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Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

Faridi RM, Kemp TJ, Dharmani-Khan P, Lewis V, Tripathi G, Rajalingam R, Daly A, Berka N, Storek J, Masood Khan F - PLoS ONE (2016)

Bottom Line: Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10-0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17-0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants.The present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors.The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.

ABSTRACT

Background: Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT.

Methods and findings: The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42-4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11-2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10-0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17-0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants.

Conclusions: The present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

No MeSH data available.


Related in: MedlinePlus

Effect of missing HLA ligands in recipients of unrelated donor HCT.Absence of one or more missing HLA ligands was scored for donor inhibitory KIR3DL2 (A3/A11), KIR3DL1 (Bw4), KIR2DL2/2DL3 (C2) and KIR2DL1 (C1) as well as activating KIR2DS1 (C2) and KIR3DS1 (Bw4). A multivariate competing risks regression analysis revealed a significantly reduced incidence of relapse (p-values <0.05) among recipients of unrelated donor HCT in which one or more HLA ligands for donor inhibitory KIR were absent.
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pone.0158242.g004: Effect of missing HLA ligands in recipients of unrelated donor HCT.Absence of one or more missing HLA ligands was scored for donor inhibitory KIR3DL2 (A3/A11), KIR3DL1 (Bw4), KIR2DL2/2DL3 (C2) and KIR2DL1 (C1) as well as activating KIR2DS1 (C2) and KIR3DS1 (Bw4). A multivariate competing risks regression analysis revealed a significantly reduced incidence of relapse (p-values <0.05) among recipients of unrelated donor HCT in which one or more HLA ligands for donor inhibitory KIR were absent.

Mentions: Among the various definitions of NK cell alloreactivity based on donor KIR and recipient HLA combinations, only ‘missing ligand model’ is applicable to HLA matched transplants [14]. In this model, the absence of a putative HLA ligand in the presence of its receptor in donor NK cells (missing ligand) mimics what would be a ‘missing self’ scenario in an individual, and would incite a response to target cell (in this case, residual malignant cells). Beneficial effects of alloreactive NK cells in reducing relapse and improving a progression free survival have been reported in a variety of transplant settings [14–17, 25, 40]. To this end, we tested the effects of missing A3/11 (KIR3DL2 ligand), Bw4 (KIR3DL1/3DS1 ligand), C1 (KIR2DL2/2DL3 ligand) and C2 (KIR2DL1/2DS1 ligand) in recipients when the corresponding receptors were present in their respective donors. A significantly reduced incidence of relapse was observed in recipients of unrelated donor transplants who were missing one or more inhibitory KIR ligands as compared to those in which all inhibitory KIR ligand(s) were present (21.6% [13.7–30.6%] vs. 63.6% [13.5–90.3%]; p = 0.001, Table 4, Fig 4A). However, similar effect was not seen in the recipients of sibling donor transplants. None of the individual donor-KIR missing-HLA combination yielded any notable effect (S2 Table), nor was there a dose effect with the number of missing KIR ligands. When a separate analysis with data stratified as per disease type (lymphoid vs. myeloid) was conducted, the effect of missing inhibitory KIR ligands on relapse did not segregate according to the type of primary disease (data not shown).


Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

Faridi RM, Kemp TJ, Dharmani-Khan P, Lewis V, Tripathi G, Rajalingam R, Daly A, Berka N, Storek J, Masood Khan F - PLoS ONE (2016)

Effect of missing HLA ligands in recipients of unrelated donor HCT.Absence of one or more missing HLA ligands was scored for donor inhibitory KIR3DL2 (A3/A11), KIR3DL1 (Bw4), KIR2DL2/2DL3 (C2) and KIR2DL1 (C1) as well as activating KIR2DS1 (C2) and KIR3DS1 (Bw4). A multivariate competing risks regression analysis revealed a significantly reduced incidence of relapse (p-values <0.05) among recipients of unrelated donor HCT in which one or more HLA ligands for donor inhibitory KIR were absent.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920429&req=5

pone.0158242.g004: Effect of missing HLA ligands in recipients of unrelated donor HCT.Absence of one or more missing HLA ligands was scored for donor inhibitory KIR3DL2 (A3/A11), KIR3DL1 (Bw4), KIR2DL2/2DL3 (C2) and KIR2DL1 (C1) as well as activating KIR2DS1 (C2) and KIR3DS1 (Bw4). A multivariate competing risks regression analysis revealed a significantly reduced incidence of relapse (p-values <0.05) among recipients of unrelated donor HCT in which one or more HLA ligands for donor inhibitory KIR were absent.
Mentions: Among the various definitions of NK cell alloreactivity based on donor KIR and recipient HLA combinations, only ‘missing ligand model’ is applicable to HLA matched transplants [14]. In this model, the absence of a putative HLA ligand in the presence of its receptor in donor NK cells (missing ligand) mimics what would be a ‘missing self’ scenario in an individual, and would incite a response to target cell (in this case, residual malignant cells). Beneficial effects of alloreactive NK cells in reducing relapse and improving a progression free survival have been reported in a variety of transplant settings [14–17, 25, 40]. To this end, we tested the effects of missing A3/11 (KIR3DL2 ligand), Bw4 (KIR3DL1/3DS1 ligand), C1 (KIR2DL2/2DL3 ligand) and C2 (KIR2DL1/2DS1 ligand) in recipients when the corresponding receptors were present in their respective donors. A significantly reduced incidence of relapse was observed in recipients of unrelated donor transplants who were missing one or more inhibitory KIR ligands as compared to those in which all inhibitory KIR ligand(s) were present (21.6% [13.7–30.6%] vs. 63.6% [13.5–90.3%]; p = 0.001, Table 4, Fig 4A). However, similar effect was not seen in the recipients of sibling donor transplants. None of the individual donor-KIR missing-HLA combination yielded any notable effect (S2 Table), nor was there a dose effect with the number of missing KIR ligands. When a separate analysis with data stratified as per disease type (lymphoid vs. myeloid) was conducted, the effect of missing inhibitory KIR ligands on relapse did not segregate according to the type of primary disease (data not shown).

Bottom Line: Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10-0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17-0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants.The present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors.The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.

ABSTRACT

Background: Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT.

Methods and findings: The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42-4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11-2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10-0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17-0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants.

Conclusions: The present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

No MeSH data available.


Related in: MedlinePlus