| Project/Area Number |
09470095
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Immunology
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
KIKUTANI Hitoshi Osaka Univ., Res.Inst.Microb.Dis., Prof., 微生物病研究所, 教授 (80161412)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KUMANOGOH Atsushi Osaka Univ., Res.Inst.Microb.Dis., Assist.Prof., 微生物病研究所, 助手 (10294125)
YOSHIDA Kenji Osaka Univ., Res.Inst.Microb.Dis., Assist.Prof., 微生物病研究所, 助手 (80294122)
YASUI Teruhito Osaka Univ., Res.Inst.Microb.Dis., Assist.Prof., 微生物病研究所, 助手 (60283074)
|
|---|
| Project Period (FY) |
1997 – 1998
|
| Project Status |
Completed (Fiscal Year 1998)
|
| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 1998: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1997: ¥9,400,000 (Direct Cost: ¥9,400,000)
|
|---|
| Keywords | CD40 / CD40 ligand / humoral immune response / autoimmunity / germinal center / class switch / 体液性免疫反応 / トランスジェニックマウス / ノックアウトマウス / シグナル伝達 / B細胞 / 胚中心形成 |
|---|
| Research Abstract |
A critical role of CD40-CD154 (CD40 ligand) interactions in humoral immune responses has been previously demonstrated by the deficiency of CD40, or CD154 in the mouse or human. To further dissect CD40 signals in antigen-driven B cell differentiation, we have attempted to reconstitute CD40-CD154 interactions in CD40-deficient mice by expressing various mutant CD40 transgenes under the control of Ig promtor/enhancer. The expression of the deletion mutant carrying only the membrane proximal region could rescue B cell differentiation in the extra-follicular area (PALS) including Ig class switching but not germinal center (GC) formation. GC formation was dependent on signals from the membrane distal region including TRAF2, 3 and 5 binding site of CD40.
The latent membrane protein 1 (LMP1), which is a transforming gene product of Epstein Barr virus (EBV), is known to bind TRAF proteins. The transgenic mice expressing LMP1 in a B cell-specific manner were crossed with CD40-deficient mice. The
… More
transgenic expression of LMPl could rescue Ig class switch but not germinal center formation of CD40-deficient mice. The affinity of antibodies produced in these mice was considerably low. It thus appears that LMP1 partly share signals with CD40.
The development of autoimmunity is often observed in patients with X-linked hyper IgM syndrome caused by defects in the CD154 gene, however, this phenomenon can not be simply explained by known functions of CD40 or CD154. To explore the mechanism how autoirnmunity develops in the absence of CD4O-CD154 interactions, we transferred T cells of CD40 (-/-) BALB/c mice into BALBc nu/nu mice, so that CD40-CD 154 interactions can be reconstituted in recipient mice. The recipients that received T cells from CD40 (-/-) but not from normal BALB/c produced various autoantibodies and developed autoimmune gastritis and sialoadenitis. Autoimmunity could be transferred by CD4^+ T cells but not CD8^+ T cells. CD40 (-/-) mice have reduced numbers of CD45RB^<dUII> CD4^+T cells that are known to consist of memory/effector T cells and regulatory T cells. Co-transfers of CD4^+ T cells from normal BALB/c could prevent development of autoiminunity induced by T cells of CD40 (-/-) mice. It thus appears that CD40-CD 154 interactions are also required for generation of regulatory T cells that suppress autoreactive T cells. Less
|
