Epitope-based human leukocyte antigen matching for transplantation.

DOI:10.1097/MOT.0000000000000107 Human leukocyte antigen (HLA) antibodies represent important risk factors for transplant rejection and failure. They are now being recognized as specific for epitopes which can be defined structurally with amino acid differences between HLA alleles. Donor-recipient compatibility should, therefore, be assessed at the epitope rather than the antigen level. HLAMatchmaker is a computer algorithm that considers each HLA antigen as a series of small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes. Previous Current Opinion articles describe the HLAMatchmaker algorithm and its usefulness in HLA epitope matching and antibody testing for organ transplantation [1,2]. There is now a website-based International Registry of Antibody-Defined HLA Epitopes (http://www.epre gistry.com.br) [3]. Its goal is to develop a repertoire of HLA epitopes that have been verified by specific antibodies. HLA epitopes can be defined structurally by molecular modeling and amino acid sequence differences between antibody-reactive and nonreactive alleles. Each HLA antigen is viewed as a collection of epitopes that can be determined according to general concepts how antibodies bind with protein epitopes. Antibodies have three heavy-chain and three light-chain Complementarity Determining Region loops that bind to a protein epitope. So-called structural epitopes may have up to 25 contact residues, each one has a centrally located ‘functional’ epitope consisting of a few residues and which plays a dominant role in the specificity of binding with antibody. HLAMatchmaker considers eplets equivalent to functional epitopes and eplets represent key elements of HLA epitopes that elicit specific antibodies. Eplets are annotated by position numbers in the amino acid sequence and standard single-letter polymorphic residues within a radius of about 3 Ångstroms. The general dimension of a structural epitope is 700–900 square Ångstrom dimensions, and one can calculate that other antibody-contacting residues on the HLA molecular surface are within a radius of about 15 Ångstroms of an eplet.