The mechanisms of the induction and maintenance of the transplantation tolerance and usage of the Treg cells as a cellular therapy for treatment allograft rejection and GvHD
| Project/Area Number |
17390355
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | National Research Institute for Child Health and Development |
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Principal Investigator |
RII Ko National Research Institute for Child Health and Development, Lab of Transplant Immunology, Natl.Inst.Res.for Child Health.&Dev., Lab Head (60321890)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUNO K. Dokkyo Medical University, Dept.of Anatomy (Macro), Professor (20094047)
KIMURA H. National Research Institute for Child Health and Development, Dept.of Surgical Research, Natl.Res.Ins.For Child Health.&Dev., Lab Head (80115477)
FUNESHINA N. National Research Institute for Child Health and Development, Dept.of Surgical Research, Natl.Res.Ins.For Child Health.&Dev., Researcher (60399483)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥14,890,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥690,000)
Fiscal Year 2007: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2005: ¥9,600,000 (Direct Cost: ¥9,600,000)
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| Keywords | transplantation immunology / tolerance / regulatory T cell / co-stimulatory molecular / GvHD / allograft / cell therapy / CD28 superagonist antibody / 免疫細胞療法 / 細胞養子移植 / 拒絶反応 / GvH反応 / FoxP3 / 制御リンパ球 / GVH反応 |
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| Research Abstract |
Induction and maintenance of peripheral tolerance are important mechanisms for the balance of the immune system. Growing evidence indicates that the CD4+CD25+ regulatory T (Treg) cells play a central role in the suppression of autoimmunity, inflammation and allograft rejection. However, the underlying mechanism of their functions remains mostly elusive and many studies suggest that the Treg cells have proven difficult to grow, expand and clone in vitro and in vivo. Therefore, the investigations of the novel molecular and/or pathway for understanding their regulatory functions and therapeutic agents that are capable of enhancement the number and activity of this T cell subset are highly desirable. The use of the multiple animal transplantation models has not only improved our understanding of tolerance induction, but also contributed to new concepts of treatment strategies involving the use of regulatory T cells. The present research project summarizes : 1) our results suggest that lymp
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hocytes with regulatory cell activity can be generated in vitro by simultaneous blockade of CD28 and ICOS co-stimulatory signals and that they inhibit alloreactive T-cell proliferation. Moreover, these generated anergic lymphocytes may potentially prolong cardiac allograft survival by adoptive transfer. The key mechanism in these generated lymphocytes may be associated with the induction of regulatory T cells ; 2) our results provides a working model for understanding the crucial roles of Treg cell-mediated immunomodulation by the PD-1/PD-L1 pathway in regulating the alloimmune responses in vivo. Understanding the functions of the inhibitory T cell co-stimulatory pathways in alloimmunity and transplantation tolerance may allow us to utilize the physiologic mechanisms that regulate alloimmune responses, and, in combination with blockades of positive co-stimulatory pathways, may provide a novel approach to achieving long-lasting and reproducible tolerance and reduction of transplantation complications such as rejection and GvHD ; 3) our results confirm that sup CD28 mAb expands rat Foxp3 expressing CD4+CD25+ nTreg cells in vivo, which maintain their unique cell surface marker profile and inhibit alloreactive T-cell proliferation. Moreover, these expanded CD4+CD25+ Treg cells potently inhibit the GvH activity and prolong cardiac allograft survival. Regardless of the feasibility of direct in vivo expansion, the ability to isolate and expand human CD25+CD4+ nTreg cells in vitro for re-infusion will allow the further biological and biochemical characterization of this unique T cell subset and expedite progress towards clinical use of Treg cells as a cellular therapy for treatment allograft rejection and GvHD. Less
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Report
(4 results)
Research Products
(28 results)
