RESUMEN
Deficiency in regulatory T cells (Tregs) is an important mechanism underlying the pathogenesis of pediatric aplastic anemia, but its specific mechanism is unclear. In our study, we aimed to investigate whether IL-2/STAT5 can regulate the proliferation of Tregs in aplastic anemia (AA) by regulating their expression of B lymphocyte-induced mature protein-1 (BLIMP-1) or interferon regulatory factor 4 (IRF4). Through clinical research and animal experiments, we found that poor activation of the IL-2/STAT5 signaling pathway may leads to low expression of BLIMP-1 in Tregs of children with AA, which leads to defects in the differentiation and proliferation of Tregs in AA. In AA model mice, treatment with IL-2c reversed the decrease in Treg proportions and reduction in Blimp-1 expression in Tregs by increasing the phosphorylation of Stat5 in Tregs. In AA, deficiency of IRF4 expression in Tregs is closely related to the deficiency of Tregs, but is not regulated by the IL-2/STAT5 pathway.
RESUMEN
Objects: This study aimed to investigate the expression patterns and clinical significance of neural cell adhesion molecule-positive (CD56+) myelomonocytes in pediatric patients with moderate aplastic anemia (mAA). Methods: Fifty-six pediatric patients with mAA were enrolled in this study. The patients' clinical characteristics, laboratory data, and response to cyclosporine therapy were obtained. CD56 expression on bone marrow myelomonocytic cells was investigated using flow cytometry. The association between aberrant CD56 expression and cyclosporine response was evaluated by a multivariate analysis. Results: CD56+ myelomonocytes were detected in 43% of the mAA cases. Aberrant CD56 expression was frequent on immature CD45dimCD16dim granulocytes and mature CD45brightCD14bright monocytes. Compared with patients with CD56- myelomonocytes (CD56- patients), patients with CD56+ myelomonocytes (CD56+ patients) were in moderate hematological condition and had a distinct bone marrow cellular composition profile, which included an increased proportion of myeloid cells and CD56bright natural killer cells and a reduced proportion of CD4+ T cells, CD8+ T cells, and B cells. The multivariate analysis determined that CD56+ myelomonocytes were a favorable factor for achieving response at 6 months after cyclosporine therapy. There was a trend towards a lower 3-year rate of evolution to severe aplastic anemia or relapse among the CD56+ patients (8%) than the CD56- patients (22%). Conclusion: CD56+ patients had an increased myeloid compartment and better prognosis compared with CD56- patients. The findings demonstrated the favorable role of CD56+ myelomonocytes in aplastic anemia progression.
RESUMEN
Acquired aplastic anemia (AA) is a recognized immune-mediated disorder and abnormally activated T lymphocyte-mediated bone marrow destruction is considered to be its main pathogenesis. Whether abnormal activation of T lymphocytes would also damage bone marrow-derived MSCs remains to be further studied. The aim of this study was to analyze the extent of T lymphocyte activation and the levels of Th1/Th2 cytokines of AA patients, and to explore the immunomodulatory effects of BM-MSCs on IL-2-stimulated T lymphocyte activation and cytokine production in vitro by means of transwell co-culture assay and flow cytometry measurement. The intermediate (CD25+) activated T cells were dominant in peripheral blood, while the early (CD69+) and late (HLA-DR+) activated T cells were predominant in bone marrow. Severe AA patients have an obviously higher proportion of CD3+CD8+CD69+ T cells than NSAA cases. The levels of IL-2 and IL-6 in AA patients were slightly elevated and INF-γ was mildly decreased in comparison with normal individuals. BM-MSCs derived from AA could not effectively inhibit the IL-2-induced activation of T cells with higher proportions of CD25+CD3+CD4+, CD69+CD3+CD4+ and CD25+CD3+CD8+ T cells after co-culture, and they showed a decreased ability to balance the Th1/Th2 cytokine production. Moreover, they had less robust osteogenic differentiation and more prone to adipogenic differentiation. We concluded that abnormally excessive T cell activation accompanied by abnormal cytokine secretion may impair the function of BM-MSCs in children with aplastic anemia.
Asunto(s)
Anemia Aplásica , Células Madre Mesenquimatosas , Niño , Humanos , Médula Ósea/patología , Linfocitos T CD8-positivos , Interleucina-2 , OsteogénesisRESUMEN
Graft failure and survival are the major problems for patients with aplastic anemia undergoing hematopoietic stem cell transplantation (HSCT). Previous studies showed that anti-HLA antibodies negatively impact engraftment in HSCT. This retrospective study of 51 pediatric patients with acquired aplastic anemia who underwent allogeneic HSCT at a single institution between 2006 and 2012 investigated the influence of anti-HLA antibodies on the outcome of HSCT. Serum samples collected before HSCT were tested for the presence of anti-HLA antibodies. Pre-existing anti-HLA antibodies were detected in 54.9% (28/51) of patients, among whom 39.2% (20/51) had anti-HLA class I antibodies. Anti-HLA antibodies were associated with worse five-yr survival (78.6% vs. 100%, p = 0.021) and higher treatment-related mortality (21.4% vs. 0%, p = 0.028) compared with antibody-negative patients. Anti-HLA class I antibody-positive patients had poorer five-yr survival (75.0%) than anti-HLA class I&II antibody-positive and antibody-negative patients (87.5% and 100.0%, respectively, p = 0.039). Presence of anti-HLA class I antibodies (p = 0.024) and older age (10 yr or more; p = 0.027) significantly increased the risk of post-HSCT mortality. Pre-existing anti-HLA antibodies negatively affect the outcome of HSCT in pediatric patients with aplastic anemia. Routine testing for anti-HLA antibodies concurrent with efficient treatment should be conducted prior to HSCT.