Blockade of the OX40 ligand prolongs corneal allograft survival.
Although corneal transplantation is one of the most common tissue transplantations and is known to have a high graft acceptance rate, occasional corneal graft rejection remains a cause of blindness. OX40, a member of the TNF receptor superfamily, is expressed on activated T cells, and transmits a costimulatory signal by binding to OX40 ligand (OX40L) expressed on several cells with antigen-presenting functions. Using a blocking monoclonal antibody (mAb) against murine OX40L, we investigated the role of OX40 in a murine model of corneal transplantation. C3H/He mouse corneas were transplanted to BALB/c mice orthotopically. Administration of anti-OX40L mAb significantly reduced allograft rejection, and increased graft survival rate to 40% at 8 weeks after transplantation, while all corneas were rejected within 5 weeks in control IgG-treated mice. Similar reduced rejection was observed when wild-type donor corneas were transplanted to OX40L-deficient recipients. In vitro study revealed that the anti-OX40L mAb treatment reduced proliferative response and IFN-gamma production of draining lymph node cells in response to stimulation with donor alloantigen. These results demonstrate that OX40L blockade is effective for prolongation of corneal allograft survival by inhibiting recipient T cell activation.
Hattori
Takaaki
T
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
Usui
Yoshihiko
Y
Okunuki
Yoko
Y
Sonoda
Yasushi
Y
Usui
Masahiko
M
Takada
Eiko
E
Mizuguchi
Junichiro
J
Yagita
Hideo
H
Okumura
Ko
K
Akiba
Hisaya
H
Takeuchi
Masaru
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D016039:Corneal Transplantation; D004353:Drug Evaluation, Preclinical; D005136:Eye Proteins / Q000276:immunology; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D053278:OX40 Ligand; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D000911:Antibodies, Monoclonal; D005136:Eye Proteins; D007519:Isoantigens; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D016753:Interleukin-10; D007371:Interferon-gamma