Molecular basis of HLA polymorphism: implications in clinical transplantation

Abstract

Polymorphism of the human leukocyte antigens (HLA) represents a major barrier to organ and hematopoietic stem cell (HSC) transplantation. The cloning and sequencing of HLA class I and II genes has not only provided a clear picture of the molecular basis of allelic polymorphism, but also allowed the development of a variety of PCR-based DNA typing techniques. Such methods are now progressively replacing serological typing for assessing donor/recipient HLA compatibility in clinical transplantation. The 100 serological HLA-A,B,Cw,DR,DQ,DP specificities now comprise more than 1300 alleles defined at the DNA sequence level. Most of the serotypes are subdivided into numerous allelic subtypes in worldwide populations (up to 50 alleles in some cases), although a limited number of alleles are detected in a given population group. In organ transplantation application of HLA molecular typing allowed to improve typing quality, leading to a more precise matching assessment with better clinical results. Knowledge of the molecular basis of class I gene polymorphisms also led to the development of new matching algorithms such as HLA-Matchmaker, based on immunogenic amino acid triplets localized on antibody-accessible external domains of class I antigens. The most impressive impact of novel DNA typing methods concerns matching for allogeneic HSC transplantation because subtle serologically silent sequence differences between allelic subtypes are efficiently recognized by alloreactive T-cells with potentially serious consequences for graft outcome. High resolution HLA class I and II matching has contributed to improve patients survival after unrelated HSC transplantation, although the relative importance of individual loci remains to be elucidated. Donor matching criteria should take into account parameters such as the time frame allowed by the patient's disease and the probability to identify a well matched donor based on the patient's HLA phenotype.