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 virus (EBV)-induced B-cell lymphoma lines and some other cell lines derived from patients with aggressive histology lymphoma. The transfer of normal human peripheral blood lymphocytes (huPBL) from EBV-seropositive donors into severe combined immune deficient (SCID) mice has been previously shown to result in the generation of human B-cell lymphomas. These tumors are similar to the highly aggressive EBV-induced lymphomas that can arise clinically after transplantation or in the setting of immunodeficiency. Treatment of huPBL-SCID chimeric mice with anti-CD40 or anti-CD20 monoclonal antibodies (MoAb) significantly delayed the development 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 treatment, all of which succumbed to lymphoma. By contrast, treatment with 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, whereas anti-CD20 antibodies had no effect. Thus, anti-CD40 exerts selective effects to allow for the engraftment of normal human B cells and prevent the emergence of EBV lymphomas. Stimulation of CD40 by antibodies or its physiologic ligand may, therefore, be of significant clinical use in the prevention of EBV-induced B lymphomas that may arise when EBV-seropositive individuals receive immunosuppressive regimens after transplantation or in immune deficiency states, such as acquired immune deficiency syndrome.
Murphy
W J
WJ
Biological Carcinogenesis and Development Program, Inc/DynCorp, NCI-FCRDC, MD 21702-1201, USA.
Funakoshi
S
S
Beckwith
M
M
Rushing
S E
SE
Conley
D K
DK
Armitage
R J
RJ
Fanslow
W C
WC
Rager
H C
HC
Taub
D D
DD
Ruscetti
F W
FW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D018951:Antigens, CD20; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens; D002471:Cell Transformation, Neoplastic; D004167:Diphtheria Toxin / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006680:HLA Antigens / Q000032:analysis; D006684:HLA-DR Antigens / Q000032:analysis; D004854:Herpesvirus 4, Human; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D016219:Immunotherapy, Adoptive; D017710:Lymphocyte Transfusion; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D013744:Tetanus Toxin / Q000276:immunology; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018951:Antigens, CD20; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D004167:Diphtheria Toxin; D006680:HLA Antigens; D006684:HLA-DR Antigens; D007136:Immunoglobulins; D013744:Tetanus Toxin