A Europe-wide strategy to enhance transplantation of highly sensitized patients on basis of Acceptable HLA mismatches

WP1: Inventory of long waiting highly sensitized patients in the different registries and their HLA phenotypes

Objective: Aim of the project is to find a compatible kidney for long waiting highly sensitized patients. The first step to be made is to make an inventory of the long waiting highly sensitized patients in the different transplant organizations participating in this project. A central database will be made, in which finally the HLA types of the highly sensitized patients from the different registries and their acceptable mismatches will be included. This database will be kept up to date during the course of the program.

Based on the information in this database the chance that a patient will be transplanted with a theoretical (WP2) and actual (WP3) donor from another population can be calculated (WP6). Furthermore, this data base will function as the waiting list for the pilot study described in WP9.

WP2: Collection of data on the HLA phenotypes in different European populations

Objective: In the pilot study we will determine the chance that a highly sensitized patient will be transplanted with an actual donor from the populations represented in this consortium (WP3) and perform some transplants to check the logistics of such an organ allocation. However, final aim is to set up a Europewide acceptable mismatch program. In order to analyze the benefit of such a program we will perform simulation studies in which we will calculate the theoretical chance that the highly sensitized patients of this consortium can by transplanted with donors derived from any European population from which the HLA phenotypes are known. In this work package an inventory will be made from the HLA phenotypes in all possible European populations.

WP3: Collection of the HLA phenotype frequencies of the actual organ donors in the different registries

Objective: Within Eurotransplant a tool has been developed to calculate the actual chance that a highly sensitized patient will be transplanted based on the HLA phenotypes of the actual organ donors, which became available in the Eurotransplant area during the last 10 years. Based on this tool, one can predict that about 35 % of the highly sensitized patients will never be transplanted with a donor derived from the Eurotransplant population. Aim of this work package is to extend this database by adding the HLA phenotypes of the actual organ donors retrieved by the organizations in the other populations. The different partners (3,4,5,6,7) will be responsible for collecting this information, while the WP leader (partner 1) will be responsible for filling the database. This database will be used for simulation studies which aim at the definition of the chance that a highly sensitized patients in the database collected in WP1 can be transplanted with a donor derived from the populations of the different participants.

WP4: Definition of the acceptable HLA mismatches of the highly sensitized patients

Objective: Basis of the acceptable mismatch program is the exact definition of the allogeneic HLA antigens towards which the patient did not form antibodies. This information is crucial for the selection of compatible donors (WP9) and for the simulation studies aiming at the definition of the chance that a patient will transplanted with a donor derived from another population (WP2, WP3, WP6).

WP5: Definition of the relevant epitopes and translation of HLA phenotypes and acceptable mismatches into epitopes

Objective: A problem for an exact definition of all acceptable HLA mismatches (WP4) is the enormous polymorphism of the HLA system. It is virtually impossible to define which of the more than 4000 HLA class I alleles are acceptable. Recent studies suggest HLA antigens can be considered as strings of epitopes, which are shared between different HLA antigens. We estimate that about 150 polymorphic residues are responsible for the induction of antibodies against all the HLA alleles. Objective of this work package is the exact definition of the relevant epitopes and testing whether the definition of acceptable epitopes rather than HLA antigens will facilitate the identification of compatible donors.

WP6: Development of a tool to calculate the chance that a highly sensitized patient will be transplanted with a donor from another European population

Objective: The databases generated by WP 1, 2, 3 and 4 will be used to calculate the chance that a highly sensitized with known acceptable HLA mismatches will be transplanted with a donor derived from one of the other populations. A computer algorithm will be developed and validated for these analyses before the actual simulations will be performed.

WP7: Development of the optimal typing technique to define the HLA antibody epitopes in donors and recipients

Objective: It is to be expected that the definition of acceptable HLA epitopes as defined in WP5 rather than HLA antigens will facilitate the search for a compatible donor for highly sensitized patients. At the moment high resolution typing by sequence-based typing (or in the future next generation sequencing) is necessary to characterize the pivotal polymorphisms in the different HLA alleles. However, high resolution typing is not routinely done in tissue typing laboratories involved in solid organ transplantation and, furthermore, in case of a deceased donor these assays take too much time. Aim of this work package is to develop and validate a simple alternative typing strategy aiming at the quick definition of the polymorphisms in the HLA genes, which are relevant for antibody induction.

WP8: Determination of the clinical relevance of donor specific endothelial cell antibodies

Objective: The allocation of organs to highly sensitized patients via the acceptable mismatch program is based on the absence of donor specific HLA antibodies. The endothelium in the graft, which is the main target for donor specific antibodies, also expresses other (non-HLA) antigens. Aim of this work package is to define the relevance of endothelial cell specific antibodies for the outcome of transplants in highly sensitized patients.

WP9: Pilot study on the actual implementation of a Europe-wide acceptable mismatch program

A Europe-wide acceptable mismatch program, the final aim of this project, would mean allocation and transportation of donor kidneys between different countries all over Europe. It is to be expected that this will be associated with logistic problems, which probably need adaptation of the current protocols. A pilot study will be performed in which some of the highly sensitized patients from the different participating transplantation programs will be transplanted with donors derived from other populations. This work package should lead to more insight in the logistics and problems associated with the future introduction of a Europe-wide acceptable mismatch program.

WP10: Project Management
Milestones
  1. Milestone number Milestone name WP package(s) involved Delivery date[1] Means of verification[2]
    1. Tool available to calculate the chance that a patient will be transplanted with a donor from another population. WP6 Month 6 Validation by different partners by analyses of transplants performed in their own populations.
    2 Computer algorithm to translate HLA antigens into epitopes and the other way around. WP5 Month 6 Validation by histocompatibility experts in the consortium.
    3 Availability of an endothelial cell crossmatch   test, which distinguishes complement fixing versus non-complement fixing antibodies WP8 Month 12 Validation by histocompatibility labs in the consortium
    4 Prototype of multiplex PCR assay for quick determination of HLA epitopes WP 7 Month 12 Validation by histocompatibility experts in the consortium.
    5 Simulation showing the advantage of donor selection from other populations. WP1,2,3,4,5 Month 18 Demonstration that a significant number of long waiting highly sensitized patients in theory can be transplanted with donors in databases developed by WP2 and WP3.
    6 Common waiting list of highly sensitized patient with acceptable HLA mismatches suitable for pilot study WP1, 4 Month 24 Validation by whole consortium
    7 Database with relevant epitopes on HLA antigens to simplify to the future search for compatible donors. WP 5 Month 30 Validation by comparing acceptable HLA antigens versus acceptable epitopes for donor selection
    8 Actual transplant performed with donors from other populations WP 9 Month 24-36 Allocation of donor kidney to a highly sensitized patient from anther population.

    [1] Month in which the milestone will be achieved. Month 1 marking the start date of the project, and all delivery dates being relative to this start date. [2] Show how you will confirm that the milestone has been attained. Refer to indicators if appropriate. For example: a laboratory prototype completed and running flawlessly; software released and validated by a user group; field survey complete and data quality validated.

Deliverables
Delive­rable No. Deliverable name WP No. Nature[1] Dissemi­nation level[2] Delivery date[3]
1. First version of patient database 1 P PP 4
2. Patient database with all requirements for simulation and allocation. 1,4 P PP 18
3. First version of database with HLA phenotype frequencies of European populations 2 P PP 12
4. Final database with HLA phenotype frequencies of European populations 2 P PU 36
5. Preliminary database with HLA phenotypes of actual organ donors 3 P PP 6
6. Database with donor HLA phenotypes for simulation studies 3 P PP 18
7 Database with patients HLA phenotypes and acceptable mismatches for pilot study 4 P PP 24
8 Prototype of algorithm to translate HLA antigens into epitopes. 5 P PP 6
9 List of relevant epitopes 5 P PU 30
10 Tool to calculate the chance to find a compatible donor 6 P PP 6
11 Prototype of multiplex PCR assay 7 P CO 12
12 Extensive version of multiplex assay 7 P PP 30
13 Adapted endothelial cell crossmatch 8 P PP 12
14 Data on relevance of endothelial cell and MICA antibodies 8 P PU 36
15 Transplantation of highly sensitized patients with donors from other populations 9 D PU 24-36
16. Project management 10 R PP 1-36
17. Recommendation with all requirements to set up and start a Europe-wide acceptable mismatch program. 1-10 R PU 36

[1]           R = Report, P = Prototype, D = Demonstrator, O = Other

[2]           PU = Public, PP = Restricted to other programme participants (including the Commission Services)

RE = Restricted to a group specified by the consortium (including the Commission Services)

CO = Confidential, only for members of the consortium (including the Commission Services)

[3]           Month in which the deliverables will be available. Month 1 marking the start date of the project, and all delivery dates being relative to this start date.