| Project/Area Number |
04404049
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Digestive surgery
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| Research Institution | Tohoku University |
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Principal Investigator |
MATUNO Seiki Tohoku Univer School of Medicine, Ophthalnology.Professor, 医学部, 教授 (80004737)
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| Co-Investigator(Kenkyū-buntansha) |
SIBUYA Kazuhiko Tohoku Univer School hospital.The secone Professor, 助手 (70260429)
TAKEDA Kazunori Tohoku Univer School of Medicine, Assistant Professor, 医学部, 講師 (20171639)
KOBARI Masao Tohoku Univer School of Medicine, Assistant Professor, 医学部, 講師 (30170369)
SUNAMURA Makoto Tohoku Univer School hospital.The second Professor, 医学部附属病院, 助手 (10201584)
角川 陽一郎 東北大学, 医学部・付属病院, 助手 (60221173)
高橋 道長 東北大学, 医学部・付属病院, 助手 (60206852)
砂村 真琴 東北大学, 医学部・付属病院, 助手
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| Project Period (FY) |
1992 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥29,000,000 (Direct Cost: ¥29,000,000)
Fiscal Year 1994: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1993: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1992: ¥19,000,000 (Direct Cost: ¥19,000,000)
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| Keywords | hybrid pancreas / islet transplantation / ICAM-1 / LFA-1 / Th1 / Th2 balance / IL-12 / ハイブリッド型人工膵 / ラ島移植 / 膵移植 / セルロース / costimulatory signal / growth factor / xenograft transplantation |
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| Research Abstract |
The purpose of this study is to develop an artificial hybrid pancreas using purified islets. In order to establish a suitable system, we have planed two main projects : 1) to identify a good agent to prevent immunoreaction, 2) to elucidate the mechanism of rejection after allogenic islet transplantation.
At first, we tried to use a cellulose type membrane to prevent the graft invasion by lymphocytes, however it did not work out well. Therefore, we have focused on the mechanism of induction of rejection tolerance from the view point of costimulatory signals and cytokines.
Immunosuppressive potentials of the blockade of ICAM-1/LFA-1 were examined in a murine islet allotransplantation model by using neutralizing monoclonal antibodies (mAbs) against these molecules. ICR derived islets were transplanted into the renal subcapsular space of streptozotocin-induced diabetic C57BL/6 mouse. Antibodies were administered immediately after transplantation at a dose of 100 mug/mouse/day for 3 or 7 days
… More
. In nontreated mice, islet grafts were rejected within 16 days (mean graft survival=10.0(]SY.+-。[)2.9 days), while treatment with anti-ICAM-1 mAb (KAT-1) alone, treatment with anti-LFA-1 mAb (KBA) alone, or with both mAbs significantly prolonged the graft survival. In particular, the combination of KAT-1 and KBA in a 7-day course produced a marked prolongation with mean graft survival of 91.3(]SY.+-。[)24.7 days, and it induced indefinite graft survival over 100 days in 88% of recipients. Expression of cytokine transcripts within islet allografts was analyzed by RT-PCR.In the mice treated with KAT-1 and KBA,the transcripts for Th1 cytokines (IL-2 and IFN-gamma) were not detected, but the expression of Th2 cytokines (IL-4 and IL-10) were enhanced and persisted over 140 days. In contrast, Th1 cytokines were dominantly expressed in the grafts from untreated mice. These results indicate that administration of anti-ICAM-1 and/or anti-LFA-1 mAbs prolongs murine islet allograft survival potentially by indicating a Th2 deviation.
Furthermore, we showed that anti-mouse-IL-12 antibodies could prolong islet allograft survival while rejection in untreated recipients was characterized by enhanced intragraft IFN-gamma and IL-2 gene expression and not IL-4 or IL-10 gene, indicating primarily a Th1 response. Anti-mouse IL-12 antibodies impared intragraft Th1 cytokine genes expression (IFN-gamma and IL2) on day 4,8 postransplant and enhanced IL-10 expression on day 10.
Our results suggest that Th1/Th2 balance play an important role in allograft survival. Less
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