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The role of missing killer cell immunoglobulin-like receptor ligands in T cell replete peripheral blood stem cell transplantation from HLA-identical siblings.
Biol Blood Marrow Transplant. 2010 Feb; 16(2):273-80.BB

Abstract

The contribution of natural killer (NK) cells to graft-versus-malignancy (GVM) effects following hematopoietic stem cell transplantation (HSCT) remains uncertain, particularly in the HLA-identical setting. A model considering missing HLA ligands to the donor's inhibitory killer cell immunoglobulin-like receptor (KIR), termed the missing KIR ligand model, has been established in T cell depleted bone marrow transplantation (BMT), but lacks validity in other cohorts with different treatment characteristics. We hypothesized that the impact of missing KIR ligands on relapse-free survival (RFS) and overall survival (OS) in T cell replete peripheral blood SCT (PBSCT) differs from that in the T cell depleted BMT setting, and retrospectively evaluated 100 consecutive, HLA-identical sibling transplantations for hematologic malignancies. In addition to KIR ligand status, we considered the donors' activating KIRs and grafted NK, T, and CD34(+) cell doses. Our findings demonstrate noninferiority for OS (P = .005) and RFS (P = .002) for the heterozygous HLA-C group KIR ligand status (C1/2; n = 47) compared with patients missing either C1 or C2 (n = 53). Similarly, OS (P = .031) and RFS (P = .034) of Bw4-positive patients was noninferior to that of patients missing a Bw4 ligand to KIR3DL1. By multivariate analysis, C1/2 heterozygous patients had a favorable risk ratio (RR) for relapse (RR = 0.28; P = .003), RFS (RR = 0.56; P = .046), and acute graft-versus-host disease grade II-IV (RR = 0.36; P = .05). Following reduced-intensity conditioning (RIC), but not standard-intensity conditioning, myeloablative (MA) transplantation, a grafted NK cell dose above the median (3.4 x 10(7)/kg) was associated with a lower risk of relapse (RR = 0.57; P = .003) and improved survival (RR = 0.78; P = .03). Overall, our findings support a role for NK alloreactivity in HLA-identical HSCT, but argue against a favorable impact of missing KIR ligands in the given setting. We conclude that the mechanism favoring the missing KIR ligand constellation in T cell depleted BMT may not operate in T cell replete PBSCT. The reasons for this differential effect remain unresolved.

Authors+Show Affiliations

Department of Internal Medicine V, Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria. johannes.clausen@i-med.ac.atNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

19857587

Citation

Clausen, Johannes, et al. "The Role of Missing Killer Cell Immunoglobulin-like Receptor Ligands in T Cell Replete Peripheral Blood Stem Cell Transplantation From HLA-identical Siblings." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 16, no. 2, 2010, pp. 273-80.
Clausen J, Kircher B, Auberger J, et al. The role of missing killer cell immunoglobulin-like receptor ligands in T cell replete peripheral blood stem cell transplantation from HLA-identical siblings. Biol Blood Marrow Transplant. 2010;16(2):273-80.
Clausen, J., Kircher, B., Auberger, J., Schumacher, P., Ulmer, H., Hetzenauer, G., Wolf, D., Gastl, G., & Nachbaur, D. (2010). The role of missing killer cell immunoglobulin-like receptor ligands in T cell replete peripheral blood stem cell transplantation from HLA-identical siblings. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 16(2), 273-80. https://doi.org/10.1016/j.bbmt.2009.10.021
Clausen J, et al. The Role of Missing Killer Cell Immunoglobulin-like Receptor Ligands in T Cell Replete Peripheral Blood Stem Cell Transplantation From HLA-identical Siblings. Biol Blood Marrow Transplant. 2010;16(2):273-80. PubMed PMID: 19857587.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of missing killer cell immunoglobulin-like receptor ligands in T cell replete peripheral blood stem cell transplantation from HLA-identical siblings. AU - Clausen,Johannes, AU - Kircher,Brigitte, AU - Auberger,Jutta, AU - Schumacher,Petra, AU - Ulmer,Hanno, AU - Hetzenauer,Gabriele, AU - Wolf,Dominik, AU - Gastl,Günther, AU - Nachbaur,David, Y1 - 2009/10/24/ PY - 2009/06/03/received PY - 2009/10/16/accepted PY - 2009/10/28/entrez PY - 2009/10/28/pubmed PY - 2010/5/4/medline SP - 273 EP - 80 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol. Blood Marrow Transplant. VL - 16 IS - 2 N2 - The contribution of natural killer (NK) cells to graft-versus-malignancy (GVM) effects following hematopoietic stem cell transplantation (HSCT) remains uncertain, particularly in the HLA-identical setting. A model considering missing HLA ligands to the donor's inhibitory killer cell immunoglobulin-like receptor (KIR), termed the missing KIR ligand model, has been established in T cell depleted bone marrow transplantation (BMT), but lacks validity in other cohorts with different treatment characteristics. We hypothesized that the impact of missing KIR ligands on relapse-free survival (RFS) and overall survival (OS) in T cell replete peripheral blood SCT (PBSCT) differs from that in the T cell depleted BMT setting, and retrospectively evaluated 100 consecutive, HLA-identical sibling transplantations for hematologic malignancies. In addition to KIR ligand status, we considered the donors' activating KIRs and grafted NK, T, and CD34(+) cell doses. Our findings demonstrate noninferiority for OS (P = .005) and RFS (P = .002) for the heterozygous HLA-C group KIR ligand status (C1/2; n = 47) compared with patients missing either C1 or C2 (n = 53). Similarly, OS (P = .031) and RFS (P = .034) of Bw4-positive patients was noninferior to that of patients missing a Bw4 ligand to KIR3DL1. By multivariate analysis, C1/2 heterozygous patients had a favorable risk ratio (RR) for relapse (RR = 0.28; P = .003), RFS (RR = 0.56; P = .046), and acute graft-versus-host disease grade II-IV (RR = 0.36; P = .05). Following reduced-intensity conditioning (RIC), but not standard-intensity conditioning, myeloablative (MA) transplantation, a grafted NK cell dose above the median (3.4 x 10(7)/kg) was associated with a lower risk of relapse (RR = 0.57; P = .003) and improved survival (RR = 0.78; P = .03). Overall, our findings support a role for NK alloreactivity in HLA-identical HSCT, but argue against a favorable impact of missing KIR ligands in the given setting. We conclude that the mechanism favoring the missing KIR ligand constellation in T cell depleted BMT may not operate in T cell replete PBSCT. The reasons for this differential effect remain unresolved. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/19857587/The_role_of_missing_killer_cell_immunoglobulin_like_receptor_ligands_in_T_cell_replete_peripheral_blood_stem_cell_transplantation_from_HLA_identical_siblings_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(09)00492-3 DB - PRIME DP - Unbound Medicine ER -