THE ROLE OF EOSINOPHILS IN THE PATHOBIOLOGY OF HODGKINS-DISEASE

Background: Even though the presence of a prominent tissue eosinophili a represents a common histopathologic feature of Hodgkin's disease (HD ), eosinophils have been mainly regarded as 'innocent' bystanders recr uited and activated during the cellular reaction typical of HD. To eva luate the putative role of eosinophils or eosinophil-derived cytokines on tumor-cell regulation in HD, we have analyzed these cells for the functional expression of surface ligands (L) of the tumor necrosis fac tor (TNF) superfamily, whose specific receptors are known to transduce proliferation signals at the surface of Hodgkin (H) and Reed-Sternber g (RS) cells. Materials and methods: Eosinophils from peripheral blood of healthy donors and patients with HD, primary hypereosinophilic syn drome (HES), or secondary hypereosinophilia (HE), were purified by den sity gradient centrifugation and immunomagnetic depletion of residual granulocytes. Results. By immunostaining and mRNA analysis, we were ab le to show that eosinophils from normal donors and patients with HD, H ES, and HE express a number of receptors and ligands of the TNF superf amily, including CD40, CD40L, CD30L, CD95/Fas, CD95/FasL and 4-1BB. In addition, we provide evidence that cytokines regulating eosinophil pr oliferation and activation, i.e., interleukin (IL)-5, IL-3, and granul ocyte-macrophage colony-stimulating factor, are able to enhance the ce llular density of several TNF superfamily ligands and/or receptors at the surface of cultured eosinophils. Finally, we have shown that nativ e CD40L and CD30L at the surface of purified eosinophils are functiona lly active and able to transduce proliferative signals on CD40+ and CD 30+ target cells, including cultured H-RS cells. Conclusions. Our data suggest that eosinophils may act as important elements in the patholo gy of HD by providing cellular ligands for TNF-superfamily receptors ( CD40, CD30, CD95/Fas) able to transduce proliferation and antiapoptoti c signals at the surface of H-RS cells. The presence on eosinophils of receptors for TNF ligands expressed by activated T cells (i.e., OX40L , Fast, CD40L, 4-1BBL), also suggest that eosinophils may contribute t o the deregulated network of interactive signals between H-RS cells, T cells, and other surrounding reactive cells.