60 Jahre HLA. Wolfgang R. Mayr.

60 Jahre HLA Wolfgang R. Mayr wolfgang.mayr@meduniwien.ac.at wolfgang.mayr@roteskreuz.at

HLA Früher HL-A Human Leukocyte Antigen, Locus A

60 / 50 Jahre HLA Dausset J: Iso-leuco-anticorps. Acta Haematol 1958; 20: 156-166 MAC = HLA-A2 Amos DB: Human Histocompatibility Locus HL-A. Science 1968; 159: 659-660 (9 Feb 1968) Seit Workshop 1975 (Aarhus/DK): HLA

Department for Blood Group Serology, University of Vienna, Austria

Department for Blood Group Serology, University of Vienna, Austria 1972

Department for Blood Group Serology 1972

INTERNATIONALE HISTOCOMPATIBILITY WORKSHOPS 1964 1965 1967 1970 1972 1975 1977 1980 Durham / USA Leiden / NL Torino / I Los Angeles / USA Evian / F Aarhus / DK Oxford / UK Los Angeles / USA 1984 München / D, Wien / A 1987 1991 1997 2002 2005 2008 2012 2017 Princeton / USA New York / USA Yokohama / J St. Malo, Paris / F Victoria / CND, Seattle I USA Melbourne / AUS Buzios, Rio / BRA Liverpool / UK Pacific Grove / USA

HLA 1968 ------------------- X --------------------------------------------------- X --------------- HLA-A1 (HL-A1) HLA-B5 (HL-A5) HLA-A2 (HL-A2) HLA-B7 (HL-A7) HLA-A3 (HL-A3) HLA-B8 (HL-A8) HLA-A9 (LA4) HLA-B12 (T12) HLA-A11 (ILN*) HLA-B13 (HN) HLA-A28 (Ba*) HLA-B35 (R*)

HLA Genkomplex

HLA GENkOMPLEX 400 Loci, ca. 300 exprimiert Department for Blood Group Serology, University of Vienna, Austria

Division of Blood Group Serology

HLA Mai 2018 Klasse I Gene A B C Allele 4200 5091 3854 Proteine 2923 3664 2644 Klasse II Gene DRB1 DQA1 DQB1 DPA1 DPB1 Allele 2165 94 1196 65 975 Proteine 1559 35 806 27 675 Klasse I Klasse II HLA 13.145 Allele 4.495 Allele >17.640 Allele Division of Blood Group Serology

Rates of new allele identification Estimation: 2.7 million HLA-A, 3.3 million HLA-B and 3.2 million HLA-C alleles in today s human population

Department for Blood Group Serology, University of Vienna, Austria Blood Donation Center for Vienna, Lower Austria and Burgenland, Austrian Red Cross

Blood Donation Center for Vienna, Lower Austria and Burgenland, Austrian Red Cross

HLA Nomenklatur Ab 1987 HLA-A*0201 HLA-A*02011, später HLA-A*020101 HLA-A*02010101 HLA-A*02 01 01 01

Definition of Histocompatibility Typing Terms Allelic Resolution: single allele as defined by the Nomenclature Report High Resolution: set of alleles that encode the same protein sequence for the antigen binding site and that excludes alleles not expressed Low Resolution: at the level of the digits composing the 1st field in the Nomenclature; corresponds to serology

Reporting of ambiguous HLA allele typing HLA alleles that share identical nucleotide sequences for the exons encoding the peptide binding domains HLA alleles that have identical nucleotide sequences across the exons encoding the peptide binding domains (exon 2 and 3 for HLA class I and exon 2 only for HLA class II alleles) will be designated by an upper case G which follows the allele designation of the lowest numbered allele in the group. For example the string of allele names below have identical exons 2 and 3 nucleotide sequences. A*02:01:01:01/02:01:01:02L/02:01:01:03/02:01:08/02:01:11/02:01:14/02:01:15/ 02:01:21/02:09/02:43N/02:66/02:75/02:83N/02:89/02:97/02:132/02:134/02:140 This string can be reduced to A*02:01:01G Division of Blood Group Serology

Reporting of ambiguous HLA allele typing HLA alleles that encode for identical peptide binding domains HLA alleles having nucleotide sequences that encode the same protein sequence for the peptide binding domains (exon 2 and 3 for HLA class I and exon 2 only for HLA class II alleles) will be designated by an upper case P which follows the allele designation of the lowest numbered allele in the group. For example the string of allele names below share the same α1 and α2 domain protein sequence encoded by exons 2 and 3. A*02:01:01:01/02:01:01:02L/02:01:01:03/02:01:02/02:01:03/02:01:04/02:01:05/02: 01:06/02:01:07/02:01:08/02:01:09/02:01:10/02:01:11/02:01:12/02:01:13/02:01:14/ 02:01:15/02:01:17/02:01:18/02:01:19/02:01:21/02:01:22/02:09/02:66/02:75/02:89/ 02:97/02:132/02:134/02:140 This string can be reduced to A*02:01P Division of Blood Group Serology

HLA IN DER TRANSFUSIONSMEDIZIN Funktion - Transplantation: Organe, Stammzellen, zelluläre Therapie - Assoziation mit Krankheiten - Arzneimittel unerwünschte Reaktionen - TA-GvHD Immunisierung - FNHTR, HTR - Thrombocytentransfusion - TRALI - Granulocytentransfusion - (NAIT?, NAIN???)

GENETIC MARKER./. DISEASE 1) Direct involvement of the gene product MHN, NAIT, RHnull, ADA-deficiency, PI*Z,... 2) Linkage marker disease gene 21-OH deficiency, idiop. haemochronmatosis; RFLPs, STRs, SNPs in abnormal genes 3) Association

HLA Class I Disease Specificity RR Idiopathic haemochromatosis A3 8 Birdshot retinopathy A29 >100 Morbus Behcet B5 6 Morbus Bechterew Ankylosing spondylitis B27 90 Postinfectious arthritis B27 40 Morbus Reiter B27 37 Acute anterior uveitis B27 10 Subacute thyreoiditis de Quervain B35 14 Chron. active Hepatitis type B (HBs-Ag positive) B35 5 Adrenogenital syndrome B47 90 Psoriasis vulgaris Cw6 13

HLA Class II Disease Specificity RR Narcolepsy DR2, DQ6 >100 Goodpasture syndrome DR2 16 Multiple sclerosis DR2 10 Dermatitis herpetiformis DR3 15 Idiopathic membranous glomerulonephretis DR3 12 Sjögren syndrome DR3 10 Idiop. M. Addison, SLE, CAH type A DR3 6 M. Basedow, myasthenia gravis DR3 4 Diabetes mellitus type I DR4,DQ8/DR3,DQ2 6 / 3 Rheumatoid arthritis DR4 4 Celiac disease DQ2 >100

HLA AND DISEASES 1. Restriction HLA class I HLA class II 2. Linkage disequilibrium with mutant genes Idiop. haemochromatosis Adrenogenital syndrome

PRESENTATION OF PEPTIDES DR3 autoimmunity Birdshot retinopathy A29 binds a peptide of a soluble retinal antigen A29-transgene mice: similar symptoms Rheumatoid arthritis DR4 binds peptides of collagen II DR4-transgene mice: symptoms like RA

BINDING OF PEPTIDES II HLA-DRB1*11:01 - peptide of the KEL*K gene product (Transplantation 2018; 58: 1171) HLA-DRB1*01:01 - pollen allergen Art v 1 (transgeneic mouse - EBioMedicine 2018) Division of Blood Group Serology

Adverse Reactions to Drugs HLA Association Rheumatoid Arthritis: associated with HLA-DRB1*04 Adverse Reaction Drug HLA Myasthenia gravis D-Penicillamin DRB1*01, DRB1*07 Nephropathy Gold DRB1*03

HLA and Drug Induced Adverse Reactions Disease Drug HLA Adverse effect Hypertonia Hydralazine DRB1*04 LE AIDS Abacavir ($) B*57:01 Hypersensitivity AIDS Nevirapine DRB1*01:01 Hypersensitivity Epilepsy,... Carbamazepine ($) B*15:02 Stevens-Johnson-Syndrome Infections (Gram+) Flucloxacilline B*57:01 Hypersensitivity ($) included in the Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels published by the FDA

HLA associations with hepatotoxicity Aithal & Daly, Nature Genetics 2010; 42: 650-651

Pharmacogenomic Biomarkers in Drug Labeling (FDA) only HLA HLA-B*57:01 Abacavir Hypersensitivity HLA-B*15:02 Carbamazepine TEN, SJS HLA-A*31:01 Carbamazepine Hypersensitivity HLA-DQB1*02:01 Lapatinib Hepatotoxicity HLA-DRB1*07:01 Lapatinib Hepatotoxicity HLA-B15:02 Oxcarbazepine TEN, SJS HLA-B57:01 Pazopanib Hepatotoxicity HLA-B15:02 Phenytoin TEN, SJS TEN: toxic epidermal necrolysis, SJS: Stevens-Johnson-syndrome

TA-GvHD Pathogenesis Caused by immunocompetent T lymphocytes transfused in a recipient who is unable to mount a host response to the cells due to HLA (one-way) compatibility (related donor, low HLA polymorphism,...) and/or immunosuppression (e.g. by fludarabine, 2-CDA) Prevention Irradiation (recommended dose 25 to 50 Gy)

Präzisionsmedizin Die Präzisionsmedizin (PM) ist ein medizinisches Modell, wobei medizinische Entscheidungen, Behandlungen, Praxen oder Produkte auf den einzelnen Patienten zugeschnitten sind. In diesem Modell werden häufig diagnostische Tests zur Auswahl geeigneter und optimaler Therapien auf der Grundlage des Genotyps eines Patienten oder anderer molekularer oder zellulärer Analysen eingesetzt. Unter Präzisionsmedizin versteht man die Anpassung der medizinischen Behandlung an die individuellen Eigenschaften eines jeden Patienten. Dabei geht es nicht buchstäblich um die Schaffung von Arzneimitteln oder Medizinprodukten, die einzigartig für einen Patienten sind, sondern um die Fähigkeit, Individuen in Subpopulationen einzuteilen, die sich in ihrer Anfälligkeit für eine bestimmte Krankheit, in der Biologie oder Prognose dieser Krankheiten oder in ihrer Reaktion auf eine bestimmte Behandlung unterscheiden.

Personalisierte Medizin Es gibt viele Überschneidungen zwischen den Begriffen "Präzisionsmedizin" und "personalisierte Medizin". Die "personalisierte Medizin" ein älterer Begriff mit einer ähnlichen Bedeutung wie die "Präzisionsmedizin". Es gab jedoch Bedenken, dass das Wort "personalisiert" fehlinterpretiert werden könnte, um zu implizieren, dass Behandlungen und Vorbeugungen für jeden Einzelnen individuell entwickelt werden; in der Präzisionsmedizin liegt der Schwerpunkt auf der Identifizierung, welche Ansätze für welche Patienten wirksam sein werden, basierend auf genetischen, ökologischen und Lifestyle-Faktoren. Dabei geht es nicht buchstäblich um die Schaffung von Arzneimitteln oder Medizinprodukten, die einzigartig für einen Patienten sind, sondern um die Fähigkeit, Individuen in Subpopulationen einzuteilen, die sich in ihrer Anfälligkeit für eine bestimmte Krankheit, in der Biologie oder Prognose dieser Krankheiten oder in ihrer Reaktion auf eine bestimmte Behandlung unterscheiden.

Cellular Therapy Main Directions Stem Cell Transplantation Dendritic Cells: in vitro sensitization by tumour antigens and reinjection in order to stimulate T cell response NK Cells: killing of tumour cells that do not express the own HLA class I gene products Cytotoxic T Lymphocytes: stimulation by tumour antigens and reinjection into patient where they attack tumour cells Regenerative Medicine: e.g. in vitro preparation of autologous skin grafts, infusion of stem cells in hearts damaged by infarctions,... Gene Therapy: introduction of gene in cells and reinfusion

HLA Typing Demands for Peptide-Based Anti-Cancer Vaccine Nagorsen D & Thiel E Cancer Immunol Immunother, 2008, in press Taken together, proper tissue typing for cancer vaccine therapies represents the main pillar for successful immunotherapy. Clinical immunotherapists should be more aware of the importance of correct HLA determination to avoid vaccination of unsuitable patients. Correct HLA determination: high resolution genotyping (at the 4- digit level), in order to determine the binding of tumour-derived peptides