Reduced TGF-beta 1 in patients with aplastic anaemia in vivo and in vitro

Transforming growth factor beta (TGF-beta) 1 is a ubiquitous bifunctional c ytokine implicated in the regulation of haemopoietic stem cells and bone ma rrow stromal cells. We analysed sera from 63 patients with aplastic anaemia and describe a significant reduction of TGF-beta 1 that was directly relat ed to their treatment status. Untreated patients (n=35), patients who did n ot respond (n=15) and those with a partial response (n=23) to treatment had significantly lower TGF-beta 1 than the normal control group (n=55), P<0.0 001, P<0.0001 and P=0.002 respectively. Patients in complete remission (n=1 5) exhibited TGF-beta 1 serum levels comparable to the control group, In ad dition, there was a correlation (r=0.83, P<0.0001) between serum TGF-beta 1 and platelet count at time of sample. We have demonstrated that the primar y source of TGF-beta 1 in peripheral blood mononuclear cell (PBMC) cultures was not CD3-positive cells. These data indicate aplastic anaemia is associ ated with a decreased TGF-beta 1 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) prod uced significantly lower levels of TGF-beta 1 (P=0.02) when compared to nor mal stroma (n=15). In the aplastic anaemia bone marrow compartment we postu late that accessory cells down-regulate TGF-beta 1 expression to allow stem cell cycling to counteract hypoplasia. As TGF-beta 1 is important in the r egulation of haemopoiesis, dysregulation of this cytokine in combination wi th previously described abnormal cytokine expression may contribute signifi cantly to the pathophysiology of aplastic anaemia by exacerbating primary s tem cell defects.