1988 Fiscal Year Final Research Report Summary
T CELL DEVELOPMENT AND AQUISITION OF SELF-NON-SELF DISCRIMINATION IN THE THYMUS
| Project/Area Number |
62570224
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Immunology
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| Research Institution | NATIONAL INSTITUTE OF RADIOLOGICAL SCIENSES |
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Principal Investigator |
SUZUKI Gen M.D. NATL. INST. RADIOL. SCI. SENIOR RESEARCH OFFICIAL, 障害臨床研究部, 主任研究官 (00179201)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEUCHI Yumiko M.D. THE SECOND DEPARTMENT OF INTERNAL MEDICINE, ASSISTANT UNIV. TOKYO,, 医学部付属病院・第2内科, 助手 (90179622)
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| Project Period (FY) |
1987 – 1988
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| Keywords | Self tolerance / Transplantation tolerance / Chimeric mice / Fetus thymus organ culture / T cell development / Cyclosporin |
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| Research Abstract |
TO ELUCIDATE POSITIVE AND NEGATIVE SELECTION IN T CELL DEVELOPMENT IN THE THYMUS, WE STARTED A SERIES OF EXPERIMENTS IN VIVO AND IN VITRO. FIRSTLY, IN ATTEMPTING TO DISSECT POSITIVE SELECTION, MONOCLONAL ANTIBODIES SPECIFIC FOR CLASS II MHC OR CD4 WERE ADDED INTO THE CULTURE MEDIUM OF FETUS THYMUS ORGAN CULTURE. THESE ANTIBODIES SPECIFICALLY ABROGATED THE GENERATION OF CD4 SINGLE POSITIVE CELLS WHILE SPARING DEVELOPMENT OF CD8 SINGLE POSITIVE CELLS OR CD48 DOUBLE POSITIVE CELLS. WHEN CYCLOSPORIN WAS ADDED, THE AGENT KNOWN TO BLOCK A SIGNAL TRANSDUCTION CASCADE INITIATED BY PERTURBATION OF TCR/CD3 COMPLEX, IT INHIBITED THE DEVELOPMENT OF BOTH CD4 AND CD8 SINGLE POSITIVE CELLS. THESE RESULT INDICATE THAT POSITIVE SELECTION MAY OCCUR UPON INTERACTION OF CD48 DOUBLE POSITIVE CELLS WITH THYMIC STROMAL CELLS.
SECONDLY, FETUS THYMUSES THAT WERE TREATED WITH 2'-DEOXYGUANOSINE TO ELIMINATE HEMPOPIETIC CELLS IN THEM WERE TRANSPLANTED BENEATH THE KIDNEY CAPSULE OF FULLY ALLOGENEIC ATHYMIC MICE. T
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CELLS IN THESE THYMIC CHIMERAS WERE TOLERANT TO CLASS II BUT NOT TO CLASS I MHC OF THE GRAFT TYPE. WHEREAS, THEY WERE FULLY TOLERANT TO BOTH CLASSES OF RECIPIENT MHC. THUS, CLASS I RESTRICTED ANTIGEN PRESENTATION BY HEMPOPIETIC CELLS, BUT NOT BY THYMIC EPITHELIUM, IS TOLEROGENIC TO DEVELOPING THYMOCYTES.
TO FURTHER INVESTIGATE THE NATURE OF SELF TOLERANCE, INTRA-THYMIC CHIMERA WAS MADE BY TWO DIFFERENT METHODS. THE FIRST ONE WAS TO MAKE PARABIOSIS OF FETUS THYMUSES IN VITRO, AND THE SECOND WAS TO RE-POPULATE 2'-DEOXYGUANOSINE-TREATED FETUS THYMUSES WITH IMMATURE THYMOCYTES IN VITRO. IN BOTH OCCASION, THY-1 POSITIVE CELLS WORKED AS TOLEROGENIC CELLS FOR CLASS I REACTIVE CTL. MOREOVER, IT WAS DEMONSTRATED THAT TOLERANCE INDUCTION DID OCCUR ON THYMOCYTES EXPRESSING TCR AT LOW DENSITY, INCLUDING CD48 DOUBLE POSITIVE CELLS AND A PART OF CD4 OR CD8 SINGLE POSITIVE CELLS.
THESE DATA FOCUS OUR ATTENTION ON QUALITATIVE DIFFERENCES BETWEEN ANTIGEN PRESENTATIONS BY HEMOPOIETIC CELLS AND THYMIC EPITHELIUM, WHICH SHOULD BE CLARIFIED IN FUTURE WORK. Less
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