PIRCHE-II: an algorithm to predict indirectly recognizable HLA epitopes in solid organ transplantation

Abstract

Human leukocyte antigen (HLA) mismatches between donors and recipients may lead to alloreactivity after solid organ transplantation. Over the last few decades, our knowledge of the complexity of the HLA system has dramatically increased, as numerous new HLA alleles have been identified. As a result, the likelihood of alloreactive responses towards HLA mismatches after solid organ transplantation cannot easily be assessed. Algorithms are promising solutions to estimate the risk for alloreactivity after solid organ transplantation. In this review, we show that the recently developed PIRCHE-II (Predicted Indirectly ReCognizable HLA Epitopes) algorithm can be used to minimize alloreactivity towards HLA mismatches. Together with the use of other algorithms and simulation approaches, the PIRCHE-II algorithm aims for a better estimated alloreactive risk for individual patients and eventually an improved graft survival after solid organ transplantation.

Patterns of 1,748 Unique Human Alloimmune Responses Seen by Simple Machine Learning Algorithms

“…An alternative approach for epitope based matching is the identification of the mismatched HLA derived epitopes that can be recognized by T cells via the indirect pathway using the PIRCHE-II algorithm. A higher PIRCHE-II score was related to both de novo donor specific HLA formation and allograft rejection (28). Our study proposes for an algorithm aiming to clarify the targets of the anti-HLA response after generation of effector alloantibodies.…”

Population Frequencies Determined by Next-generation Sequencing Provide Strategies for Prospective HLA Epitope Matching for Transplantation

“…Complementary genomic and proteomic methods have clarified the structural biology of HLA antigens, enabling more precise understanding of the complex and sequential mechanisms of allorecognition by T and B lymphocytes [14][15][16] . Two cardinal groups of epitopes are now recognized, those involved in indirect recognition of the donor HLA antigen array by recipient T cell which are predicted through the PIRCHE algorithm 17 , and those which are antibody-accessible and are involved in the humoral response, predicted through the HLAMatchmaker algorithm 10 . Studies confirm that the mismatch between donor and recipient for each of these two sets of molecular targets is directly related to the risk of rejection and graft loss 11,12,[18][19][20] .…”

Toward defining the immunogenicity of HLA epitopes: Impact of HLA class I eplets on antibody formation during pregnancy

“…3 Another approach computable on the basis of AA sequences, useful for pre-SOT risk assessment, the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE-II) algorithm, considers whether mismatched HLA is "presentable" as peptides within the binding cleft of the recipient's HLA class II of antigen-presenting cells (APCs) or B-cells in order to provide T-cell help for proper B-cell activation. 4 A different level of analysis is reached by comparing tertiary protein structures of donor-and recipient-HLA because antigen allogenicity and immunogenicity are largely impacted by the three-dimensional (3D) conformation of critical AA patches. Resulting nonself 3Dstructures on donor-HLA can be used to determine functional binding elements potentially targeted by structural B-cell receptors (BCR) and antibodies, termed eplets, 5 or to assess the degree of different electrostatic potentials (EMS-3D) between mismatched AA and AA-patches.…”

“…It was shown that the total AA‐mismatch load is predicting the risk for the development of de novo donor‐specific antibodies (DSA) more precisely than conventional HLA matching 3 . Another approach computable on the basis of AA sequences, useful for pre‐SOT risk assessment, the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE‐II) algorithm, considers whether mismatched HLA is “presentable” as peptides within the binding cleft of the recipient's HLA class II of antigen‐presenting cells (APCs) or B‐cells in order to provide T‐cell help for proper B‐cell activation 4 …”