De novo donor-specific antibodies in renal transplantation
| dc.contributor.author | Wiebe, Chris | |
| dc.contributor.examiningcommittee | Rush, David (Internal Medicine) HayGlass, Kent (Immunology) Wilkins, John (Biochemistry & Medical Genetics) | en_US |
| dc.contributor.supervisor | Nickerson, Peter (Immunology) | en_US |
| dc.date.accessioned | 2014-07-02T20:57:11Z | |
| dc.date.available | 2014-07-02T20:57:11Z | |
| dc.date.issued | 2012-05 | en_US |
| dc.date.issued | 2013-10 | en_US |
| dc.degree.discipline | Immunology | en_US |
| dc.degree.level | Master of Science (M.Sc.) | en_US |
| dc.description.abstract | The natural history for patients with de novo donor-specific antibodies (dnDSA) and the risk factors for its development have not been well defined. Furthermore, clinical and histologic correlation with serologic data is limited. We studied 315 consecutive renal transplants without pre-transplant donor-specific antibody (DSA), with a mean follow-up of 6.2 ± 2.9 years. Protocol (n = 215) and for cause (n = 163) biopsies were analyzed. Solid phase assays were used to screen for dnDSA post-transplant. A total of 47 out of 315 (15%) patients developed dnDSA at a mean of 4.6 ± 3.0 years post-transplant. Independent predictors of dnDSA were HLA-DRβ1 MM > 0 (OR 5.66, p < 0.006); and non-adherence (OR 8.75, p < 0.001); with a strong trend toward clinical rejection episodes preceding dnDSA (OR 1.57 per rejection episode, p=0.061). The median 10-year graft survival for those with dnDSA was lower than the No dnDSA group (57% vs. 96%, p < 0.0001). Pathology consistent with antibody-mediated injury occurred and progressed in patients with dnDSA in the absence of graft dysfunction. Furthermore, non-adherence and cellular rejection contributed to both dnDSA development and the risk of progression to graft loss. (Human leukocyte antigen) 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 a subset of 286 donor–recipient pairs in which samples were available for high-resolution HLA-typing. 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 mismatch (10 for HLA-DR, 17 for HLA-DQ) was defined that was associated with minimal development of Class II dnDSA using a receiver operating characteristic analysis. Applying these thresholds, 0% and 2.7% of patients developed dnDSA against HLA-DR and HLA-DQ, respectively, after a median of 6.9 years follow-up. Epitope specificity analysis revealed that 3 HLA-DR and 3 HLA-DQ epitopes were independent multivariate predictors of Class II dnDSA when mismatched between the donor and recipient. 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. | en_US |
| dc.description.note | October 2014 | en_US |
| dc.identifier.citation | Am J Transplant 12:5, 1157-67 | en_US |
| dc.identifier.citation | Am J Transplant 13:12, 3114-22 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/23678 | |
| dc.language.iso | eng | en_US |
| dc.publisher | Wiley Periodicals Inc | en_US |
| dc.rights | open access | en_US |
| dc.subject | transplantation | en_US |
| dc.subject | donor-specific antibody | en_US |
| dc.subject | allograft rejection | en_US |
| dc.subject | HLA | en_US |
| dc.title | De novo donor-specific antibodies in renal transplantation | en_US |
| dc.type | master thesis | en_US |