Ameliorating effect of anti-Fas ligand MAb on wasting disease in murine model of chronic colitis.
Fas/Fas ligand (FasL) interaction has been implicated in the pathogenesis of various diseases. To clarify the involvement of Fas/FasL in the pathogenesis of intestinal inflammation, we investigated the preventive and therapeutic effects of neutralizing anti-FasL monoclonal antibody (MAb) on the development of chronic colitis induced by adaptive transfer of CD4+CD45RBhigh T cells to SCID mice. Administration of anti-FasL MAb from 1 day after T cell transfer (prevention study) resulted in a significant improvement of clinical manifestations such as wasting and diarrhea. However, histological examination showed that mucosal inflammation in the colon, such as infiltration of T cells and macrophages, was not improved by the anti-FasL MAb treatment. In vitro studies showed that anti-FasL MAb did not inhibit IFN-gamma production by anti-CD3/CD28-stimulated lamina propria CD4+ T cells but suppressed TNF-alpha and IL-1beta production by lamina propria mononuclear cells. Therapeutic administration of anti-FasL MAb from 3 wk after T cell transfer also improved ongoing wasting disease but not intestinal inflammation. These results suggest that the Fas/FasL interaction plays a critical role in regulating systemic wasting disease but not local intestinal inflammation.
Dan
N
N
Dept. of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Kanai
T
T
Totsuka
T
T
Iiyama
R
R
Yamazaki
M
M
Sawada
T
T
Miyata
T
T
Yagita
H
H
Okumura
K
K
Watanabe
M
M
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000032:analysis; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002908:Chronic Disease; D003092:Colitis / Q000150:complications* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000032:analysis; D008264:Macrophages / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000276:immunology; D019282:Wasting Syndrome / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D017493:Leukocyte Common Antigens