ABSTRACT
A correction to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
Imatinib mesylate (IM) therapy has been shown to induce lower T cell counts in chronic myelogenous leukemia (CML) patients and an interference of IM with T cell receptor (TCR) signaling has been invoked to explain this observation. However, IL-7 and TCR signaling are both essential for lymphocyte survival. This study was undertaken to determine whether IM interferes with IL-7 or TCR signaling to explain lower T cell counts in patients. At diagnosis, CML patients have typically lower CD4+ counts in their blood, yet CD8+ counts are normal or even increased in some. Following the initiation of IM treatment, CD4+ counts were further diminished and CD8+ T lymphocytes were dramatically decreased. In vitro studies confirmed IM interference with TCR signaling through the inhibition of ERK phosphorylation and we showed a similar effect on IL-7 signaling and STAT5 phosphorylation (STAT5-p). Importantly however, using an in vivo mouse model, we demonstrated that IM impaired T cell survival through the inhibition of IL-7 and STAT5-p but not TCR signaling which remained unaffected during IM therapy. Thus, off-target inhibitory effects of IM on IL-7 and STAT5-p explain how T cell lymphopenia occurs in patients treated with IM.
Subject(s)
Imatinib Mesylate/administration & dosage , Interleukin-7/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , STAT5 Transcription Factor/genetics , Animals , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Cell Count , Cell Line, Tumor , Humans , Imatinib Mesylate/adverse effects , Interleukin-7/antagonists & inhibitors , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Lymphopenia/genetics , Lymphopenia/pathology , Mice , Phosphorylation/drug effects , Receptors, Antigen, T-Cell/genetics , STAT5 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
In a previous prospective study on 62 patients who underwent an HLA-matched allogeneic stem cell transplantation, we have observed that proportion of donor-derived CCR7(+)/CD4(+) T cells in the graft provided a predictive indicator of acute GVHD without interfering on chronic GVHD and relapse rate. Here we present our results on a confirmatory cohort of 137 consecutive patients. Indeed patients who received more than 76% of CCR7(+)/CD4(+) T cells in the graft developed more often acute GVHD be it of low or high grade than those who did not. Determination of the CCR7(+)/CCR7(neg) ratio of CD4(+) T cells in the graft provides a predictive indicator of acute GVHD and could help to define strategies of partial selective T cell depleted transplantation.
Subject(s)
Bone Marrow Transplantation , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/transplantation , Graft vs Host Disease/immunology , Immunologic Memory , Peripheral Blood Stem Cell Transplantation , T-Lymphocyte Subsets/transplantation , Acute Disease , Adolescent , Adult , Aged , Allografts/immunology , CD4-Positive T-Lymphocytes/immunology , Child , Female , Graft Survival/immunology , Hematologic Neoplasms/therapy , Humans , Immunophenotyping , Living Donors , Lymphocyte Depletion , Male , Middle Aged , Prospective Studies , Receptors, CCR7/analysis , T-Lymphocyte Subsets/immunology , Treatment Outcome , Young AdultABSTRACT
In previous studies, we observed that a high proportion of donor-derived CD4(+) T cells expressing the chemokine receptor 7 (CCR7) was a major determinant of acute GVHD, without interfering with the incidence of other post-transplant outcomes, especially relapse and nonrelapse mortality rates. Here, we investigated in vitro the impact of partially selective CD4(+)/CCR7(+) T lymphocytes on acquired anti-infective immune response in 10 donors who underwent G-CSF-primed PBSC collection. Similar quantitative and functional proliferative reactions were observed in lymphocyte cultures in the presence of adenovirus and pp65 Ags with unmanipulated and partially depleted donor samples. No responses were observed in the presence of human T-cell lymphotropic virus type 1 used as a negative control. These results complete the proof of concept needed to build a clinical trial investigating partially selective CD4(+)/CCR7(+) T cell-depleted allo-SCT.
Subject(s)
CD4-Positive T-Lymphocytes/transplantation , Cell Separation/methods , Graft vs Host Disease/prevention & control , Lymphocyte Depletion/methods , Lymphocyte Transfusion/methods , Receptors, CCR7/metabolism , Acute Disease , Adult , Bone Marrow Transplantation/adverse effects , Bone Marrow Transplantation/methods , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , Cell Proliferation , Enzyme-Linked Immunosorbent Assay/methods , Female , Flow Cytometry/methods , Fluoresceins , Fluorescent Dyes , Graft vs Host Disease/immunology , Hematologic Neoplasms/therapy , Humans , Interferon-gamma/metabolism , Lymphocyte Transfusion/adverse effects , Male , Succinimides , Tissue Donors , TritiumABSTRACT
To assess the impact of homeostatic expansion on the occurrence of acute GVHD after reduced intensity conditioning (RIC) transplantation, systemic levels of IL-7 and IL-15 and expression of their specific receptor chains were prospectively investigated in 45 fully HLA-matched allograft recipients. IL-7 and IL-15 levels peaked at four- to fivefold over pre-conditioning values. IL-7 levels were inversely correlated to absolute T-cell counts. Peak IL-15 levels positively correlated to concurrent CRP levels, but normalized earlier than IL-7. These results indicate that the kinetic course of IL-7 depends mainly on initiation of T-cell recovery, while IL-15 depends more on peri-transplant inflammation after RIC. Longer duration of the rise in IL-7 levels was associated with preservation of a normal CD4/CD8 ratio. In all, 16 (35%) patients developed grade 2-4 acute GVHD at a median of 42 days post graft, preceded by higher IL-7 levels and more downregulation of IL-7 receptor α chain on CD4(+) T cells than in patients without acute GVHD, suggesting enhanced homeostatic expansion. In multivariate analysis, IL-7 level measured on day +30 was the foremost predictive factor for grade 2-4 acute GVHD (P=0.002). Measurement of IL-7 level after RIC transplantation might help predict risk of subsequent acute GvHD.
Subject(s)
Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation/methods , Interleukin-15/blood , Interleukin-7/blood , Transplantation Conditioning/methods , Adolescent , Adult , Aged , Female , Flow Cytometry , Graft vs Host Disease/blood , Humans , Male , Middle Aged , Young AdultABSTRACT
T-cell reconstitution after allo-SCT initially depends on homeostatic peripheral expansion of donor T cells, the level of which may promote the differentiation of alloreactive and tumor-reactive effectors. IL-7 and IL-15 exert their effect as key homeostatic cytokines. We prospectively investigated plasma levels of IL-7 and IL-15 in a homogeneous group of 40 patients in CR of their hematologic malignancy undergoing myeloablative, fully (10/10) HLA-matched BMT. IL-7 and IL-15 proceeded along similar kinetic courses, peaking at wide ranges (3.8-30.2 and 14.3-66 pg/ml, respectively) on day +14 when all patients were profoundly lymphopenic. Occurrence and grade of subsequent acute GVHD were significantly associated with heightened day +14 IL-7 and IL-15 levels. Association of peak IL-7 level to grade 2-4 acute GVHD was confirmed by Cox multivariate analysis (hazard ratio (HR)=5.38; P=0.022). Malignancy relapse was significantly associated with reduced day +14 levels of IL-15 (Cox multivariate analysis: HR=0.93; P=0.035). Plasma IL-7 and IL-15 levels in the early post transplantation period are therefore biomarkers that can help predict subsequent development of acute GVHD and malignancy relapse.
