The role of cytokines in classical Hodgkin lymphoma.

The clinical and pathologic features of classical Hodgkin lymphoma (cHL) reflect an abnormal immune response that is thought to be due to the elaboration of a variety of cytokines by the malignant Reed-Sternberg (RS) cells or surrounding tissues. The majority of cHL cases are characterized by expression of tumor necrosis factor receptor (TNFR) family members and their ligands, as well as an unbalanced production of Th2 cytokines and chemokines. Activation of TNFR members results in constitutive activation of nuclear factor-kappa B (NF-kappa B), a transcription factor important for the in vitro and in vivo growth of RS cell lines. The expression of Th2 cytokines and chemokines leads to the reactive infiltrate of eosinophils, Th2 cells, and fibroblasts characteristic of cHL, and can also contribute to a local suppression of Th1 cell-mediated cellular immune response. Another particularly important growth and survival factor for RS cell lines is the Th2 cytokine interleukin 13, which is also commonly expressed by primary RS cells. In approximately 40% of cHL cases, the presence of Epstein-Barr virus influences the Th1/Th2 balance toward the production of Th1 cytokines and chemokines, but this shift is apparently insufficient for the stimulation of an effective antitumor cell-mediated immune response. This review summarizes the current literature on cytokine expression by and activity on RS cell lines and primary cHL tissues, examines cytokine signaling pathways in RS cells, and discusses the role that cytokines play in the specific clinical and pathologic features of cHL.