Tolerance induction of alloreactive T cells and regulation of graft rejection

• Project/Area Number: 04454207
• Research Category: Grant-in-Aid for General Scientific Research (B)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: FUJIWARA Hiromi Osaka Univ.Med.Sch.Assoc.Prof., 医学部, 助教授 (70116094)
• Co-Investigator(Kenkyū-buntansha): KOSUGI Atsushi Res.Development Cosp of Japan, 研究者
• Project Period (FY): 1992 – 1993
• Project Status: Completed (Fiscal Year 1993)
• Budget Amount: ¥6,700,000 (Direct Cost: ¥6,700,000); Fiscal Year 1993: ¥2,600,000 (Direct Cost: ¥2,600,000); Fiscal Year 1992: ¥4,100,000 (Direct Cost: ¥4,100,000)
• Keywords: tolerance / transplantation immunology / helper T cells / DST / immunosuppresive drugs / アロ抗原反応性T細胞 / 拒絶反応

Research Abstract

One of major issues in transplantation immunology is to develop methods to regulate allograft responses. This study investigated an approach to regulate allograft responses by either a single DST(donor-specific transfusion), repeated administrasion of immunosuppressive drugs (FK506 or rapamycin) or the combination of these. The follwing were revealed : (1)Allo class 1 MHC-reactive helper T cells (Th) consist of (a)CD4^+ and CD8^+ Th with the capacity to produce high levels of IL-2 and (b) CD4^+ Th with the limited capacity of IL-2 production. The former is susceptible to donor-specific transfusion (DST) and rendered easily tolerant by a single DST, whereas the latter is DST-resistant. (2)In the donor-host combination involving the DSP-susceptible and DST-resistant Th subsets, the induction and maintenance of tolerance of the former is inhibited by the operation of the DSP-resistant subset, indicating the modulation of allograft responses based on cellular interactions. (3)It was found that FK506 or rapamycin at suboptimal deses was effective for suppressing allograft rejection responses by the combination with a single DST under which either of these treatments alone failed to inhibit rejection responses. Thus, by presenting a practical approach for producing a beneficial effect on immunomodulation of allograft responses using DST and by demonstrating cellular mechanisms underlying such an immunomodulation, the present study may provide a significant contribution to transplantation immunology.

Research Products

• [Publications] Sugihara,S et al.: "Thyroiditis-inducing T cell lines and clones derived from autoimmune thyroiditis lesions induced in mice by the elimination of regulatory T cell subset." J.Immunol.150. 683-694 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Iwata,H.et al.: "Suppression of allograft responses by combining donor alloantigen-specific i.v.presensitization with suboptimal doses of FK506." Transplantation. 56. 173-180 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kita,Y.et al.: "Thymic stroma-derived T cell inhibitory factor(TSTIF).I.TSTIF induces inhibition of antigen-stimulated T cell proliferation." Thymus-J.of T cell Biology. 21. 159-173 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tai,X-G.et al.: "Thymic stroma-derived T cell inhibitory factor(TSTIF).II.TSTIF acts on the antigen-stimuylated cell to inhibit antigen-stimulated T cell proliferation." Thymus-J.of T cell Biology. 21. 247-258 (1993)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Iwata,H.et al.: "Suppression of allograft responses by combining alloantigen-specific i.v.presensitization with suboptimal doses of rapamycin." International Immunol.6. 93-99 (1994)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Mizuhara,H.et al.: "T cell activation associated hepatic injury:Mediation by tumor necrosis factor and protection by interleukin-6." J.Exp.Med.(in press). (1994)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sugihara, S et al.: "Thyroiditis-inducing T cell lines and clones derived from autoimmune thyroiditis lesions induced in mice by the elimination of regulatory T cell subset." 150. 683-694 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Iwata, H.et al.: "Suppression of allograft responses by combining donor alloantigen-specific i.v.presensitization with suboptimal doses of FK506." 56. 173-180 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kita, Y.et al.: "Thymic stroma-derived T cell inhibitory factor (TSTIF). I.TSTIF induces inhibition of antigen-stimulated T cell proliferation." 21. 159-173 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tai, X-G.et al.: "Thymic stroma-derived T cell inhibitory factor (TSTIF).II TSTIF acts on the antigen-stimuylated cell to inhibit antigen-stimulated T cell proliferation." 21. 247-258 (1993)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Iwata, H.et al.: "Suppression of allograft responses by combining alloantigen-specific I.v.presensitization with suboptimal doses of rapamycin." 6. 93-99 (1994)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Mizuhara, H.et al.: "T cell activation associated hepatic injury : Mediation by tumor necrosis factor and protection by interleukin-6." (in press). (1994)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sugihara,S.et al.: "Thyroiditis-inducing T cell lines and clones derived from autoimmune thyroiditis lesions induced in mice by the elimination of regulatory T cell subset." J.Immunol.150. 683-694 (1993)
• [Publications] Iwata,H.et al.: "Suppression of allograft responses by combining donor alloantigen-specific i.v.presensitization with suboptimal doses of FK506." Transplantation. 56. 173-180 (1993)
• [Publications] Kita,Y.et al.: "Thymic stroma-derived T cell inhibitory factor(TSTIF).I.TSTIF induces inhibition of antigen-stimulated T cell proliferation." Thymus-J.of T cell Biology. 21. 159-175 (1993)
• [Publications] Tai,X-G.et al.: "Thymic stroma-derived T cell inhibitory factor(TSTIF).II.TSTIF acts on the antigen-stimuylated cell to inhibit antigen-stimulated T cell proliferation." Thymus-J.of T cell Biology. 21. 247-258 (1993)
• [Publications] Iwata,H.et al.: "Suppression of allograft responses by combining alloantigen-specific i.v.presensitization with suboptimal doses of rapamycin." International Immunol.6. 93-99 (1994)
• [Publications] Mizuhara,H.et al.: "T cell activation assosiated hepatic injury:Mediation by tumor necrosis factor and protection by interleukin-6." J.Exp.Med.(in press). (1994)
• [Publications] S.Hori et al.: "Cell-Cell interaction in graft rejection responses:Induction of anti-allo-class IH-2 tole rance is prevented by immune responses against allo-classII H-2 antigens co-expressed on tole ragen." J.Exp,Med.175. 99-109 (1992)
• [Publications] Y.Takai et al: "Identification of IL-7-dependent bone marrow-derived Thy-l^-B220^-lymphoid cell clones that rearrange and express both immunoglobulin and T cell receptor genes." J.Immunol.148. 1329-1337 (1992)
• [Publications] N.Seki et al.: "TypeII collagen-induced murine arthritis:Induction of arthritis depends on antigen-presenting cell function as well as host's susceptibility to anti-collagen immune response." J.Immunol.148. 3093-3099 (1992)
• [Publications] A.Kosugi et al: "Instability of Tcell receptor complex that is associated with rapid degradation of 〓 chains in immature CD4^+CD8^+thymocytes." Proc.Natl.Acad Sci.U.S.A.89. 9494-9498 (1992)
• [Publications] H.Iwata et al: "Suppression of allograft responses by compining donor alloantigen-specific i.v.presen〓itization with suboptimal doses of FK 506" Transplantation. (1993)
• [Publications] S.Sugihara et al: "Thyroiditis-inducing Tcell lines and clones derived from autoimmune thyroiditis lesions induced in mice by the elimination of regulatoly Tcell subset." J.Immunol. (1993)