state of these cells was studied by evaluating the inhibitory capacity of cyclosporine on helper and cytotoxic T cells and/or a monoclonal antibody directed against CD8 on cytotoxic T cells. This study shows that neither a significant difference in the number nor activation state of donor-directed helper and cytotoxic T cells before transplantation could be detected when patients who acutely rejected their grafts were compared with patients who still had a well-functioning kidney graft after more than 10 years. Moreover, no significant differences in the donor-specific T cell repertoire were found when patients who had been subject to multiple rejection episodes were compared with patients who experienced few complications after transplantation. Therefore, we conclude that in individuals who have not been sensitized to HLA antigens of the donor, the donor-specific peripheral T cell allorepertoire prior to transplantation is not predictive of kidney graft survival.

Cell-mediated immunity against minor histocompatibility (mH) antigens is assumed to contribute to the development of graft-vs.-host disease in recipients of HLA-identical bone marrow grafts. To investigate the role of antihost-specific cytotoxic effector cells, we analyzed patients' T cell cultures after transplantation, in a chromium release assay using T lymphoblasts from patients and donors as target cells. Sixteen patients were studied between 1 and 25 months after grafting. Specific antihost cytotoxic T cell activity was detected in 4 of 5 patients with acute GVHD and in 5 of 5 patients with chronic GVHD, but also in 5 of 6 patients without any clinical signs of GVHD. Generally, the antihost Tc cell activity appeared within the first 3 months, increased to a maximum between 3 and 6 months, and gradually disappeared thereafter. This time effect was significant (P = 0.002). There was a suggestive trend in patients with chronic GVHD toward developing higher and more persistent levels of antihost Tc cell activity than in those without GVHD. Yet, these results can no longer support our earlier finding that the generation of antihost Tc cells is associated with the development of GVHD, since antihost Tc cells could be generally detected whether or not GVHD occurred. Our findings do not a priori exclude an effector cell role for Tc cells in GVHD but strongly indicate that other risk factors must be involved as well.

Bone marrow transplantation was first used successfully exactly 30 years ago, in children with congenital immune deficiencies.1 The demonstration that bone marrow transplantation was also effective...

An HLA-B7 antiserum showed cross-reactivity with HLA-B8, Bw41, a split of B40 (Bw60) and possibly Bw22 and B27, thus detecting one or more determinants on these antigens similar to an antigenic site on HLA-B7 usually not detected by other B7-antisera. The cross-reactions were demonstrable by adsorption of antibodies on lymphocytes followed by release at 37 degrees C, which enabled the detection of weak and otherwise hardly detectable reactivity. Released antibody molecules were detected in two different assays: (1) Antibody-dependent cellular cytotoxicity (ADCC) with HLA-B7 positive target cells (fluorochromasia micro ADCC). (2) Inhibition of MLC reactions with B7 positive stimulator cells. The B7-antibody, as detected in both assays, was released in decreasing activity from Bw41 greater than B8 greater than Bw60 much greater than B7 greater than (B27 = Bw22) positive cells. The order of sensitivity in which the various antigens were detected in ADCC assays in which the antiserum activity was measured directly on various target cells was different, viz. HLA-B7 greater than Bw60 = B27 greater than Bw41 greater than B8. Bw22 was not detected. Absorption studies demonstrated that HLA-B7 positive cells bound more B7 antibody activity than B8 positive cells. However, antibody molecules bound to B7 positive cells were mainly released as immune complexes, which could be dissociated by treatment with acid. In contrast, B7 antibody molecules bound to B8 positive cells were released as free antibody molecules. This marked difference in shedding properties further explained the previously described B7 specific unresponsiveness in MLC of HLA-B8 (and also Bw41) positive responder cells after sensitization with the B7 antiserum (de Rooij et al. 1980).

This study was undertaken to examine the humoral immune response against endothelial antigens of the donor kidney in human renal allograft recipients. Sera from 61 transplant recipients who received 62 grafts were studied for the presence of circulating endothelial antibodies (CEAb) using an indirect immunofluorescence technique with a pretransplant biopsy of the graft as a substrate. IgG antibodies directed against the endothelium of peritubular capillaries were found in the sera of 6 of the 10 patients with graft rejection within 7 weeks after transplantation, whereas these antibodies were not found in the absence of rejection (P less than 0.001). Immunofluorescence studies of post-transplant biopsies showed IgG along the endothelium of peritubular capillaries only in the grafts of patients with CEAb. Eluates from these grafts contained IgG antibodies that bound to the endothelium of the donor as shown by the indirect immunofluorescence technique. Absorption of endothelial antibody (EAb)-positive sera with human platelets or Wistar strain rat erythrocytes showed that the EAb were not directed against serologically defined HLA antigens or against heterophile antigens on rat erythrocytes. We conclude from this study that the presence of antibodies directed against endothelial antigens is associated with poor graft prognosis and that these antibodies may be responsible for the rejection process.

Forty-one patients, suffering from severe aplastic anaemia were treated either with ALG alone (27 patients) or ALG followed by infusion of allogeneic bone marrow (14 patients). Eighteen patients (67 per cent) are presently alive after ALG alone at over 100 to over 550 days. Fourteen (52 per cent) showed sustained improvement of haematopoiesis, two are alive without change, one recovered autologous haematopoiesis after cyclophosphamide conditioning and transfusion of HLA identical marrow and one is lost to follow-up. Eight patients (57 per cent) are currently alive after ALG and transfusion of haplotype identical marrow with self-sustaining autologous haematopoiesis at over 200 days to over four and a half years. No lethal complications occurred and none of the bone marrow infusions led to permanent engraftment or graft-versus-host disease. The mechanism of action is not known, but our results support the hypothesis that unspecified autoimmune reactions block the normal outgrowth of haematopoietic precursor cells in a substantial number of patients with aplastic anaemia. This therapeutic approach seems to offer good chances of survival, especially for those patients who do not have an HLA identical sibling. Its value should be further investigated.

The leucocyte migration test (LMT) has been studied in 20 recipients of renal allografts. Splenic and lymph node cells extracts prepared by homo-genation were used as antigens in the incubation medium. Inhibition of LMT was observed in 4 out of 5 patients with chronic rejection, 2 out of 13 patients in good clinical condition receiving kidney transplant, I in acute rejection and 1 with a non-functioning kidney. In some patients inhibition was already present several days before overt clinical rejection. In patients with good renal function and stable clinical conditions the majority of the tests were negative but 6 out of 11 sera from patients in good condition inhibited the migration of normal leucocytes. We were unable to find a patient with both positive LMT and serum inhibition test (SIT).

Data on the effect of HLA-A and HLA-B matching between unrelated donors and recipients focus mainly on graft survival. After linking the follow-up data of the European Dialysis and Transplant Association and those of the Eurotransplant Foundation, the effect of HLA-A and HLA-B matching on recipient survival could be studied. Recipients of well-matched kidneys — i.e., without mismatches for the HLA-A and B antigens — had 51 per cent graft survival at five years, whereas recipients of grafts mismatched for four antigens had 32 per cent graft survival at five years. The overall P value between the five different mismatch classes was 0.0005. Patient survival at five years was 72 per cent in recipients of a kidney without HLA-A and B mismatches and 54 per cent in recipients of a completely mismatched donor kidney (overall, P = 0.001). These results suggest that matching for the HLA antigens has a beneficial long-term effect not only on renal-allograft survival but also on patient survival. (N Engl J M...

HLA-DR typing results of 47 skin transplant donor-recipient pairs were analysed. HLA-A, B, and C typing and mixed lymphocyte culture (MLC) testing was also included in this study. Skin transplants exchanged between HLA-A-, B-, and DR-identical, MLC-negative donor-recipient pairs had the longest graft survival (mean survival time, 17 days), whereas skin grafts exchanged between completely nonidentical donor-recipient combinations had the shortest survival (mean survival time, 10 days). Because of the correlation between identity for the DR antigens and the low or nonreactivity in the MLC test, identity for DR will predict a better skin graft survival than nonidentity. It was concluded that the best match between donor and recipient of a graft, using only serological techniques, is one where there is identity for HLA-A, B, and DR.

Cell-mediated lympholysis (CML) reactivity against the splenocytes of the kidney donor might be a good in vitro correlate of the homograft reaction. The present study was performed in an attempt to determine whether CML nonreactivity between unrelated donor-recipient combinations occur and, if so, under what conditions. We were able to show that CML nonreactivity occurs between unrelated donor-recipient combinations in 70% of the nonrejecting patients, whereas all of the rejecting patients were CML reactive. Patients with CML nonreactivity did clinically well more frequently than those that were CML reactive. The question as to whether or not such variables as HLA-A, B, and DR match and sex, the number of pretransplant blood transfusions, and the degree of presensitization, etc. predispose to the development of donor-specific CML nonreactivity was studied as well. Sex and compatibility for HLA-B antigens between donor and recipient might be such factors.

The influence of grafting more than one skin transplant simultaneously on one recipient was investigated. When a mixed lymphocyte culture (MLC)-negative skin was transplanted along with an MLC-positive skin, the MLC-negative skin survived for a significantly shorter time than when transplanted alone. This indicated that the MLC-positive skin provided a stimulus that could provide help to reject the MLC-negative skin. This finding might be important clinically. When an MLC-negative transplant is given to a patient, one should not transfuse this patient with MLC-positive leukocyte-rich blood.

SUMMARY The major histocompatibility system of the dog (DL-A) was studied in more detail by immunogenetical methods. Suggestive evidence for the existence of two closely linked DL-A (sub)loci was found. The definition of three alleles at the first sublocus was clear for both mongrel and beagle populations. Three additional specificities appear to recognize antigens of a second sublocus, at least in the beagle colony. Differences in the frequency of the described specificities were shown between the mongrel and the beagle populations.

The identification of a number of leukocyte antigens of chimpanzees is described. Suggestive evidence was obtained that some of the isoantisera recognize specificities of a hypothetical genetic system of chimpanzee antigens which, in analogy with the human HL-A system, is tentatively called ChL-A. We demonstrated the similarity of several ChL-A specificities with human antigens of the HL-A system by typing chimpanzee cells with monospecific human sera and human cells with chimpanzee isoantisera. Several chimpanzee sera contained antibodies of distinct HL-A specificity when used for human tissue typing (HL-A1, 7, and 11); antigens 4a and 4b appear to be distributed in an alternate fashion, also, on cells of unrelated chimpanzees.