DIFFERENT CLUSTERS OF IMMUNOLOGIC VARIABLES ARE ASSOCIATED WITH CHRONIC GVHD AND RELAPSE IN A DYNAMICAL MODEL
(Abstract release date: 05/19/16)
EHA Library. Skert C. 06/09/16; 133055; E1506
Dr. Cristina Skert
Contributions
Contributions
Abstract
Abstract: E1506
Type: Eposter Presentation
Background
The long-term efficacy of allogeneic haematopoietic stem cell transplantation (SCT) relies primarily on the Graft-versus-tumor (GVT) effect, which partially overlaps with Graft versus Host disease (GvHD), the most common cause of morbidity and mortality in HSCT. Immune parameters that univocally associate with GVHD or GVT have not been identified yet.
Aims
In this study, lymphocyte subsets together with TCR-repertoire analysis, and index of thymic and bone marrow output were evaluated at different time points, in order to identify possible predictors of chronic GVHD and ineffective GVT.
Methods
Prospective evaluations of lymphocyte subsets, thymic and bone marrow output were performed in 40 patients before SCT, at 30, 90, 180 days and 1 year after SCT. CD4+/CD8+ naïve, central memory, effector memory, terminally differentiated effector memory (TEMRA) cells, subsets of regulatory T-lymphocytes, immature B cells, naïve, switched and unswitched memory B cells, memory double negative (IgD-CD27-) B cells were analysed by flow cytometry. Analysis of thymic and bone marrow output was performed by detection of T cell receptor excision circles (TRECs) and kappa-deleting recombination circles (KRECs). TRECs and KRECs were simultaneously quantified by a duplex quantitative Real-Time PCR. Heteroduplex assay was used to perform TCR-repertoire analysis. A 2-step multivariate analysis was performed using principal component analysis (PCA) and Cox regression analysis, to solve the problem of the high number of variables (immunological, patients- and transplant related) in comparison with the relatively limited and heterogeneous pool of patients.
Results
Chronic GVHD was observed in 9 patients (median time: 7 months, range 4-10). In 2-step multivariate analysis, lower values of regulatory effector memory lymphocytes at day +30 and lower percentage of CD8+TEMRA cells at +90, together with lower values of immature B cells and KRECs at +180 were inversely correlated with chronic GVHD (HR 0,4; p=0,002) . The relapse rate (30%; median time: 9 months, range 3-48) was used as clinical index of ineffective GVT. The following clusters (C) of immunological parameters were associated with relapse: C1(pre-transplant lower values of CD4+central memory, all regulatory, and regulatory central memory cells; HR 4,0 p=0,02); C2(pre-transplant higher percentage of mature B cells, lower values of switched memory B cells and KRECs at day+90; HR 0,1 p=0,008).
Conclusion
Different clusters of immunological parameters at different time points were evidenced as predictors of cGVHD and ineffective GVT, allowing a clear-cut distinction between these immunological reactions. Changes in pre- and post-transplant B-lymphopoietic microenvironment and imbalances in the subsets of B-cells may influence GVHD and GVT. The atypical association of regulatory T-cells with GVHD may be explained by the relative efficiency of different subsets of regulatory T-cells (naïve>memory), as shown in some experimental models. The correlation of CD8+TEMRA at +90 with chronic GVHD may early indicate a persistently activated and dysregulated immune system. The validation of these clusters of immunological parameters as specific early predictors of GVHD or GVT, even before SCT, could potentially allow the development of pre-emptive and targeted therapies.
Session topic: E-poster
Type: Eposter Presentation
Background
The long-term efficacy of allogeneic haematopoietic stem cell transplantation (SCT) relies primarily on the Graft-versus-tumor (GVT) effect, which partially overlaps with Graft versus Host disease (GvHD), the most common cause of morbidity and mortality in HSCT. Immune parameters that univocally associate with GVHD or GVT have not been identified yet.
Aims
In this study, lymphocyte subsets together with TCR-repertoire analysis, and index of thymic and bone marrow output were evaluated at different time points, in order to identify possible predictors of chronic GVHD and ineffective GVT.
Methods
Prospective evaluations of lymphocyte subsets, thymic and bone marrow output were performed in 40 patients before SCT, at 30, 90, 180 days and 1 year after SCT. CD4+/CD8+ naïve, central memory, effector memory, terminally differentiated effector memory (TEMRA) cells, subsets of regulatory T-lymphocytes, immature B cells, naïve, switched and unswitched memory B cells, memory double negative (IgD-CD27-) B cells were analysed by flow cytometry. Analysis of thymic and bone marrow output was performed by detection of T cell receptor excision circles (TRECs) and kappa-deleting recombination circles (KRECs). TRECs and KRECs were simultaneously quantified by a duplex quantitative Real-Time PCR. Heteroduplex assay was used to perform TCR-repertoire analysis. A 2-step multivariate analysis was performed using principal component analysis (PCA) and Cox regression analysis, to solve the problem of the high number of variables (immunological, patients- and transplant related) in comparison with the relatively limited and heterogeneous pool of patients.
Results
Chronic GVHD was observed in 9 patients (median time: 7 months, range 4-10). In 2-step multivariate analysis, lower values of regulatory effector memory lymphocytes at day +30 and lower percentage of CD8+TEMRA cells at +90, together with lower values of immature B cells and KRECs at +180 were inversely correlated with chronic GVHD (HR 0,4; p=0,002) . The relapse rate (30%; median time: 9 months, range 3-48) was used as clinical index of ineffective GVT. The following clusters (C) of immunological parameters were associated with relapse: C1(pre-transplant lower values of CD4+central memory, all regulatory, and regulatory central memory cells; HR 4,0 p=0,02); C2(pre-transplant higher percentage of mature B cells, lower values of switched memory B cells and KRECs at day+90; HR 0,1 p=0,008).
Conclusion
Different clusters of immunological parameters at different time points were evidenced as predictors of cGVHD and ineffective GVT, allowing a clear-cut distinction between these immunological reactions. Changes in pre- and post-transplant B-lymphopoietic microenvironment and imbalances in the subsets of B-cells may influence GVHD and GVT. The atypical association of regulatory T-cells with GVHD may be explained by the relative efficiency of different subsets of regulatory T-cells (naïve>memory), as shown in some experimental models. The correlation of CD8+TEMRA at +90 with chronic GVHD may early indicate a persistently activated and dysregulated immune system. The validation of these clusters of immunological parameters as specific early predictors of GVHD or GVT, even before SCT, could potentially allow the development of pre-emptive and targeted therapies.
Session topic: E-poster
Abstract: E1506
Type: Eposter Presentation
Background
The long-term efficacy of allogeneic haematopoietic stem cell transplantation (SCT) relies primarily on the Graft-versus-tumor (GVT) effect, which partially overlaps with Graft versus Host disease (GvHD), the most common cause of morbidity and mortality in HSCT. Immune parameters that univocally associate with GVHD or GVT have not been identified yet.
Aims
In this study, lymphocyte subsets together with TCR-repertoire analysis, and index of thymic and bone marrow output were evaluated at different time points, in order to identify possible predictors of chronic GVHD and ineffective GVT.
Methods
Prospective evaluations of lymphocyte subsets, thymic and bone marrow output were performed in 40 patients before SCT, at 30, 90, 180 days and 1 year after SCT. CD4+/CD8+ naïve, central memory, effector memory, terminally differentiated effector memory (TEMRA) cells, subsets of regulatory T-lymphocytes, immature B cells, naïve, switched and unswitched memory B cells, memory double negative (IgD-CD27-) B cells were analysed by flow cytometry. Analysis of thymic and bone marrow output was performed by detection of T cell receptor excision circles (TRECs) and kappa-deleting recombination circles (KRECs). TRECs and KRECs were simultaneously quantified by a duplex quantitative Real-Time PCR. Heteroduplex assay was used to perform TCR-repertoire analysis. A 2-step multivariate analysis was performed using principal component analysis (PCA) and Cox regression analysis, to solve the problem of the high number of variables (immunological, patients- and transplant related) in comparison with the relatively limited and heterogeneous pool of patients.
Results
Chronic GVHD was observed in 9 patients (median time: 7 months, range 4-10). In 2-step multivariate analysis, lower values of regulatory effector memory lymphocytes at day +30 and lower percentage of CD8+TEMRA cells at +90, together with lower values of immature B cells and KRECs at +180 were inversely correlated with chronic GVHD (HR 0,4; p=0,002) . The relapse rate (30%; median time: 9 months, range 3-48) was used as clinical index of ineffective GVT. The following clusters (C) of immunological parameters were associated with relapse: C1(pre-transplant lower values of CD4+central memory, all regulatory, and regulatory central memory cells; HR 4,0 p=0,02); C2(pre-transplant higher percentage of mature B cells, lower values of switched memory B cells and KRECs at day+90; HR 0,1 p=0,008).
Conclusion
Different clusters of immunological parameters at different time points were evidenced as predictors of cGVHD and ineffective GVT, allowing a clear-cut distinction between these immunological reactions. Changes in pre- and post-transplant B-lymphopoietic microenvironment and imbalances in the subsets of B-cells may influence GVHD and GVT. The atypical association of regulatory T-cells with GVHD may be explained by the relative efficiency of different subsets of regulatory T-cells (naïve>memory), as shown in some experimental models. The correlation of CD8+TEMRA at +90 with chronic GVHD may early indicate a persistently activated and dysregulated immune system. The validation of these clusters of immunological parameters as specific early predictors of GVHD or GVT, even before SCT, could potentially allow the development of pre-emptive and targeted therapies.
Session topic: E-poster
Type: Eposter Presentation
Background
The long-term efficacy of allogeneic haematopoietic stem cell transplantation (SCT) relies primarily on the Graft-versus-tumor (GVT) effect, which partially overlaps with Graft versus Host disease (GvHD), the most common cause of morbidity and mortality in HSCT. Immune parameters that univocally associate with GVHD or GVT have not been identified yet.
Aims
In this study, lymphocyte subsets together with TCR-repertoire analysis, and index of thymic and bone marrow output were evaluated at different time points, in order to identify possible predictors of chronic GVHD and ineffective GVT.
Methods
Prospective evaluations of lymphocyte subsets, thymic and bone marrow output were performed in 40 patients before SCT, at 30, 90, 180 days and 1 year after SCT. CD4+/CD8+ naïve, central memory, effector memory, terminally differentiated effector memory (TEMRA) cells, subsets of regulatory T-lymphocytes, immature B cells, naïve, switched and unswitched memory B cells, memory double negative (IgD-CD27-) B cells were analysed by flow cytometry. Analysis of thymic and bone marrow output was performed by detection of T cell receptor excision circles (TRECs) and kappa-deleting recombination circles (KRECs). TRECs and KRECs were simultaneously quantified by a duplex quantitative Real-Time PCR. Heteroduplex assay was used to perform TCR-repertoire analysis. A 2-step multivariate analysis was performed using principal component analysis (PCA) and Cox regression analysis, to solve the problem of the high number of variables (immunological, patients- and transplant related) in comparison with the relatively limited and heterogeneous pool of patients.
Results
Chronic GVHD was observed in 9 patients (median time: 7 months, range 4-10). In 2-step multivariate analysis, lower values of regulatory effector memory lymphocytes at day +30 and lower percentage of CD8+TEMRA cells at +90, together with lower values of immature B cells and KRECs at +180 were inversely correlated with chronic GVHD (HR 0,4; p=0,002) . The relapse rate (30%; median time: 9 months, range 3-48) was used as clinical index of ineffective GVT. The following clusters (C) of immunological parameters were associated with relapse: C1(pre-transplant lower values of CD4+central memory, all regulatory, and regulatory central memory cells; HR 4,0 p=0,02); C2(pre-transplant higher percentage of mature B cells, lower values of switched memory B cells and KRECs at day+90; HR 0,1 p=0,008).
Conclusion
Different clusters of immunological parameters at different time points were evidenced as predictors of cGVHD and ineffective GVT, allowing a clear-cut distinction between these immunological reactions. Changes in pre- and post-transplant B-lymphopoietic microenvironment and imbalances in the subsets of B-cells may influence GVHD and GVT. The atypical association of regulatory T-cells with GVHD may be explained by the relative efficiency of different subsets of regulatory T-cells (naïve>memory), as shown in some experimental models. The correlation of CD8+TEMRA at +90 with chronic GVHD may early indicate a persistently activated and dysregulated immune system. The validation of these clusters of immunological parameters as specific early predictors of GVHD or GVT, even before SCT, could potentially allow the development of pre-emptive and targeted therapies.
Session topic: E-poster
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