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Several studies from various centers have indicated that the PIRCHE epitope matching scores in solid organ-transplanted patients may correlate with the incidence of de novo production of donor specific antibodies (DSA). According to these data, patients with high PIRCHE scores have higher incidence of de novo DSA compared with recipients with low PIRCHE scores.

De novo DSA

De novo donor-specific HLA antibodies (dnDSA) are recognized as a risk factor for premature allograft failure. DSA production occurs exclusively via the indirect allorecognition pathway in which foreign HLA is processed by the recipient’s professional antigen-presenting cells and presented via HLA class II (primarily HLA- DRB1) to CD4+ T cells. Consequently, activated CD4+ T cells provide further help to other effector immune cells in the generation of alloreactive CD8 + T cells and antibody-producing B cells. Indirect T-cell recognition of allogeneic HLA depends on HLA derived peptides that differ between host and graft. These HLA-derived peptides are likely presented on shared HLA. HLA-derived peptides being identical between donor and recipient should be ignored by the alloimmune system, as T-cells recognizing these peptides should have been deleted from the repertoire due to thymic selection. Thus, the GvHD reaction after transplantation should be evoked by recipient-specific peptides. In order to predict permissibility of HLA mismatches PIRCHE predicts the presentation of allogeneic HLA derived peptides on shared HLA. Any difference in presentable peptides derived from donor-versus recipient alleles is regarded a PIRCHE.

PIRCHE

The Prediction of Indirectly ReCognized HLA Epitopes (PIRCHE) is a new algorithm to estimate the potential of a T-cell related graft versus host immune response against mismatching HLA after transplantation. The PIRCHE algorithm has the goal to provide additional data to support the decision about the best donor for a particular patient, in case no full matching donor is available.

Eric Spierings, PhD is the inventor of the PIRCHE algorithm. His working group published the proof of concept, which showed increased PIRCHE numbers in kidney transplanted patients correlate with immunogenicity of HLA antibodies.

The PIRCHE score is calculated between patient and donor at the time of allocation and does not change over time.

PIRCHE forecasts T-cell related immune responses against HLA derived peptides after transplantation. In contrast to existing technologies, the indirect pathway of allorecognition is in focus. This takes another important functional aspect of HLA molecules into account: HLAs load peptides into their characteristic binding grooves to present it to the antigen-peptide-specific receptors of T-cells.

In transplantation, mismatched HLA proteins are introduced to the immune system. When being processed by enzymes or the proteasome, peptides are derived that are unknown to the T-cells, making them a potential target for immune responses. The technology of PIRCHE predicts these peptides only by using the HLA typing of patient and donor. The number of PIRCHEs presented on HLA class-I and -II are called PIRCHE-I and –II.

The hypothesis is that the PIRCHE algorithm may be a better predictor for histocompatibility of kidney transplants, dnDSA formation, and allograft survival than classical antigen matching.