Improved Survival with Inhibitory Killer Immunoglobulin Receptor (KIR) Gene Mismatches and KIR Haplotype B Donors after Nonmyeloablative, HLA-Haploidentical.

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Improved Survival with Inhibitory Killer Immunoglobulin Receptor (KIR) Gene Mismatches and KIR Haplotype B Donors after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation Heather J. Symons, M. Sue Leffell, Nancy D. Rossiter, Marianna Zahurak, Richard J. Jones, Ephraim J. Fuchs Biology of Blood and Marrow Transplantation Volume 16, Issue 4, Pages 533-542 (April 2010) DOI: 10.1016/j.bbmt.2009.11.022 Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Models of natural killer cell alloreactivity after allogeneic cell transplantation. (A) The KIR ligand incompatibility, or ligand-ligand model predicts NK cell alloreactivity in the GVH direction (depicted by jagged arrow) when the recipient lacks expression of an inhibitory KIR ligand, in this case a member of the HLA-C1 group, that is present in the donor. This model assumes the presence of functional donor NK cells expressing KIR2DL2, the receptor for HLA-C1 molecules, as their inhibitory receptor. (B) The receptor-ligand model predicts NK cell alloreactivity in the GVH direction when the recipient lacks the expression of an HLA ligand for a verified donor inhibitory KIR. The HLA type of donor cells is not considered in this model. (C) The missing ligand model predicts NK cell alloreactivity in the GVH direction when recipient cells lacks expression of at least 1 of the HLA ligands (C1, C2, or Bw4) for a verified donor inhibitory KIR. As in B, the HLA type of the donor is not considered in this model. (D) The KIR gene-gene model predicts NK alloreactivity when the donor and recipient are mismatched for KIR gene content. This model characterizes the KIR genotype of both donor and recipient, and asks whether differences in the expression of individual inhibitory or stimulatory genes between the donor and the recipient KIR (ie, donor includes inhibitory KIR genes that the recipient is missing or vice versa) have any effect on the outcome of allogeneic SCT. Inhibitory KIR genes are shown here as unshaded boxes, whereas black boxes represent activating KIR genes. In the example shown, the donor has several activating and inhibitory genes that the recipient lacks. This example also illustrates the KIR haplotype characterization. In this case, the donor is haplotype group B, based on the presence of several activating KIR genes, whereas the recipient is haplotype group A based on the presence of inhibitory genes and only 1 activating gene. Biology of Blood and Marrow Transplantation 2010 16, 533-542DOI: (10.1016/j.bbmt.2009.11.022) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Nonmyeloablative haploidentical BMT conditioning and postgrafting immunosuppresive regimen. Biology of Blood and Marrow Transplantation 2010 16, 533-542DOI: (10.1016/j.bbmt.2009.11.022) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Overall outcomes among nonmyeloablative haploidentical BMT recipients. Cumulative incidence of (A) aGVHD, grades II-IV and III-IV, (B) NRM and (C), Relapse. (D) OS, and (E) EFS. Biology of Blood and Marrow Transplantation 2010 16, 533-542DOI: (10.1016/j.bbmt.2009.11.022) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Gene-gene inhibitory KIR mismatches and OS, EFS and relapse. (A) OS. (B) EFS. (C) Cumulative incidence of relapse. Biology of Blood and Marrow Transplantation 2010 16, 533-542DOI: (10.1016/j.bbmt.2009.11.022) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 OS, EFS, and NRM for haplotype A recipients of B donors. (A) OS. (B) EFS. (C) Cumulative incidence of NRM. Biology of Blood and Marrow Transplantation 2010 16, 533-542DOI: (10.1016/j.bbmt.2009.11.022) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 OS and EFS for haplotype B recipients of A donors. (A) OS. (B) EFS. Biology of Blood and Marrow Transplantation 2010 16, 533-542DOI: (10.1016/j.bbmt.2009.11.022) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions