CD30 has long been recognized as a unique antigen on lymphomas of T or B origin of immature to the fully differentiated state. CD30 moreover has been found to be associated with disease progression in anaplastic large cell lymphoma. CD30 is expressed as a disease marker in allergic conditions and CD30 expression is associated with progression of HIV disease, with Epstein-Bar virus infection and transformation and with HTLV associated lymphomas. Finally, CD30 over-expression is found in Omenn's syndrome, a severe combined immunodeficiency of unknown etiology, characterized by high Il-5 levels, eosinophilia and IgE production. CD30 signaling functions via TRAF proteins have recently been elucidated. Similar to other members of the TNF-R family of receptors, CD30 signals have a dual role for activation, proliferation and anti-apoptosis; or for apoptosis. CD30 expression itself is favored by a TH2 environment and suppressed by Ifn-gamma. It is postulated and will be tested in this application that CD30 expressed on lymphomas provides a selective advantage to lymphomas or other CD30 positive cells through its co- stimulatory activity, by promoting proliferation and increasing resistance to apoptosis. This hypothesis will be examined 1. by analyzing pathways regulating TRAF2 activity which is primarily responsible for anti apoptotic signals through Jun-N-terminal kinase (JNK) and NFkappaB activation; 2. by CD30-L gene ablation to eliminate CD30-L triggered CD30 signals and signaling by CD30 induction on ongoing immune responses to tumors in vivo and in vitro.
Showing the most recent 10 out of 12 publications
