Transforming Growth Factor (TGF) beta has been shown to have a potentially important role in such areas as fetal development, bone repair, wound healing, lymphocyte growth regulation and tumor biology. To date activation of this growth factor has required in vitro acidification (pH 1- 2), an event incompatible with normal physiology. It has recently been demonstrated that Reed-Sternberg cells from Hodgkin's disease secrete TGFbeta active at physiologic pH. This Hodgkin's TGF has a high molecular weight (350,000) as compared to TGFbeta (25,000) but cross-reacts with anti-TGFbeta, competes for TGFbeta cell membrane receptors and is associated with cellular expression of mRNA for TGFbeta. The biological activity of Hodgkin's TGF is similar to that of TGFbeta but is markedly reduced by acidification (97%) and destroyed by exogenous and endogenous proteases. Acidification or exposure to detergents releases the immunoreactive 25,000 dalton TGFbeta peptide with markedly reduced, but measurable biological activity. It is proposed to study the production of a similar high molecular weight form of TGFbeta by other Reed-Sternberg cells including long term and primary Reed-Sternberg cell cultures. Lymph nodes replaced by Hodgkin's disease will be extracted to determine the presence of high molecular weight TGFbeta. Antibodies will be studied which react with platelet TGFbeta and Hodgkin's TGF in ELISA, Western blotting, and histological localization. Monoclonal antibodies will be reviewed to identify those specifically active against epitopes on Hodgkin's TGF and not reactive with platelet TGFbeta. The amino acid sequence of several Hodgkin's TGFs will be determined and compared to the N-terminal sequence of platelet TGFbeta. Using a previously tested cDNA probe for TGFbeta mRNA, in situ hybridization will be used to study tissues involved by Hodgkin's disease and controls. The results of these studies may indicate the discovery of a unique or characteristic form of TGFbeta secreted by Reed-Sternberg cells which provides an important marker for this elusive cell. This finding 1) might permit unequivocal evidence for the Reed-Sternberg cell origin of various Hodgkin's cell lines, and 2) might ultimately lead the way to greater understanding of the biology of the Reed-Sternberg cell and it's presumed central role in Hodgkin's disease.
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