Haematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte‐mediated inhibition of CFU‐GM and alterations in T‐cell receptor V_β profiles

Abstract

Summary.We have demonstrated that 44% of myelodysplastic syndrome (MDS) patients with cytopenia have a haematological response to antithymocyte globulin (ATG). Three ATG responders and two non-responders with refractory anaemia were further studied for lymphocytemediated inhibition of bone marrow using a standard CFU-GM assay. In responders, peripheral blood lymphocytes (PBL) added at a 5:1 ratio suppressed CFU-GM by 54 Ϯ 9% (P ¼ 0·04) and was reversed by ATG treatment. Pre-treatment marrow depleted of CD3 lymphocytes, increased CFU-GM by 32% (P ¼ 0·02) in an ATG responder, but not in a nonresponder. CD3 lymphocytes from 6-month post-treatment marrow did not inhibit pre-treatment CFU-GM, indicating ATG had affected the T cells. Pre-treatment marrow depleted of CD8 lymphocytes, increased CFU-GM by 60% (P ¼ 0·01) and 49% (P ¼ 0·03) in two ATG responders, but not in a non-responder. Inhibition required cell-cell interaction through MHC I. TCR Vb families, analysed by SSCP, changed from clonal to polyclonal in one ATG responder after 6 months, but clones persisted in a non-responder. These results indicate patients with refractory anaemia who respond to ATG have CD8 T-cell clones that mediate MHC-I-restricted suppression of CFU-GM which are replaced by polyclonal T cells that do not suppress CFU-GM after ATG treatment.

Prevalence and clinical association of clonal T-cell expansions in Myelodysplastic Syndrome

“…2,3 Investigations of immunosuppressive therapies have shown that a subset of MDS patients experience sustained erythroid improvement with response rates ranging from 15 to 45%. [4][5][6][7][8][9][10][11][12] Univariant and multivariant statistical analyses have identified clinical and biological features associated with clinical response to immunosuppressive therapy, which served as the basis for the generation of response predictive models. [4][5][6][13][14][15][16][17][18] In these analyses, bone marrow hypocellularity, HLA-DR15 phenotype, younger age, lower platelet count and shorter duration of transfusion requirement were associated with response to immunosuppressive therapy.…”

Increased immature hematopoietic progenitor cells CD34+/CD38dim in myelodysplasia

“…Despite being a heterogeneous group of disorders based on the diverse morphologic, genetic, biologic, and clinical characteristics, they all derive from a molecular defect (an intrinsic or acquired primary event) in the hematopoietic progenitor cells (HPC) (1). Multiple altered extrinsic factors have concomitantly been described: (1) those affecting the BM microenvironment (2) and (2) T cell autoimmunemediated myelosuppression (3)(4)(5). Another biological observation is an increase in BM cell apoptosis.…”

Monocytes are activated in patients with myelodysplastic syndromes and can contribute to bone marrow failure through CD40–CD40L interactions with T helper cells

“…Most previous work has focused on the role of lymphocytes in this process. Autologous T cells inhibit growth of progenitor cells in MDS, 2,3 and this effect can disappear after successful treatment with ATG. 2 A role of immune-mediated suppression of hematopoiesis has been most extensively defined in trisomy 8 MDS.…”

“…Autologous T cells inhibit growth of progenitor cells in MDS, 2,3 and this effect can disappear after successful treatment with ATG. 2 A role of immune-mediated suppression of hematopoiesis has been most extensively defined in trisomy 8 MDS. Consistent with what was shown for the general population of MDS patients, 4,6,7 Sloand et al 5 have demonstrated that expanded clonal populations of T cells can be found in all patients with trisomy 8.…”

“…In vitro experiments demonstrate that autologous T lymphocytes can suppress MDS progenitor growth. 2,3 Clonal and oligoclonal T cell expansions can be found in about half of the patients 2,4-7 and these clones have been shown to suppress hematopoiesis in vitro. 5 Compelling evidence for the effective role of T cells in the process of BM failure comes from the observation that up to 30% of low-risk MDS patients respond to immunosuppressive agents such as cyclosporine A (CsA), 8 and/or anti-thymocyte globulin (ATG) [9][10][11][12][13][14] which mainly target activated T cells.…”