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Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

PubMedID: 25582053 Complement-mediated humoral rejection has become the main focus of research in organ transplantation. The aim of this study was to investigate the possible association of the complement C5aR gene 450 C/T polymorphism in antibody-mediated renal allograft rejection. This polymorphism was investigated in 290 first deceased donor kidney graft recipients with well functioning grafts and no rejection treatment during the first transplant year (WFG), 265 recipients with graft failure within the first transplant year (F), and 187 healthy controls. Frequency of the 450 CT genotype was lower in the total population of 555 kidney recipients (4.7%) than in 187 healthy controls (8.6%), but the difference was not statistically significant (P=0.065). A significantly higher frequency of CT genotype was found in F patients (CT: 6.8%) when compared to WFG patients (CT: 2.8%, P=0.027). The CT genotype was also significantly lower in WFG patients than in healthy controls (P=0.009). Low frequency of the C5aR 450 CT genotype, which apparently is a feature of certain kidney diseases, appears to be associated with good graft outcome in kidney transplantation and might be helpful for identifying recipients who are at low risk for graft rejection. © 2015 John Wiley & Sons A/S. Deutsche Forschungsgemeinschaft: GZ:446TUR112/8/05

Studies of the effect of minor H antigen mismatching on the outcome of renal transplantation are scarce and concern mainly single center studies. The International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 16 laboratories of the IHIW, the role of 15 autosomal, 10 Y-chromosome encoded minor H antigens and 3 CD31 polymorphisms, was investigated in relation to the incidence of renal graft rejection and graft loss in 444 human leukocyte antigens (HLA)-identical sibling renal transplantations. Recipient and donor DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, C19Orf48, LB-ECGF-1, CTSH, LRH-1, LB-ADIR and HY. The correlation between minor H antigen mismatch and the primary outcome graft rejection or graft loss was statistically analyzed. The incidence of rejection was very low and no correlation was observed between one or more minor H antigen mismatch(es) and a rejection episode (n = 36), of which only eight resulted in graft loss. In summary, in our study cohort of 444 renal transplants, mismatching for neither autosomal nor HY minor H antigens correlate with rejection episodes or with graft loss.

Natural IgG anti-F(ab')2 Abs are part of the physiologic immune repertoire and have important immunoregulatory functions. Although previous work suggested that some of these Abs recognize epitopes located in the constant region of the F(ab')2 molecule, an exact epitope mapping has not been performed. We found that the anti-F(ab')2 Ab binds strongly to F(ab')2 but only weakly to Fab fragments. Fab fragments are lacking the core and lower hinge region. In our experiments, we show that the IgG anti-F(ab')2 Ab binds strongly to a synthetic double chain peptide (225-237/225'-237') comprising the core and lower hinge region of the human IgG1 molecule. In contrast, it binds only weakly to the same peptide in monomeric form (225-237) or to a short double chain hinge peptide (225-232/225'-232'). The double chain peptides comprise a cyclic region between the two cystine bridges and an exocyclic region. Previous nuclear magnetic resonance analyses showed that the cyclic portion of the short double chain hinge peptide adopts the same conformation as that found in the intact IgG1 molecule. The dichroic properties of the short and long double chain hinge peptides indicate that they have identical conformations in their cyclic regions, but have different conformations in their exocyclic regions. The conformational differences in the exocyclic regions explain the binding of the Ab to the long double chain hinge peptide and the lack of binding to the short one. The circular dichroism spectrum of the monomeric hinge peptide, which is not recognized by the Ab, is consistent with the absence of an ordered peptide structure. These findings lead us to conclude that the IgG anti-F(ab')2 Ab recognizes a conformational IgG1 hinge epitope.

Whether potential kidney transplant recipients should be transfused or not in preparation for a transplant is controversial. Although a beneficial effect of transfusions on graft survival had been shown in numerous previous publications, a recent analysis of the Collaborative Transplant Study data provided evidence that the transfusion effect had nearly disappeared during the years 1984 and 1985} In contrast to this observation is the data of the American UCLA Registry in which a strong improvement effect of transfusions on grafts is evident even in the 1984/1985 period.? Because the data are in disagreement, and because a reason for the discrepant results has not been found, it is currently impossible to make definite recommendations concerning the use of transfusions for transplant preconditioning. The greatest uncertainty with respect to the recent improvement of results in nontransfused recipients in the Collaborative Transplant Study data is the possibility that sampling errors might have explained the unexpected observation. With the relatively small number of non-transfused patients that was available for analysis, the likelihood of statistical error is not negligible. It was therefore particularly interesting to see whether the results obtained in a subsequent series of transplants, namely those performed in 1986, would either confirm or disprove the previous Collaborative Transplant Study report.

Bone marrow transplantation has become the treatment of choice for certain hematologic diseases. However, only 30-40% of patients who might benefit from this procedure have a suitable family donor. Consequently, many centers have begun to explore the use of unrelated volunteer donors. Initial results have demonstrated the feasibility of this approach. As a result, a national effort has begun to recruit HLA-typed volunteers in order to establish a registry of individuals who would be willing to serve as bone marrow donors. This manuscript explores the potential impact of establishing such a registry. We find that a registry of attainable size could more than double the number of marrow transplants now being performed. However, even with a registry of enormous size, it will still not be possible to identify an HLA-matched donor for some patients.

Whether matching for HLA antigen "splits" results in better transplant outcome than matching for "broad" HLA antigens was investigated in 30,000 first cadaver kidney transplants. At three years, there was an 18% difference between the survival rates of grafts with 0 or 4 mismatches among transplants typed for HLA-A and B antigen splits whereas the difference in transplants typed for broad antigens was only 2%. Analysis of HLA-A, B antigens together with HLA-DR antigens showed an even greater advantage of matching for antigen splits: the difference in survival at three years between grafts with 0 or 6 mismatches for HLA-A, B, DR was 31% when antigen splits were analysed, in contrast to a 6% difference with broad antigens. These results indicate that typing for HLA antigen splits is important in renal transplantation, that the potential benefit of HLA matching in renal transplantation is greater than currently accepted, and that HLA typing and kidney allocation routines must be refined in order to exploit this potential.

In an analysis of over 4000 cyclosporine-treated recipients of second kidney transplants we observed a strong effect of HLA matching in living-related and cadaver transplants. In contrast to the results obtained in first cadaver transplants, second cadaver transplants benefited substantially from matching for HLA-A locus antigens. The strongest effect of matching was found when HLA-A, HLA-B, and HLA-DR antigens were analyzed together: 214 second grafts with no mismatch had a survival rate of 82 +/- 3% at two years in contrast to a 49 +/- 4% rate in 149 grafts with 6 mismatches (P less than 0.0001, log rank). Patients whose first graft functioned for more than 1 year had a significantly higher second graft survival rate than patients with shorter first graft duration. Because the effect of HLA matching is particularly strong in patients with less than 1 year first graft duration, it is suggested that HLA well-matched kidneys should be allocated to them with priority.

An excellent correlation of predicted and observed cadaver kidney graft survival rates was obtained using a nine-factor computer model. A total of 924 recipients for whom a greater than 80% 1-year survival rate was predicted had an observed rate of 84.6%, whereas 179 recipients with a predicted 1-year success rate of less than 40% had an observed rate of 38.2%. Our model gives improved results as compared with previously published methods. We anticipate that the model's predictive power can be further refined, and that patient selection and organ sharing will benefit from the application of sophisticated computer models for the prediction of transplant success.

Lymphoid and dendritic cells of donor origin can be detected in the recipient several years after a solid organ transplantation. This phenomenon is termed microchimerism and could play a role in the induction of tolerance. The fate of other hematopoietic cells transferred by liver transplantation, in particular of stem and progenitor cells, is unknown. For this reason, we studied peripheral blood and bone marrow samples of 12 patients who had received a liver transplant from an HLA-DR mismatched donor. Eight patients were long-term survivors between 2.8 and 10.1 years after allografting. CD34(+) cells from bone marrow were highly enriched with the use of a 2-step method, and a nested polymerase chain reaction was applied to detect donor cells on the basis of allelic differences of the HLA-DRB1 gene. Rigorous controls with DRB1 specificities equal to the donor and host were included. In 5 of 8 long-term liver recipients, donor-specific CD34(+) cells could be detected in bone marrow. Microchimerism in the CD34(+) cell fraction did not correlate to the chimeric status in peripheral blood. In conclusion, our results demonstrate a frequent microchimerism among bone marrow-derived CD34(+) cells after liver transplantation. The functional role of this phenomenon still needs to be defined. (Blood. 2000;96:763-767)

Whether kidneys from cadaver donors should be exchanged among transplant centers is controversial. We analyzed the effect of matching for HLA-B and HLA-DR antigens on graft survival in patients treated with cyclosporine. The results in 9369 recipients of kidneys obtained and transplanted in the same center were compared with those in 5553 recipients of kidneys shipped from one center to another. In both patient subgroups, the association of HLA matching with graft survival was statistically significant (P less than 0.0001). Moreover, well-matched exchanged kidneys survived better than poorly matched locally transplanted kidneys. Among patients receiving their first cadaver transplant, graft survival at one year was 13 percentage points higher (P less than 0.0001) in exchanged kidneys without mismatches than in local kidneys with four mismatches. Among patients receiving their second transplant, graft survival was 21 percentage points higher (P less than 0.001). Kidney preservation for up to 48 hours did not affect graft survival significantly. Transplantation of poorly matched local kidneys preserved with a short period of cold ischemia (less than 24 hours) had significantly lower rates of success than did transplantation of well-matched exchanged kidneys with a longer period of cold ischemia (up to 48 hours) (P less than 0.0001). Our data indicate that the exchange of cadaver kidneys among transplant centers to obtain grafts with better HLA matching can improve the success rate of renal transplantation.

Introduction: donor-derived modified immune cells (MIC) induced long-term specific immunosuppression against the allogeneic donor in preclinical models of transplantation. In a phase I clinical trial (TOL-1 Study), MIC treatment resulted in a cellular phenotype that was directly and indirectly suppressive to the recipient's immune system allowing for reduction of conventional immunosuppressive therapy. Here, we describe a protocol for a randomised controlled, multicentre phase-IIb clinical trial of individualised immunosuppression with intravenously administered donor MIC compared with standard-of-care (SoC) in living donor kidney transplantation (TOL-2 Study). Methods and analysis: sixty-three living donor kidney transplant recipients from six German transplant centres are randomised 2:1 to treatment with MIC (MIC group, N=42) or no treatment with MIC (control arm, N=21). MIC are manufactured from donor peripheral blood mononuclear cells under Good Manufacturing Practice conditions. The primary objective of this trial is to determine the efficacy of MIC treatment together with reduced conventional immunosuppressive therapy in terms of achieving an operational tolerance-like phenotype compared with SoC 12 months after MIC administration. Key secondary endpoints are the number of patient-relevant infections as well as a composite of biopsy-proven acute rejection, graft loss, graft dysfunction or death. Immunosuppressive therapy of MIC-treated patients is reduced during follow-up under an extended immunological monitoring including human leucocyte antigen-antibody testing, and determination of lymphocyte subsets, for example, regulatory B lymphocytes (Breg) and antidonor T cell response. A Data Safety Monitoring Board has been established to allow an independent assessment of safety and efficacy. Ethics and dissemination: ethical approval has been provided by the Ethics Committee of the Medical Faculty of the University of Heidelberg, Heidelberg, Germany (AFmu-580/2021, 17 March 2022) and from the Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institute, Langen, Germany (Vorlage-Nr. 4586/02, 21 March 2022). Written informed consent will be obtained from all patients and respective donors prior to enrolment in the study. The results from the TOL-2 Study will be published in peer-reviewed medical journals and will be presented at symposia and scientific meetings. Trial registration number NCT05365672., Preparation of the study was funded by the Federal Ministry of Education and Research, Berlin, Germany (FKZ 161B0560A, 161B0560B, and FKZ 031B0560A, 031B0560B), and TolerogenixX GmbH, Heidelberg, Germany (N/A). Conduct of the study is funded by TolerogenixX GmbH (N/A).

Transplantation offers a unique opportunity to demonstrate the complementary roles of randomized controlled trials and outcome research. The surgery and collaboration necessary for the transplant procedure makes randomization and blinding difficult. Because essentially every recipient is included in a transplant registry, sampling bias is minimized. Regulatory agencies generally do not consider outcomes research when assessing efficacy of new drugs or medical interventions. This workgroup summary examines the suitability of outcomes research to complement results of randomized controlled trials and related issues: efficacy versus effectiveness, internal versus external validity, data types, limitations, and analysis methodologies. Many advances in outcomes research have been pioneered in transplantation. A case is made for regulatory and reimbursement authorities to use outcomes research when making efficacy, effectiveness, and coverage decisions in transplantation.