ANTIBODIES TO CD40 PREVENT EPSTEIN-BARR VIRUS-MEDIATED HUMAN B-CELL LYMPHOMAGENESIS IN SEVERE COMBINED IMMUNE-DEFICIENT MICE GIVEN HUMAN PERIPHERAL-BLOOD LYMPHOCYTES

CD40 is expressed on both normal and neoplastic B lymphocytes. Signal transduction through CD40 in vitro has been shown to exert stimulatory effects on normal B cells and inhibitory effects on Epstein-Barr viru s (EBV)-induced B-cell lymphoma lines and some other cell lines derive d from patients with aggressive histology lymphoma. The transfer of no rmal human peripheral blood lymphocytes (huPBL) from EBV-seropositive donors into severe combined immune deficient (SCID) mice has been prev iously shown to result in the generation of human B-cell lymphomas. Th ese tumors are similar to the highly aggressive EBV-induced lymphomas that can arise clinically after transplantation or in the setting of i mmunodeficiency. Treatment of huPBL-SCID chimeric mice with anti-CD40 or anti-CD20 monoclonal antibodies (MoAb) significantly delayed the de velopment of EBV-induced B-cell lymphoma. However, the effects of the two MoAb were mechanistically distinct. Anti-CD40 treatment prevented lymphoma generation, while still allowing for functional human B-cell engraftment in the huPBL-SCID mice compared with mice receiving no tre atment, all of which succumbed to lymphoma. By contrast, treatment wit h anti-CD20 significantly inhibited total human B-cell engraftment in the SCID recipients, which accounted for the absence of lymphomas. In vitro assays examining the transformation of human B cells by EBV also indicated that anti-CD40 could directly inhibit EBV-transformation, w hereas anti-CD20 antibodies had no effect. Thus, anti-CD40 exerts sele ctive effects to allow for the engraftment of normal human B cells and prevent the emergence of EBV lymphomas. Stimulation of CD40 by antibo dies or its physiologic ligand may, therefore, be of significant clini cal use in the prevention of EBV-induced B lymphomas that may arise wh en EBV-seropositive individuals receive immunosuppressive regimens aft er transplantation or in immune deficiency states, such as acquired im mune deficiency syndrome.