Activity 1: Improving Donor Matching Through Epitope Typing

HLA matching at the epitope level offers new opportunities to identify compatible donors for kidney transplant candidates. It has been demonstrated that transplantation with significant epitope mismatches often result in the formation of new donor specific antibodies (DSA) and result in antibody mediated rejection (AMR).

These epitopes may be recognized by B-cells or T-cells, and algorithms have been derived to define both. For example, HLAMatchmaker is a computer algorithm that deduces B-cell epitope (‘eplet’ in HLAMatchmaker) mismatches from allele-level donor-recipient HLA types.

The HLA Epitope Registry (www.Epregistry.com.br) lists all eplet mismatches that have been verified by HLA antibodies. ElliPro (derived from Ellipsoid and Protrusion) considers the three-dimensional structure of protein antigens and assigns a protrusion score to each residue on proteins. It has recently been shown that the ElliPro score, together with intrinsic properties of amino acid residues defining eplets, allow better differentiation of class I eplets likely to be verified by antibodies (epitopes) than those which are not (non-epitopes). Finally, the PIRCHE (Predicted Indirectly ReCognizable Epitopes) algorithm determines donor-recipient HLA-A/B/C, DRB, and DQB-derived T-helper epitopes to estimate the risk of antibody development (96, 97).

Activity 1A

To Develop Web-Based Programs For National Epitope Matching.

The likelihood of transplantation success is strongly correlated with the degree of HLA class I and class II epitope similarity between donors and recipient. The aim of the activity is to determine the frequency of HLA class I and class II epitopes in the Canadian population. This will aid in optimizing transplantation success. The frequencies calculations will be used to estimate 1) the probability of compatibility for each recipient in relation to new donors and 2) the quantitative impact of cumulative epitope mismatches between graft donor and recipient on the risk of AMR. These findings will help the Canadian Blood Services to develop unique web-based calculators that generate each of these frequency-based measures of clinical utility to the Canadian transplant program and may also be made available globally to other units, regions and countries.

Our Partner Agencies

As part of our commitment to a stronger patient-oriented research approach in this project, we have recruited a Patient and Family Advisory Group to inform, shape and provide feedback to the development.

Activity 1B

To Implement Efficient Genomic Methods For Recipient and Donor Epitope Typing

The development of a national epitope matching strategy requires unambiguous DNA-level sequence for the 11 polymorphic HLA genes. This data would need to be stored in a centralized Canadian Blood Services registry for all potential kidney recipients and donors. Furthermore, the complete HLA sequence typing would need to be determined within a 6 hour window for the deceased donors because delays in transplantation following the surgical recovery negatively correlate with the long-term survivability and function of the organ. Our goal is to develop a HLA genotyping methodology which provides: 1) unambiguous DNA-level HLA typing of recipients and deceased donors, (b) protocols that can be easily standardized across all 14 Canadian HLA laboratories, and (c) continuous quality assurance to guarantee national performance and precision.