TRANSFORMING GROWTH-FACTOR-BETA AS ENDOGENOUS GROWTH INHIBITOR OF CHRONIC LYMPHOCYTIC-LEUKEMIA B-CELLS

Chronic lymphocytic leukemia (CLL) B cells are hyporesponsive or refra ctory to mitogens and growth factors in vitro. This study examined whe ther transforming growth factor beta (TGF-beta), a potent inhibitor of lymphocyte proliferation may play a role in the growth regulation of CLL B cells. CLL B cells from all donors treated expressed detectable TGF-beta 1 mRNA. In vitro release of TGF-beta by unstimulated cultures , or cultures stimulated by antibody to cell surface immunoglobulin (a nti-mu) plus phorbol 12-myristate 13-acetate (PMA) was higher in CLL t han in normal B cells. High levels of TGF-beta activity were also dete cted in plasma samples of CLL patients. The role of TGF-beta in growth regulation of CLL B cells was tested in assays using different B cell activators. Purified neoplastic B cells from most CLL patients prolif erated in response to anti-mu, or the combination of anti-mu plus PMA. Levels of CLL B cell proliferation were lower than observed in normal B cells. Some CLL were refractory to these stimuli. Antibody to CD40 induced proliferation of CLL B cells from all donors tested when prese nted on Fc gamma RII (CDw32)-expressing L cells. Neutralizing antibodi es to TGF-beta increased CLL B cell proliferation in the absence or pr esence of additional stimuli. These effects were dose dependent and sp ecific. Exogenous TGF-beta completely inhibited CLL B cell proliferati on induced by anti-mu, PMA, and anti-TGF-beta. CLL B cell proliferatio n induced by anti-CD40 was reduced by exogenous TGF-beta. However, eve n at high doses, TGF-beta did not completely inhibit the anti-CD40 eff ect. In summary, TGF-beta is overexpressed in CLL. CLL B cells are sen sitive to TGF-beta and this cytokine functions as an autocrine growth inhibitor accounting at least in part for reduced proliferative respon ses of these leukemic cells and for the slow progression of the malign ant process in vivo.