Authors:
R. Carapito (Strasbourg, FR)
N. Jung (Strasbourg, FR)
M. Kwemou (Strasbourg, FR)
M. Untrau (Strasbourg, FR)
S. Michel (Strasbourg, FR)
A. Pichot (Strasbourg, FR)
G. Giacometti (Strasbourg, FR)
C. Macquin (Strasbourg, FR)
W. Ilias (Strasbourg, FR)
A. Morlon (Strasbourg, FR)
I. Kotovo (Strasbourg, FR)
P. Apostolova (Freiburg, DE)
A. Schmitt-Graeff (Freiburg, DE)
A. Cesbron (FR)
K. Gagne (Nantes, FR)
M. Oudshoorn (Leiden, NL)
B. Van der Holt (Rotterdam, NL)
M. Labalette (Lille, FR)
E. Spierings (Utrecht, NL)
C. Picard (Marseille, FR)
P. Loiseau (Paris, FR)
R. Tamouza (Paris, FR)
A. Toubert (Paris, FR)
A. Parissiadis (Strasbourg, FR)
V. Dubois (Lyon, FR)
X. Lafarge (Bordeaux, FR)
M. Maumy-Bertrand (Strasbourg, FR)
F. Bertrand (Strasbourg, FR)
L. Vago (Milano, IT)
F. Ciceri (Milan, IT)
C. Paillard (Strasbourg, FR)
S. Querol (Barcelona, ES)
J. Sierra (Barcelona, ES)
K. Fleischhauer (Essen, DE)
A. Nagler (Tel Aviv, IL)
M. Labopin (Paris, FR)
H. Inoko (Atsugi, Kanagawa, JP)
P. A. von dem Borne (Leiden, NL)
J. Kuball (Utrecht, NL)
M. Ota (Matsumoto, Nagano, JP)
Y. Katsuyama (Matsumoto, JP)
M. Michallet (Lyon, FR)
B. Lioure (Strasbourg, FR)
R. Peffault de Latour (Paris, FR)
D. Blaise (Marseille, FR)
J. Cornelissen (Rotterdam, NL)
I. Yakoub-Agha (Lille, FR)
F. Claas (Leiden, NL)
P. Moreau (Nantes, FR)
N. Milpied (Bordeaux, FR)
D. Charron (Paris, FR)
M. Mohty (Paris, FR)
R. Zeiser (Freiburg, DE)
G. Socié (Paris, FR)
S. Bahram (Strasbourg, FR)
The success of unrelated hematopoietic cell transplantations (HCT) relies greatly on Human Leukocyte Antigen (HLA) matching between patient and donor. But even in HLA matched transplantations, adverse clinical outcomes such as graft-versus-host-disease (GvHD) remain alarmingly high. The highly polymorphic MHC class I chain-related gene A (MICA) encodes a stress-induced glycoprotein interacting with NKG2D, an activating receptor expressed on the surface of cytotoxic CD8+ αβ and γδ T lymphocytes and natural killer cells. MICA may act as a transplantation antigen and therefore matching of donors and patients at the MICA locus could have a beneficial effect for patients undergoing unrelated HSCT. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical impact of MICA-mismatches in a large multicentre cohort of 922 unrelated transplantations matched 10/10 for HLA-A, -B, -C, -DRB1, and –DQB1. We further examined severe acute GvHD patients with respect to MICA and NKG2D expression using immunohistochemical staining on intestinal biopsies and flow cytometry on PBMCs, respectively. Among the 922 pairs, 113 (12.3%) were mismatched for MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (HR, 1.83; 95% CI, 1.50 to 2.23; P<0.001), chronic GvHD (HR, 1.50; 95% CI, 1.45 to 1.55; P<0.001) and non-relapse mortality (HR, 1.35; 95% CI, 1.24 to 1.46; P<0.001). The increased risk of GvHD was mirrored by a lower risk of relapse (HR, 0.50; 95% CI, 0.43 to 0.59; P<0.001), indicating a possible graft-versus-leukemia effect. In addition, expression of MICA and its ligand NKG2D were shown to be induced in intestinal tissue and circulating CD8+ T cells of acute grades III-IV GvHD patients, respectively. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GvHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.