Xenoantigen Deletion and Chemical Immunosuppression Can Prolong Renal Xenograft Survival

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d1090160e182">Objective:</h5> <p id="P1">Xenotransplantation using pig organs could end the donor organ shortage for transplantation, but humans have xenoreactive antibodies that cause early graft rejection. Genome editing can eliminate xenoantigens in donor pigs to minimize the impact of these xenoantibodies. Here we determine whether an improved crossmatch and chemical immunosuppression could result in prolonged kidney xenograft survival in a pig-to-rhesus preclinical model. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d1090160e187">Methods:</h5> <p id="P2">Double xenoantigen (Gal and Sda) knockout (DKO) pigs were created using CRISPR/Cas. Serum from rhesus monkeys (n=43) was cross matched with cells from the DKO pigs. Kidneys from the DKO pigs were transplanted into rhesus monkeys (n=6) that had the least reactive cross matches. The rhesus recipients were immunosuppressed with anti-CD4 and anti-CD8 T cell depletion, anti-CD154, mycophenolic acid, and steroids. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d1090160e192">Results:</h5> <p id="P3">Rhesus antibody binding to DKO cells is reduced, but all still have positive CDC and flow crossmatch. Three grafts were rejected early at 5, 6, and 6 days. Longer survival was achieved in recipients with survival to 35 days, 100 days, and 435 days. Each of the three early graft losses was secondary to IgM antibody mediated rejection. The 435-day graft loss occurred secondary to IgG antibody mediated rejection. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d1090160e197">Conclusions:</h5> <p id="P4">Reducing xenoantigens in donor pigs and chemical immunosuppression can be used to achieve prolonged renal xenograft survival in a preclinical model, suggesting that if a negative crossmatch can be obtained for humans that prolonged survival could be achieved. </p> </div><p id="P5">Xenotransplantation is hampered by the presence of pre-formed antibodies. Here we reduced xenoantigen expression on pig kidneys through genetic engineering and identified ideal donor-recipient pairs through cross-matching. The outcomes of six pig to non-human primate life-sustaining kidney xenotransplants are presented. </p>

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Desensitization in HLA-incompatible kidney recipients and survival.

Robert Montgomery, Bonnie Lonze, Karen E. King … (2011)

More than 20,000 candidates for kidney transplantation in the United States are sensitized to HLA and may have a prolonged wait for a transplant, with a reduced transplantation rate and an increased rate of death. One solution is to perform live-donor renal transplantation after the depletion of donor-specific anti-HLA antibodies. Whether such antibody depletion results in a survival benefit as compared with waiting for an HLA-compatible kidney is unknown. We used a protocol that included plasmapheresis and the administration of low-dose intravenous immune globulin to desensitize 211 HLA-sensitized patients who subsequently underwent renal transplantation (treatment group). We compared rates of death between the group undergoing desensitization treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group). In the treatment group, Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons). Live-donor transplantation after desensitization provided a significant survival benefit for patients with HLA sensitization, as compared with waiting for a compatible organ. By 8 years, this survival advantage more than doubled. These data provide evidence that desensitization protocols may help overcome incompatibility barriers in live-donor renal transplantation. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Charles T. Bauer Foundation.).

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Rituximab and intravenous immune globulin for desensitization during renal transplantation.

Ashley A Vo, Marina Lukovsky, Mieko Toyoda … (2008)

Few options for transplantation currently exist for patients highly sensitized to HLA. This exploratory, open-label, phase 1-2, single-center study examined whether intravenous immune globulin plus rituximab could reduce anti-HLA antibody levels and improve transplantation rates. Between September 2005 and May 2007, a total of 20 highly sensitized patients (with a mean [+/-SD] T-cell panel-reactive antibody level, determined by use of the complement-dependent cytotoxicity assay, of 77+/-19% or with donor-specific antibodies) were enrolled and received treatment with intravenous immune globulin and rituximab. We recorded rates of transplantation, panel-reactive antibody levels, cross-matching results at the time of transplantation, survival of patients and grafts, acute rejection episodes, serum creatinine values, adverse events and serious adverse events, and immunologic factors. The mean panel-reactive antibody level was 44+/-30% after the second infusion of intravenous immune globulin (P<0.001 for the comparison with the pretreatment level). At study entry, the mean time on dialysis among recipients of a transplant from a deceased donor was 144+/-89 months (range, 60 to 324). However, the time to transplantation after desensitization was 5+/-6 months (range, 2 to 18). Sixteen of the 20 patients (80%) received a transplant. At 12 months, the mean serum creatinine level was 1.5+/-1.1 mg per deciliter (133+/-97 micromol per liter), and the mean survival rates of patients and grafts were 100% and 94%, respectively. There were no infusion-related adverse events or serious adverse events during the study. Long-term monitoring for infectious complications and neurologic problems revealed no unanticipated events. These findings suggest that the combination of intravenous immune globulin and rituximab may prove effective as a desensitization regimen for patients awaiting a transplant from either a living donor or a deceased donor. Larger and longer trials are needed to evaluate the clinical efficacy and safety of this approach. (ClinicalTrials.gov number, NCT00642655.) 2008 Massachusetts Medical Society

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Class II HLA epitope matching-A strategy to minimize de novo donor-specific antibody development and improve outcomes.

Julia Wiebe, D Pochinco, T D Blydt-Hansen … (2013)

De novo donor-specific antibody (dnDSA) develops in 15-25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA-DR/DQ/DP conformational epitopes for 286 donor-recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus-specific epitope mismatches were more numerous in patients who developed HLA-DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA-DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA-DR, 17 for HLA-DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA-DR and HLA-DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA-DR and 3 HLA-DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA-DR and DQ epitope matching outperforms traditional low-resolution antigen-based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long-term graft outcome.