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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.

Matsuoka S, Tsurui H, Abe M, Terashima K, Nakamura K, Hamano Y, Ohtsuji M, Honma N, Serizawa I, Ishii Y, Takiguchi M, Hirose S, Shirai T - J. Exp. Med. (2003)

Bottom Line: 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.In mouse models with T/NKT cell activation-associated fulminant hepatitis, administration of mAb RE2 almost completely inhibited the development of liver cell injuries.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.

ABSTRACT
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.

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(A) Effects of potential inhibitors on cytotoxic activity of mAb RE2 to T cell clone MS-S2 cells. Inhibitors were added 1 or 2 h before the cytotoxicity assay. Percentages of dead cells were determined by trypan blue dye exclusion. (B) Cytotoxic sensitivity to mAb RE2 of Con A–activated splenic cells from various mouse strains. Splenic cells were first activated with 2 μg/ml of Con A for 24 h at 37°C, and then incubated with given concentrations of mAb RE2 for 1 h in the absence of complement.
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fig1: (A) Effects of potential inhibitors on cytotoxic activity of mAb RE2 to T cell clone MS-S2 cells. Inhibitors were added 1 or 2 h before the cytotoxicity assay. Percentages of dead cells were determined by trypan blue dye exclusion. (B) Cytotoxic sensitivity to mAb RE2 of Con A–activated splenic cells from various mouse strains. Splenic cells were first activated with 2 μg/ml of Con A for 24 h at 37°C, and then incubated with given concentrations of mAb RE2 for 1 h in the absence of complement.

Mentions: To precisely characterize the mechanism of mAb RE2-induced cell death, we first examined effects of several potential inhibitors on in vitro cytotoxic activity of mAb RE2 to the killing-susceptible murine T cell line MS-S2, in the absence of complement. The caspase inhibitors, Z-VAD-fmk (13) and Z-Asp-DCB (14); PI-3 kinase inhibitors, wortmannin (6) and LY294002 (15), and an inhibitor of phosphatase 1, 2A, 2C, okadaic acid (8) did not inhibit the cytotoxic activity (Fig. 1 A). As Con A–activated splenic cells from Fas-deficient MRL-lpr/lpr mice were also susceptible to the cytotoxic activity of mAb RE2 (Fig. 1 B), it was evident that this cell death differs from that involving the Fas/Fas ligand, caspase, phosphatase 1, 2A, 2C, and PI-3 kinase pathways.


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.

Matsuoka S, Tsurui H, Abe M, Terashima K, Nakamura K, Hamano Y, Ohtsuji M, Honma N, Serizawa I, Ishii Y, Takiguchi M, Hirose S, Shirai T - J. Exp. Med. (2003)

(A) Effects of potential inhibitors on cytotoxic activity of mAb RE2 to T cell clone MS-S2 cells. Inhibitors were added 1 or 2 h before the cytotoxicity assay. Percentages of dead cells were determined by trypan blue dye exclusion. (B) Cytotoxic sensitivity to mAb RE2 of Con A–activated splenic cells from various mouse strains. Splenic cells were first activated with 2 μg/ml of Con A for 24 h at 37°C, and then incubated with given concentrations of mAb RE2 for 1 h in the absence of complement.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2194093&req=5

fig1: (A) Effects of potential inhibitors on cytotoxic activity of mAb RE2 to T cell clone MS-S2 cells. Inhibitors were added 1 or 2 h before the cytotoxicity assay. Percentages of dead cells were determined by trypan blue dye exclusion. (B) Cytotoxic sensitivity to mAb RE2 of Con A–activated splenic cells from various mouse strains. Splenic cells were first activated with 2 μg/ml of Con A for 24 h at 37°C, and then incubated with given concentrations of mAb RE2 for 1 h in the absence of complement.
Mentions: To precisely characterize the mechanism of mAb RE2-induced cell death, we first examined effects of several potential inhibitors on in vitro cytotoxic activity of mAb RE2 to the killing-susceptible murine T cell line MS-S2, in the absence of complement. The caspase inhibitors, Z-VAD-fmk (13) and Z-Asp-DCB (14); PI-3 kinase inhibitors, wortmannin (6) and LY294002 (15), and an inhibitor of phosphatase 1, 2A, 2C, okadaic acid (8) did not inhibit the cytotoxic activity (Fig. 1 A). As Con A–activated splenic cells from Fas-deficient MRL-lpr/lpr mice were also susceptible to the cytotoxic activity of mAb RE2 (Fig. 1 B), it was evident that this cell death differs from that involving the Fas/Fas ligand, caspase, phosphatase 1, 2A, 2C, and PI-3 kinase pathways.

Bottom Line: 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.In mouse models with T/NKT cell activation-associated fulminant hepatitis, administration of mAb RE2 almost completely inhibited the development of liver cell injuries.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus