Aberrant T cell responses in the bone marrow microenvironment of patients with poor graft function after allogeneic hematopoietic stem cell transplantation

Abstract

BackgroundPoor graft function (PGF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, whether abnormalities of T cell subsets in the bone marrow (BM) immune microenvironment, including Th17, Tc17, Th1, Tc1, Th2, Tc2 cells and regulatory T cells (Tregs), are involved in the pathogenesis of PGF remains unclear.MethodsThis prospective nested case–control study enrolled 20 patients with PGF, 40 matched patients with good graft function (GGF) after allo-HSCT, and 20 healthy donors (HD). Th17, Tc17, Th1, Tc1, Th2, Tc2 cells, Tregs and their subsets were analyzed by flow cytometry.ResultsA significantly higher proportion of stimulated CD4+ and CD8+ T cells that produced IL-17 (Th17 and Tc17) was found in the BM of PGF patients than in the BM of GGF patients and HD, whereas the percentages of Tregs in PGF patients were comparable to those in GGF patients and HD, resulting in a dramatically elevated ratio of Th17 cells/Tregs in the BM of PGF patients relative to those in GGF patients. Moreover, both CD4+ and CD8+ T cells were polarized towards a type 1 immune response in the BM of PGF patients.ConclusionsThe present study revealed that aberrant T cell responses in the BM immune microenvironment may be involved in the pathogenesis of PGF after allo-HSCT. These findings will facilitate the optimization of immune regulation strategies and improve the outcome of PGF patients post-allotransplant.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1159-y) contains supplementary material, which is available to authorized users.

An unbalanced monocyte macrophage polarization in the bone marrow microenvironment of patients with poor graft function after allogeneic haematopoietic stem cell transplantation

“…Collectively, the evidence shows that changes in MФ differentiation, polarization, and activation in the local milieu can play a decisive role in the pathogenesis of autoimmune and inflammatory diseases. Recently, we reported that elevated BM Th1/Th2 and Tc1/Tc2 ratios were involved in the occurrence of PGF (Wang et al , ; Kong et al , ). Consistent with the previous reports and our previous work, we found an aberrant monocyte distribution and MФ polarization towards M1 in the BM of PGF patients.…”

“…Our previous reports indicate that dysregulated Th1 cell/Th2 cell, Tc1 cell/Tc2 cell, and Th17 cell/Treg ratios in the BM immune microenvironment are involved in the pathogenesis of PGF (Wang et al , ; Kong et al , ). In the current study, MФs reached unbalanced polarization states that were similar to the Th1/Th2 polarization state, which represents an activated immune state.…”

“…Poor graft function was defined as the presence of 2 or 3 cytopenic counts (absolute neutrophils <0·5 × 10 9 /l, platelets ≤20 × 10 9 /l, or haemoglobin ≤70 g/l) for at least 3 consecutive days beyond day +28 post‐transplantation with a transfusion requirement, associated with hypoplastic‐aplastic BM, in the presence of complete donor chimerism (Kong et al , , ,b, ; Shi et al , ; Wang et al , ). Patients with evidence of severe graft‐versus‐host disease (GvHD) or haematological relapse after transplantation were excluded.…”

Dysfunctional Bone Marrow Mesenchymal Stem Cells in Patients with Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

“…Murine studies demonstrated that effective hematopoiesis in the bone marrow (BM) depends on the interaction between HSCs and the specific BM microenvironment [5][6][7][8]. Therefore, in previous studies we focused on the quantity and function of HSCs and BM microenvironment elements in PGF patients [9][10][11][12][13][14]. Lower numbers and dysfunctional characteristics of CD34 + cells were found in the BM of PGF patients [9,11,12].…”

“…Moreover, defective BM endosteal cells, endothelial progenitor cells, and perivascular cells were present in PGF patients [9,12,13]. In addition, aberrant T cell responses were observed in the BM microenvironment of PGF patients [10,14]. Despite considerable progress, the mechanisms involved in the pathophysiology of PGF remain poorly understood.…”