NK cells expressing inhibitory KIR for non-self-ligands remain tolerant in HLA-matched sibling stem cell transplantation.
Natural killer (NK)-cell alloreactivity in recipients of hematopoietic stem cell grafts from HLA-identical siblings is intriguing and has suggested breaking of NK-cell tolerance during the posttransplantation period. To examine this possibility, we analyzed clinical outcomes in a cohort of 105 patients with myeloid malignancies who received T cell-replete grafts from HLA-matched sibling donors. Presence of inhibitory killer cell immunoglobulin-like receptors (KIRs) for nonself HLA class I ligands had no effect on disease-free survival, incidence of relapse, or graft-versus-host disease. A longitudinal analysis of the NK-cell repertoire and function revealed a global hyporesponsiveness of NK cells early after transplantation. Functional responses recovered at approximately 6 months after transplantation. Importantly, NKG2A(-) NK cells expressing KIRs for nonself HLA class I ligands remained tolerant at all time points. Furthermore, a direct comparison of NK-cell reconstitution in T cell-replete and T cell-depleted HLA-matched sibling stem cell transplantation (SCT) revealed that NKG2A(+) NK cells dominated the functional repertoire early after transplantation, with intact tolerance of NKG2A(-) NK cells expressing KIRs for nonself ligands in both settings. Our results provide evidence against the emergence of alloreactive NK cells in HLA-identical allogeneic SCT.
Björklund
Andreas T
AT
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Schaffer
Marie
M
Fauriat
Cyril
C
Ringdén
Olle
O
Remberger
Mats
M
Hammarstedt
Christina
C
Barrett
A John
AJ
Ljungman
Per
P
Ljunggren
Hans-Gustaf
HG
Malmberg
Karl-Johan
KJ
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D020014:K562 Cells / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D007951:Leukemia, Myeloid / Q000276:immunology / Q000601:surgery; D019520:Living Donors; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000601:surgery; D036102:Peripheral Blood Stem Cell Transplantation; D054340:Receptors, KIR / Q000235:genetics / Q000276:immunology*; D012189:Retrospective Studies; D035781:Siblings; D014184:Transplantation, Homologous; D055815:Young Adult
D006680:HLA Antigens; D007166:Immunosuppressive Agents; D054340:Receptors, KIR