Dynamics of T cell subpopulation in patients with aplastic anemia during immunosuppressive therapy

Abstract

Background. Aplastic anemia (AA) is a non-tumor and rare disease of the blood system, characterized by deep pancytopenia due to the development of bone marrow aplasia with immune-mediated damage of hematopoietic stem cells. Research results indicate the presence of antigenic effects leading to pathological activation and dysregulation of the T cells in the bone marrow with increased production of pro-inflammatory cytokines that damage hematopoietic stem cells. The triggering factor that initiates the cascade of immune reactions is currently unknown. The high efficiency of immunosuppressive therapy (IST), which allows achieving remission in the majority of AA patients, is evidence of the immune genesis of the disease. The pathogenesis of AA is currently being actively studied. The participation of T cell subpopulations in immune response is beyond doubt, but the issues of their significance in the AA pathogenesis have not been fully studied. A more detailed understanding of the AA development mechanisms is necessary for the development of long-term effective treatment.Aim. To investigate the T cells subpopulation in bone marrow of AA patients during IST.Materials and methods. The study included 41 patients over 18 years of age with newly diagnosed acquired AA without previous IST. Treatment was carried out according to a protocol including horse antithymocyte globulin and cyclosporine. Flow cytometry was used to detect T cell subpopulations. Bone marrow examination was performed at three time points: initially, 3 and 6 months after initiation of combined IST.Results. Multidirectional changes in the T cell subpopulations ratio before the start of IST were found in all AA patients included in the prospective study: most patients had a higher proportion of effector CD4+ and CD8+ T cells (61 and 83 % of patients, respectively), memory CD4+ T cells (63 % of patients), and a lower proportion of naive CD4+ and CD8+ T cells (81 and 51 % of patients, respectively) compared to donors (p <0.05). The abnormal T cell subpopulation ratios that cause abnormal immune response are most pronounced in the very severe form of AA. When responding to treatment, no significant changes in T cells subpopulation were found either before the start of IST or 6 months after compared with donors. In the absence of treatment response, a higher proportion of effector CD4+ and CD8+ T cells, memory CD4+ T cells, and a lower proportion of naive CD4+ and CD8+ T cells were detected compared to donors already before the start of IST (p <0.05). Of all cytometric parameters, a significant relationship was obtained between effector CD8+ T cells dynamics and response to treatment (p = 0.040). The number of these cells at the onset and control points significantly correlated with the response to IST. In patients who have not responded to treatment by the 3rd month from IST initiated, there is a further increase in effector CD8+ T cells number, despite the IST continuation, which dictates the need to intensify IST in the shortest possible time (between the 3rd and 6th months) in these patients, namely, a 2nd course of equine antithymocyte globulin and continuation of cyclosporine therapy or individual consideration of alternative treatment (allogeneic hematopoietic stem cell transplantation).Conclusion. Studying the T cells subpopulation dynamics, in particular effector T cells, allows us to determine the tactics of further treatment in the early stages of IST in order to select the optimal treatment program for each AA patient.