Reduced TGF‐β1 in patients with aplastic anaemia in vivo and in vitro

Abstract

Summary. Transforming growth factor b (TGF-b) 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 signi®cant reduction of TGF-b1 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 signi®-cantly lower TGF-b1 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-b1 serum levels comparable to the control group. In addition, there was a correlation (r 0´83, P < 0´0001) between serum TGF-b1 and platelet count at time of sample. We have demonstrated that the primary source of TGF-b1 in peripheral blood mononuclear cell (PBMC) cultures was not CD3-positive cells. These data indicate aplastic anaemia is associated with a decreased TGF-b1 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 signi®cantly lower levels of TGF-b1 (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-b1 expression to allow stem cell cycling to counteract hypoplasia. As TGF-b1 is important in the regulation of haemopoiesis, dysregulation of this cytokine in combination with previously described abnormal cytokine expression may contribute signi®cantly to the pathophysiology of aplastic anaemia by exacerbating primary stem cell defects.

Cytokine gene polymorphisms in acquired bone marrow failure

“…The increased prevalence of hypersecreting genotypes and the known proinflammatory effects of IL-6 in other autoimmune disorders favor the latter possibility. Although our AA patients tended to have the higher producing TGFb1 genotype, this finding is not congruent with published serum measurements in which a deficiency of TGFb1 was described [21]. This discrepancy may be explained by the interactions between cytokines and other regulatory genes that may affect the levels of individual cytokines.…”

Basal level of Th17 immune response is not enhanced in aplastic amemia

“…The absence of TGF-b induced a shift from Th17 profile to Th1 profile in human Th17 differentiation assay [9]. Previous data has shown lower levels of TGF-b in patients with AA compared to healthy controls [10], which implies the pivotal pathway for Th17 cell differentiation is attenuated in AA. IL-6 is another important cytokine promoting Th17 polarization, and also a primary Th17-derived cytokine [9].…”

Persistent injury-associated anemia: the role of the bone marrow microenvironment

“…17 Therefore, TGF-β1 has been shown to have a greater inhibitory effect on primitive hematopoietic progenitors. 18 Hematopoietic stressors, such as bleeding, can trigger hematopoietic adaptation that sacrifices HPC quiescence to meet the need for new blood cell production. 19 This would explain why expression of TGF-β1 seven days after LCHS and LCHS/CS was significantly decreased.…”