TY - JOUR
T1 - Multicenter analyses demonstrate significant clinical effects of minor Histocompatibility Antigens on GvHD and GvL after HLA-matched related and unrelated Hematopoietic stem cell transplantation
AU - Spierings, Eric
AU - Kim, Yeung Hyen
AU - Hendriks, Matthijs
AU - Borst, Eric
AU - Sergeant, Ruhena
AU - Canossi, Angelica
AU - Oudshoorn, Machteld
AU - Loiseau, Pascale
AU - Dolstra, Harry
AU - Markiewicz, Miroslaw
AU - Leffell, Mary S.
AU - Pereira, Noemi
AU - Kircher, Brigitte
AU - Turpeinen, Hannu
AU - Eliaou, Jean François
AU - Gervais, Thibaut
AU - Laurin, David
AU - Enczmann, Jürgen
AU - Martinetti, Miryam
AU - Thomson, Jackie
AU - Oguz, Fatma
AU - Santarone, Stella
AU - Partanen, Jukka
AU - Siekiera, Urszula
AU - Alessandrino, Emilio Paolo
AU - Kalayoglu, Sevgi
AU - Brand, Ronald
AU - Goulmy, Els
N1 - Funding Information:
We thank Dr. J. McCluskey, Dr. B. Tait, and Dr. F. Christiansen for giving us the opportunity to organize the minor H antigen component under the auspices of the 14th International Histocompatibility and Immunogenetics Workshop Symposium in Melbourne and to publish these results. We thank Dr. Effie Petersdorf, Dr. Mari Malkki, and Fred Hutchinson Cancer Research Center for participation in the minor H antigen working group of the 14th International HLA and Immunogenetic Workshop and for providing clinical data to this analysis funded by CA018029 from the National Institutes of Health, USA. This study was supported in part by grants of the Leukemia and Lymphoma Society of America , the 6th Framework Programme “Allostem” of the European Commission , the Netherlands Organization for Scientific Research (NWO,Spinoza-award) , and the Macropa Foundation .
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - Graft-versus-host disease (GvHD)
KW - Graft-versus-leukemia (GvL)
KW - Hematopoietic stem cell transplantation
KW - Human
KW - Minor H antigens
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U2 - 10.1016/j.bbmt.2013.06.001
DO - 10.1016/j.bbmt.2013.06.001
M3 - Article
C2 - 23756210
AN - SCOPUS:84880425257
VL - 19
SP - 1244
EP - 1253
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
SN - 1083-8791
IS - 8
ER -