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CD56bright natural killer regulatory cells in filgrastim primed donor blood or marrow products regulate chronic graft-versus-host disease: the Canadian Blood and Marrow Transplant Group randomized 0601 study results.

ABSTRACT: Randomized trials have conclusively shown higher rates of chronic graft-versus-host disease with filgrastim-stimulated apheresis peripheral blood as a donor source than unstimulated bone marrow. The Canadian Blood and Marrow Transplant Group conducted a phase 3 study of adults who received either filgrastim-stimulated apheresis peripheral blood or filgrastim-stimulated bone marrow from human leukocyte antigen-identical sibling donors. Because all donors received the identical filgrastim dosing schedule, this study allowed for a controlled evaluation of the impact of stem cell source on development of chronic graft-versus-host disease. One hundred and twenty-one evaluable filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow patient donor products were immunologically characterized by flow cytometry and tested for their association with acute and chronic graft-versus-host disease within 2 years of transplantation. The immune populations evaluated included, regulatory T cells, central memory and effector T cells, interferon γ positive producing T cells, invariate natural killer T cells, regulatory natural killer cells, dendritic cell populations, macrophages, and activated B cells and memory B cells. When both filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow were grouped together, a higher chronic graft-versus-host disease frequency was associated with lower proportions of CD56bright natural killer regulatory cells and interferon γ-producing T helper cells in the donor product. Lower CD56bright natural killer regulatory cells displayed differential impacts on the development of extensive chronic graft-versus-host disease between filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow. In summary, while controlling for the potential impact of filgrastim on marrow, our studies demonstrated that CD56bright natural killer regulatory cells had a much stronger impact on filgrastim-stimulated apheresis peripheral blood than on filgrastim-stimulated bone marrow. This supports the conclusion that a lower proportion of CD56bright natural killer regulatory cells results in the high rate of chronic graft-versus-host disease seen in filgrastim-stimulated apheresis peripheral blood. clinicaltrials.gov Identifier: 00438958.

SUBMITTER: Kariminia A

PROVIDER: S-EPMC5664398 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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CD56bright natural killer regulatory cells in filgrastim primed donor blood or marrow products regulate chronic graft-versus-host disease: the Canadian Blood and Marrow Transplant Group randomized 0601 study results.

Kariminia Amina A Ivison Sabine S Ng Bernard B Rozmus Jacob J Sung Susanna S Varshney Avani A Aljurf Mahmoud M Lachance Sylvie S Walker Irwin I Toze Cindy C Lipton Jeff J Lee Stephanie J SJ Szer Jeff J Doocey Richard R Lewis Ian I Smith Clayton C Chaudhri Naeem N Levings Megan K MK Broady Raewyn R Devins Gerald G Szwajcer David D Foley Ronan R Mostafavi Sara S Pavletic Steven S Wall Donna A DA Couban Stephan S Panzarella Tony T Schultz Kirk R KR

Haematologica 20170921 11

Randomized trials have conclusively shown higher rates of chronic graft-versus-host disease with filgrastim-stimulated apheresis peripheral blood as a donor source than unstimulated bone marrow. The Canadian Blood and Marrow Transplant Group conducted a phase 3 study of adults who received either filgrastim-stimulated apheresis peripheral blood or filgrastim-stimulated bone marrow from human leukocyte antigen-identical sibling donors. Because all donors received the identical filgrastim d ...[more]

PMID: 28935847

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Project description:Objectives: We aimed to analyze the effect of cold ischemia time (CIT) on post-transplant graft function through mixed-effect model analysis to reduce the bias caused by paired mate kidneys. Methods: We reviewed all kidney transplantation records from 2015 to 2019 at our center. After applying the exclusion criteria, 561 cases were included for analysis. All donor characteristics, preservation and matching information, and recipient characteristics were collected. Transplant outcomes included delayed graft function (DGF) and estimated glomerular filtration rate (eGFR). Generalized linear mixed models were applied for analysis. We also explored potential effect modifiers, namely, donor death category, expanded criteria donors, and donor death causes. Results: Among the 561 cases, 79 DGF recipients developed DGF, and 15 recipients who died after surgery were excluded from the eGFR estimation. The median stable eGFR of the 546 recipients was 60.39 (47.63, 76.97) ml/min/1.73 m2. After adjusting for confounding covariates, CIT had a negative impact on DGF incidence [odds ratio = 1.149 (1.006, 1.313), P = 0.041]. In the evaluation of the impact on eGFR, the regression showed that CIT had no significant correlation with eGFR [β = -0.287 (-0.625, 0.051), P = 0.096]. When exploring potential effect modifiers, only the death category showed a significant interaction with CIT in the effect on eGFR (P interaction = 0.027). In the donation after brain death (DBD) group, CIT had no significant effect on eGFR [β = 0.135 (-0.433, 0.702), P = 0.642]. In the donation after circulatory death/donation after brain death followed by circulatory death (DCD/DBCD) group, CIT had a significantly negative effect on eGFR [β= -0.700 (-1.196, -0.204), P = 0.006]. Compared to a CIT of 0-6 h, a CIT of 6-8 or 8-12 h did not decrease the post-transplant eGFR. CIT over 12 h (12-16 h or over 16 h) significantly decreased eGFR. With the increase in CIT, the regenerated eGFR worsened (P trend = 0.011). Conclusion: Considering the effect of paired mate kidneys, the risk of DGF increased with prolonged CIT. The donor death category was an effect modifier between CIT and eGFR. Prolonged CIT did not reduce the eGFR level in recipients from DBDs but significantly decreased the eGFR in recipients from DCDs/DBCDs. This result indicates the potential biological interaction between CIT and donor death category.

Project description:Several recipient biomarkers are reported to predict graft dysfunction, but these are not useful in decision making for the acceptance or allocation of deceased donor kidneys; thus, it is necessary to develop donor biomarkers predictive of graft dysfunction. To address this issue, we prospectively enrolled 94 deceased donors and their 109 recipients who underwent transplantation between 2010 and 2013 at 4 Korean transplantation centers. We investigated the predictive values of donor urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and L-type fatty acid binding protein (L-FABP) for reduced graft function (RGF). We also developed a prediction model of RGF using these donor biomarkers. RGF was defined as delayed or slow graft function. Multiple logistic regression analysis was used to generate a prediction model, which was internally validated using a bootstrapping method. Multiple linear regression analysis was used to assess the association of biomarkers with 1-year graft function. Notably, donor urinary NGAL levels were associated with donor AKI (P = 0.014), and donor urinary NGAL and L-FABP were predictive for RGF, with area under the receiver-operating characteristic curves (AUROC) of 0.758 and 0.704 for NGAL and L-FABP, respectively. The best-fit model including donor urinary NGAL, L-FABP, and serum creatinine conveyed a better predictive value for RGF than donor serum creatinine alone (P = 0.02). In addition, we generated a scoring method to predict RGF based on donor urinary NGAL, L-FABP, and serum creatinine levels. Diagnostic performance of the RGF prediction score (AUROC 0.808) was significantly better than that of the DGF calculator (AUROC 0.627) and the kidney donor profile index (AUROC 0.606). Donor urinary L-FABP levels were also predictive of 1-year graft function (P = 0.005). Collectively, these findings suggest donor urinary NGAL and L-FABP to be useful biomarkers for RGF, and support the use of a new scoring system based on donor biomarkers to facilitate decision-making in acceptance and allocation of deceased donor kidneys and contribute to maximal organ utilization.

Dataset Information

CD56bright natural killer regulatory cells in filgrastim primed donor blood or marrow products regulate chronic graft-versus-host disease: the Canadian Blood and Marrow Transplant Group randomized 0601 study results.

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CD56<sup>bright</sup> natural killer regulatory cells in filgrastim primed donor blood or marrow products regulate chronic graft-<i>versus</i>-host disease: the Canadian Blood and Marrow Transplant Group randomized 0601 study results.

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