Anti-CD137 antibodies in the treatment of autoimmune disease and cancer.
CD137 (4-1BB), is an inducible T-cell costimulatory receptor and a member of the tumor necrosis factor receptor (TNFR) superfamily. It is expressed on activated T cells and activated natural killer (NK) cells, but is constitutively expressed on a population of splenic dendritic cells (DCs). The natural counter receptor for CD137 is 4-1BB ligand, a member of the TNF superfamily that is weakly expressed on naïve or resting B cells, macrophages, and DCs. Upon activation, the level of 4-1BBL expression increases on these cells. In T cells CD137-induced signals lead to the recruitment of TRAF family members and activation of several kinases, including ASK-1, MKK, MAPK3/ MAPK4, p38, and JNK/SAPK. Kinase activation is then followed by the activation and nuclear translocation of several transcription factors, including ATF-2, Jun, and NF-kappaB. CD137-mediated T-cell costimulation as measured by enhanced proliferation and cytokine production can be induced by anti-CD137 monoclonal antibodies (MAbs) or by employing immobilized 4-1BB ligand. In addition to augmenting suboptimal TCR-induced proliferation, CD137-mediated signaling protects T cells, and in particular, CD8+ T cells from activation-induced cell death (AICD). Although studies with CD137-deficient or 4-1BBL-deficient mice failed to demonstrate any loss of essential immunological function, or other noteworthy deficits, we have found that 4-1BBL-deficient mice failed to generate a strong antiviral immune response following lymphocytic choriomeningitis virus (LCMV) peptide vaccination. We further found that although compromised, the immune response to LCMV vaccination in these mice could be fully restored by injecting them with anti-CD137 MAbs at the time of vaccination. Finally, we have found that injecting normal mice with anti-CD137 MAbs had profound effects on their ability to develop immune responses to allo- and autoantigens. The results of these studies discussed in this article provide a rationale for assessing the potential use of anti-CD137 MAbs for therapeutic purposes.
Mittler
Robert S
RS
Department of Surgery and Emory Vaccine Research Center, Emory University School of Medicine, 954 Gatewood Road, Atlanta, GA 30329, USA. mittler@rmy.emory.edu
Foell
Juergen
J
McCausland
Megan
M
Strahotin
Simona
S
Niu
Liguo
L
Bapat
Abhijit
A
Hewes
L Becker
LB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9