Regulation of T cell activation in vitro and in vivo by targeting the OX40-OX40 ligand interaction: amelioration of ongoing inflammatory bowel disease with an OX40-IgG fusion protein, but not with an OX40 ligand-IgG fusion protein.
OX40 is a member of the TNFR superfamily, and is found predominantly on activated CD4-positive T cells. In vitro an OX40-IgG fusion protein inhibits mitogen- and Ag-driven proliferation and cytokine release by splenocytes and lymph node T cells. In contrast, an OX40 ligand-IgG fusion protein enhanced proliferative responses. In normal mice, OX40-positive cells are observed only in lymphoid tissues, including Peyer's patches of the gut. In mice with hapten-induced colitis or IL-2 knockout mice with spontaneous colitis, OX40-positive cells are found infiltrating the lamina propria. Administration of the OX40-IgG fusion protein to mice with ongoing colitis (but not the OX40 ligand-IgG) ameliorated disease in both mouse models of inflammatory bowel disease. This was evidenced by a reduction in tissue myeloperoxidase; reduced transcripts for TNF-alpha, IL-1, IL-12, and IFN-gamma; and a reduction in the T cell infiltrate. Targeting OX40 therefore shows considerable promise as a new strategy to inhibit ongoing T cell reactions in the gut.
Higgins
L M
LM
Department of Paediatric Gastroenterology, St. Bartholemew's and The Royal London School of Medicine and Dentistry, St. Bartholomew's Hospital, United Kingdom.
McDonald
S A
SA
Whittle
N
N
Crockett
N
N
Shields
J G
JG
MacDonald
T T
TT
D000818:Animals; D016466:CHO Cells; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000628:therapy; D003208:Concanavalin A / Q000494:pharmacology; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics* / Q000502:physiology; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics*; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D053278:OX40 Ligand; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D048069:Tumor Necrosis Factors
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505716:TNFRSF4 protein, human; C089251:TNFSF4 protein, human; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors; D003208:Concanavalin A