Specific immunosuppression of corneal allograft rejection by combination of anti-VLA-4 and anti-LFA-1 monoclonal antibodies in mice.
It has been reported that allograft rejection is mediated by a variety of adhesion molecules. Using a corneal allograft model in mice, we studied the role of very late antigen (VLA)-4 and leukocyte function-associated antigen (LFA)-1 adhesion molecules in corneal allograft rejection and the effects of monoclonal antibodies (mAbs) to them in suppressing corneal rejection. C3H/He donor corneas were transplanted into BALB/c corneal beds. The allografted mice were treated with a control mAb (M18/2), mAbs to VLA-4, or LFA-1 or their combination by i.p. injection until day 7. The expression of VLA-4, LFA-1, major histocompatibility complex (MHC) class II antigens, interleukin (IL)-2, IL-2 receptor and interferon gamma (IFNgamma) in the grafted cornea were studied immunohistochemically. Cytotoxic T lymphocyte (CTL) responses to donor alloantigens were assessed. The skins from a syngeneic donor or a third-part strain were transplanted 8 weeks after the initial keratoplasty onto the mice treated with anti-LFA-1 plus anti-VLA-4 mAbs. Fourteen of 16 allografts in non-treated mice and control mAb-treated mice became opaque by 2 weeks after transplantation. At 2 weeks, non-treated allografts showed expression of MHC class II antigens on keratocytes and mononuclear cells at the host-graft junction. Also, mononuclear cells expressing VLA-4, LFA-1, IL-2, IL-2 receptor and IFNgammawere present in the stroma at the host-graft junction. The allografts treated with either anti-VLA-4 or anti-LFA-1 alone, or anti-VLA-4 plus anti-LFA-1 remained transparent for more than 2 weeks, and the survival rates at 14 weeks was 0%, 16.7%, and 75.0%, respectively. The combined use of anti-VLA-4 and anti-LFA-1 mAbs prolonged graft survival significantly (P<0.05) at 14 weeks as compared with anti-LFA-1 mAb alone. At 3 weeks, CTL responses to donor alloantigens were depressed in mice treated with either anti-LFA-1 alone or anti-LFA-1 plus anti-VLA-4. Specific prolongation of donor-syngeneic skin was observed after treatment with the combination of these two mAbs. These results indicate that VLA-4 and LFA-1 have important roles in rejection process of corneal allografts, and that the combined use of mAbs to these molecules has remarkable effects on inducing alloantigen-specific immunosuppression in corneal transplantation.
Hori
J
J
Department of Ophthalmology, University of Tokyo Faculty of Medicine, Tokyo, Japan.
Isobe
M
M
Yamagami
S
S
Mizuochi
T
T
Tsuru
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016516:CD4-CD8 Ratio; D016039:Corneal Transplantation / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007165:Immunosuppression Therapy; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000276:immunology* / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic
D000911:Antibodies, Monoclonal; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D015375:Receptors, Interleukin-2; D016201:Receptors, Lymphocyte Homing