A monoclonal antibody to the alpha2 domain of murine major histocompatibility complex class I that specifically kills activated lymphocytes and blocks liver damage in the concanavalin A hepatitis model.
We earlier found that a rat monoclonal antibody (mAb) RE2 can induce rapid death of murine activated, but not resting, lymphocytes and lymphocyte cell lines, in a complement-independent manner, a cell death differing from typical apoptosis or necrosis. We here found that this cell death is independent of pathways involving Fas, caspase, and phosphoinositide-3 kinase. With the advantage of producing human B cell line transfectants with stable expression of human/mouse xeno-chimeric MHC class I genes, we found that RE2 epitope resides on the murine class I alpha2 domain. However, the alpha3 domain plays a key role in transducing the death signal, which mediates extensive aggregation of the MHC class I-integrin-actin filament system, giving rise to membrane blebs and pores. In mouse models with T/NKT cell activation-associated fulminant hepatitis, administration of mAb RE2 almost completely inhibited the development of liver cell injuries. Taken collectively, this form of cell death may be involved in homeostatic immune regulation, and induction of this form of cell death using the mAbs may be potentially therapeutic for subjects with immunological diseases mediated by activated lymphocytes.
Matsuoka
Shuji
S
Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Tsurui
Hiromichi
H
Abe
Masaaki
M
Terashima
Kazuo
K
Nakamura
Kazuhiro
K
Hamano
Yoshitomo
Y
Ohtsuji
Mareki
M
Honma
Nakayuki
N
Serizawa
Isao
I
Ishii
Yasuyuki
Y
Takiguchi
Masafumi
M
Hirose
Sachiko
S
Shirai
Toshikazu
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death; D002460:Cell Line; D003208:Concanavalin A; D004195:Disease Models, Animal; D000939:Epitopes; D005805:Genes, MHC Class I; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000473:pathology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D011993:Recombinant Fusion Proteins; D003208:Concanavalin A