Chronic overexpression of membrane‐bound flt3 ligand by T lymphocytes in severe aplastic anaemia

Abstract

Aplastic anaemia (AA) is an immune‐mediated bone marrow failure associated with high serum levels of flt3 ligand (FL). We examined expression of the membrane‐bound isoform of FL in peripheral blood and bone marrow cells from AA patients at diagnosis (n = 16) and after immunosuppressive (IS) treatment (n = 36). Flow cytometry demonstrated strongly increased FL levels on the cell surface of T lymphocytes in AA relative to normal controls (P < 0·0001). T‐cell‐specific expression of membrane‐bound FL was confirmed by confocal microscopy. FL mRNA and total cellular FL protein levels were increased about threefold. Overexpression of FL in AA was observed for up to 20 years after IS treatment. FL levels correlated inversely with CD34+ cell numbers and the colony‐forming ability of AA bone marrow (R = −0·68 and −0·85 respectively). Histological examination of spleen specimens and bone marrow biopsies gave no evidence of degeneration or fibrosis due to prolonged exposure to high FL. Levels of membrane‐bound FL were not increased in autoimmune diseases (n = 23), including rheumatoid arthritis and lupus erythematosus, nor in graft‐versus‐host disease (n = 8). Chronic overexpression of FL on the surface of T lymphocytes in AA, but not in other T‐cell‐mediated disorders, suggests that membrane‐bound FL plays a role in cell–cell interactions in bone marrow failure and may be important for long‐term haemopoietic recovery.

Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis

“…It has been previously reported that the presence of activated T cells in the BM may affect the growth and survival characteristics of BM hematopoietic progenitor cells or even the hematopoiesis supporting capacity of BM stromal cells by inducing intricate cell-tocell interactions and proinflammatory cytokine production. 26,[29][30][31][32][33][34][35] In agreement with previous reports, we found increased numbers of activated T cells in PB of our MS patients, 15,[36][37][38] and also increased proportions of activated T cells in patients' BM. Interestingly, the proportion of HLA-DR þ and CD38 þ cells in patient BM CD3 þ cells inversely correlated with the number of CFCs in the BMMC fraction, suggesting that activated T cells may be implicated in the defective clonogenic potential of hematopoietic progenitor cells in MS.…”

“…Overproduction of FL by activated T cells has also been reported as a hematopoietic rescue mechanism in response to BM failure in patients with aplastic anemia. 31 On the other hand, the levels of SDF-1, a cytokine operating in the process of homing of CD34 þ hematopoietic progenitors in the BM, did not differ significantly between MS patients and healthy controls, suggesting probably a normal engraftment support of BM stroma in MS patients undergoing ASCT.…”

“…Interestingly, the levels of FL strongly correlated with the percentages of BM CD3 þ T cells (r ¼ 0.748, P ¼ 0.0068) suggesting a T-cell-related compensatory mechanism to the impaired haemopoietic progenitor cell clonogenic potential. [29][30][31] Discussion There is accumulating evidence suggesting that ASCT may have a beneficial effect in refractive cases of MS with respect to abrogation of brain inflammatory process or even to stabilization of the disease and disability prevention. [18][19][20][21][32][33][34] Studies in other autoimmune diseases have already shown abnormalities in BM hematopoiesis [7][8][9][10] capable of affecting the mobilization and/or the engraftment of stem cells in patients undergoing ASCT.…”

Serum FLT‐3 ligand in a busulphan‐induced model of chronic bone marrow hypoplasia in the female CD‐1 mouse

“…1996). Similarly, a study by Pfister et al. (2001) reported that membrane bound FL is increased on CD4 + and CD8 + lymphocytes of severe AA patients.…”

Gene expression profiling in CD34 cells to identify differences between aplastic anemia patients and healthy volunteers

“…The precise antigenic targets of cytotoxic T cells are unknown, and the effects of T-cell attack on hematopoietic target cells are poorly characterized. Although the expression levels of a few genes, such as FMS-related tyrosine kinase3 ligand (FLT3L) and GATA2, appear to be different in AA patients and healthy donors, [15][16][17] a more general transcriptome pattern of CD34 cells in AA patients has not been described.…”