title: Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation.
abstract: The effect of minor H antigen mismatching on the occurrence of graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) after HLA-matched hematopoietic stem cell transplantation (HSCT) has mainly been demonstrated in single-center studies. Yet, the International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 20 laboratories of the IHIW, the roles of 10 autosomal and 10 Y chromosome-encoded minor H antigens were investigated on GvHD and relapse incidence in 639 HLA-identical related donor (IRD) and 210 HLA-matched unrelated donor (MUD) HSCT recipients. Donor and recipient DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, and HY. The correlations with the primary outcomes GvHD (acute or chronic GvHD), survival, and relapse were statistically analyzed. The results of these multicenter analyses show that none of the HLA class I-restricted HY antigens were found to be associated with any of the primary outcomes. Interestingly, of the HLA class II-restricted HY antigens analyzed, HLA-DQ5 positive recipients showed a significantly increased GvHD-free survival in female-to-male HSCT compared with male-to-female HSCT (P = .013). Yet, analysis of the overall gender effect, thus independent of the known HY antigens, between the gender groups demonstrated an increased GvHD incidence in the female-to-male transplantations (P < .005) and a decreased GvHD-free survival in the female-to-male transplantations (P < .001). Of all autosomally encoded minor H antigens, only mismatching for the broadly expressed minor H antigen HA-8 increased the GvHD incidence in IRD HSCT (Hazard ratio [HR] = 5.28, P < .005), but not in MUD HSCT. Most striking was the influence of hematopoietic restricted minor H antigens on GvL as mismatching for hematopoietic minor H antigens correlated with lower relapse rates (P = .078), higher relapse-free survival (P = .029), and higher overall survival (P = .032) in recipients with GvHD, but not in those without GvHD. In conclusion, the significant GvHD effect of the broadly expressed minor H antigen HA-8 favors matching for HA-8 in IRD, but not in MUD, patient/donor pairs. The GvHD-GvL association demonstrating a significant lower relapse in hematopoietic minor H antigen mismatched patient/donor pairs underlines their clinical applicability for adoptive immunotherapy, enhancing the GvL effect in a GvHD controllable manner.
authors.affiliation: Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. spierings@umcutrecht.nl
authors.forename: Eric
authors.initials: E
authors.lastname: Spierings
authors.forename: Yeung-Hyen
authors.initials: YH
authors.lastname: Kim
authors.forename: Matthijs
authors.initials: M
authors.lastname: Hendriks
authors.forename: Eric
authors.initials: E
authors.lastname: Borst
authors.forename: Ruhena
authors.initials: R
authors.lastname: Sergeant
authors.forename: Angelica
authors.initials: A
authors.lastname: Canossi
authors.forename: Machteld
authors.initials: M
authors.lastname: Oudshoorn
authors.forename: Pascale
authors.initials: P
authors.lastname: Loiseau
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Markiewicz
authors.forename: Mary S
authors.initials: MS
authors.lastname: Leffell
authors.forename: Noemi
authors.initials: N
authors.lastname: Pereira
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kircher
authors.forename: Hannu
authors.initials: H
authors.lastname: Turpeinen
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Eliaou
authors.forename: Thibaut
authors.initials: T
authors.lastname: Gervais
authors.forename: David
authors.initials: D
authors.lastname: Laurin
authors.forename: Jürgen
authors.initials: J
authors.lastname: Enczmann
authors.forename: Miryam
authors.initials: M
authors.lastname: Martinetti
authors.forename: Jackie
authors.initials: J
authors.lastname: Thomson
authors.forename: Fatma
authors.initials: F
authors.lastname: Oguz
authors.forename: Stella
authors.initials: S
authors.lastname: Santarone
authors.forename: Jukka
authors.initials: J
authors.lastname: Partanen
authors.forename: Urszula
authors.initials: U
authors.lastname: Siekiera
authors.forename: Emilio Paolo
authors.initials: EP
authors.lastname: Alessandrino
authors.forename: Sevgi
authors.initials: S
authors.lastname: Kalayoglu
authors.forename: Ronald
authors.initials: R
authors.lastname: Brand
authors.forename: Els
authors.initials: E
authors.lastname: Goulmy
mesh_terms: D000328:Adult; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006648:Histocompatibility / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D061349:Unrelated Donors
chemical_list: D015778:Minor Histocompatibility Antigens
keywords: Graft-versus-host disease (GvHD); Graft-versus-leukemia (GvL); Hematopoietic stem cell transplantation; Human; Minor H antigens