| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Background. It has been reported that donor-specific tolerance to a cardiac allograft can be achieved after thc intrathymic (IT) injection of donor splenocytes and a single intraperitoneal injection of anti-lymphocyte serum (ALS) in a fully MHC-disparate rat combination. The aim of the present study was to identify thc intracellular signaling pathways required for the induction of this tolerance.
Materials and Methods. Male Buffalo (BUF; RT1ィイD1bィエD1) rats at 6 to 8 weeks of age underwent IT injection of 25 x 10ィイD16ィエD1 Lewis (LEW ; RT1ィイD11ィエD1) splenocytes and simultaneously received an intraperitoneal injection of 1 ml ALS (day 0). To examine the intracellular signal transduction, the BUF recipients were treated with genistein (protein tyrosine kinases inhibitor, 20mg/kg/day, i.p.), tacrolimus (FK506, calcineurin inhibitor, 1mg/kg/day, s.c) or cyclosporine A (CsA, calcineurin inhibitor, 5mg/kg/day, s.c.) for 7 days from 1 day before IT injection plus ALS (day-1〜5). All BUF recipient
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s underwent transplantation with a heterotopic LEW cardiac allograft on day 21.
Results. IT injection of donor splenocytes plus ALS induced indefinite cardiac allograft survival in 90% of thc BUF recipients. Early treatment of thc BUF recipients with genistein (day -1〜5), but not delay treatment ( day7〜13 ) abrogated the induction of the tolerance. IT injection of splenocytes from genistein (20mg/kg/day, 7 days, i.p.)-treated LEW donor plus ALS resulted in indefinite survival of cardiac allografts in all recipients, indicating that genistein treatment does not interfere the signal expression on the donor splenocytes to induce tolerance. In contrast to genistein, treatment with FK506 or CsA of the recipients received IT injection plus ALS resulted in indefinite or prolonged survival of cardiac allografts. It was confirmed that genistein, FK506, or CsA did not reduce the effect of ALS on lymphocyte depletion in the thymus and periphery of BUF rats.
Conclusions. Activation of protein tyrosine kinases but not calcineurin was required for the intracellular signal transduction to induce the tolerance after intrathymic injection of donor splenocytes plus ALS. Less
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