MECHANISMS OF REJECTION: Edited by Mandy L. FordDeciphering the clinical relevance of allo-human leukocyte antigen cross-reactivity in mediating alloimmunity following transplantationRowntree, Louise C.a,b; Nguyen, Thi H.O.c; Gras, Stephanieb,d; Kotsimbos, Tom C.a,e; Mifsud, Nicole A.b Author Information aDepartment of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Commercial Road, Melbourne bInfection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton cDepartment of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville dAustralian Research Council Centre of Excellence for Advanced Molecular Imaging eDepartment of Medicine, Central Clinical School, Monash University, Clayton, VIC, Australia Correspondence to Nicole A. Mifsud, Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, 23 Innovation Walk, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia. Tel: +613 9902 9311; e-mail: [email protected] Current Opinion in Organ Transplantation: February 2016 - Volume 21 - Issue 1 - p 29-39 doi: 10.1097/MOT.0000000000000264 Buy Metrics Abstract Purpose of review Despite a growing awareness regarding the potential of cross-reactive virus-specific memory T cells to mediate alloimmunity, there has been limited clinical evaluation on allograft immunopathology. This review will explore published models of human T-cell cross-reactivity and discuss criteria required to drive this mechanism as a contributing cause of allograft dysfunction in transplantation. Recent findings Published models of human allogeneic (allo)-human leukocyte antigen (HLA) cross-reactivity have enabled dissection of the cross-reactive T cell receptor/peptide/major histocompatibility complex (TCR/peptide/MHC) interaction. In many of the models, the cross-reactive T cells express a unique TCR, although the relevance of a public cross-reactive TCR repertoire has yet to be determined. Equally, allopeptide identity, a vital component driving cross-recognition, remains unknown in the majority of models thereby prompting further characterization utilizing novel technologies. Although clinical studies examining the presence and impact of specific cross-reactive virus-specific T cells have been minimally explored, the existing data suggest that there may be a marginal set of requirements that need to be satisfied before the potentially damaging effects of allo-HLA cross-reactivity can be realized. Summary Our understanding of allo-HLA cross-reactivity continues to evolve as improved technology and novel strategies allow us to better question the contribution of allo-HLA cross-reactivity in clinically relevant allograft dysfunction. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.