| Budget Amount *help |
¥30,550,000 (Direct Cost: ¥23,500,000、Indirect Cost: ¥7,050,000)
Fiscal Year 2007: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2006: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2005: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
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| Research Abstract |
Fc receptors play pivotal roles in immune regulation, and their dysregulation leads to immune-related diseases including allergic inflammationand aud autoimmunity. We have obtained in this project the following accomplishments:
1) Establishment of the importance of inhibitory Fcγ receeptor, FcγRIIB, in immune regulation and autoimmune dieseases, such as autoimmune glomerulonephritis.
2) Establishment of animal models for immune disorders by the use of Feγ receptor gene-targeted mice.
3) Establishment of immune cells with the immortalized growth and immune functions by the use of SV40LT-transgenic mice.
Among these, in particular, we have identified the pivotal roles of activating-type Fcγ receptors, but not inhibitory FcγRIB, in the development of autoimmune diabetes of NOD mice. Type 1 diabetes mellitus (T1D) in humans is an organ-specific autoimmune disease in which pancreatic islet β cell are ruptured by autoreactive T cells. NOD mice, the most commonly used animal model of T1D, show ea
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rly infiltration of leukocytes in the islets (insulitis), resulting in islet destruction and diabetes later. NOD mice produce various islet β cell-specific autoantibodies, although it remains a subject of debate regarding whether these autoantibodies contribute to the development of T1D or not. To investigate the possible role of FcγRs in NOD mice, we have generated several FcγR-less NOD lines, namely FcR common γ chain (FcRγ)-deficient ((NOD.γ^<-/->), FcγRIII-deficient (NOD.III^<-/->), FcγRIIB-deficient (NOD.IIB^<-/->), and both FcRγ and Fcγ and FcγRIIB-deficient NOD (NOD.null) mice. We have shown significant protection from diabetes in NOD.γ^<-/->, NOD.III^<-/->, and NOD.null but not in NOD.IIB^<-/-> mice even with grossly comparable production of autoantibodies among them. Insulitis in NOD.γ^<-/-> mice was also alleviated. Adoptive transfer of bone marrow-derived dendritic cells or NK cells from NOD mice rendered NOD.γ^<-/-> animals more susceptible to diabetes, suggesting a possible scenario in which activating FcγRIII on NK cells trigger antibody-dependent effector functions and inflammation. These findings highlight the critical roles of activating FcγRs in the development of T1D, and indicate that FcγRs are novel targets for therapies for T1D. Less
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