Reduced TGF-beta1 in patients with aplastic anaemia in vivo and in vitro.
Transforming growth factor beta (TGF-beta) 1 is a ubiquitous bifunctional cytokine implicated in the regulation of haemopoietic stem cells and bone marrow stromal cells. We analysed sera from 63 patients with aplastic anaemia and describe a significant reduction of TGF-beta1 that was directly related to their treatment status. Untreated patients (n = 35), patients who did not respond (n = 15) and those with a partial response (n = 23) to treatment had significantly lower TGF-beta1 than the normal control group (n = 55), P < 0.0001, P < 0.0001 and P = 0.002 respectively. Patients in complete remission (n = 15) exhibited TGF-beta1 serum levels comparable to the control group. In addition, there was a correlation (r = 0.83, P < 0.0001) between serum TGF-beta1 and platelet count at time of sample. We have demonstrated that the primary source of TGF-beta1 in peripheral blood mononuclear cell (PBMC) cultures was not CD3-positive cells. These data indicate aplastic anaemia is associated with a decreased TGF-beta1 expression in peripheral blood circulation, which may be a direct consequence of thrombocytopenia. In vitro stromal layers grown from aplastic patient bone marrow (n = 14) produced significantly lower levels of TGF-beta1 (P = 0.02) when compared to normal stroma (n = 15). In the aplastic anaemia bone marrow compartment we postulate that accessory cells down-regulate TGF-beta1 expression to allow stem cell cycling to counteract hypoplasia. As TGF-beta1 is important in the regulation of haemopoiesis, dysregulation of this cytokine in combination with previously described abnormal cytokine expression may contribute significantly to the pathophysiology of aplastic anaemia by exacerbating primary stem cell defects.
Rizzo
S
S
Department of Haematology, St George's Hospital Medical School, London. srizzo@sghms.ac.uk
Killick
S B
SB
Patel
S
S
Ball
S E
SE
Wadhwa
M
M
Dilger
P
P
Gordon-Smith
E C
EC
Gibson
F M
FM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000097:blood* / Q000628:therapy; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D017154:Stromal Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016212:Transforming Growth Factor beta