Analysis of immunological mechanism and inhibition of post-transplant coronary artery disease in mice.

1997 Fiscal Year Final Research Report Summary

• Project/Area Number: 08457304
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Kyushu University
• Principal Investigator: YASUI Hisataka Kyushu University, Facul.of Med., professor, 医学部, 教授 (20089923)
• Co-Investigator(Kenkyū-buntansha): FUKUMURA Fumio Kyusu University Facul.of Med., Assistant Professor, 医学部, 助手 (80264026) ; TOMITA Yukihiro Kyusu University Facul.of Med., Assistant Professor, 医学部, 助手 (90180174)
• Project Period (FY): 1996 – 1997
• Keywords: Cyclophasphamicle / heart transphantantion / coronary artery disease / prevention

Research Abstract

Intoroduction. A cyclophosphamide-induced tolerance system in mice that primarily consists of donor spleen cells (SC) injection fellowed by CP-treatment was found useful for inducing a long-lasting allo-tolerance to various solid organs. In the present study, we investigated whether post-transplant coronary disease (PTCAD) occurs in mice induced by CP-induced tolerance system, and evaluated the degree of tolerance to prevent PTCAD.Methods. To develop a reproducible model of PTCAD,we exchaged heterotopic cardiac allografts between MHC-matched but minor H antigen-mismatched donor*recipient comvination of AKR (H-2<@D14@>D1, Thy1.1, Mis-1<@D12@>D1) *C3H (H-2<@D14@>D1, Thy1.2, Mis-1<@D16@>D1). Recipeint C3H mice were treated with 1x10<@D18@>D1 SC on day 0 and 200 or 100mg/kg CP on day 2. The cardiac grafts were followed by palpation and removed for pathologic study. Result. In this combination, AKR heart grafts (HG) into untrreated C3H mice survived over 100 days, but were finally rejected 150-250 days after transplant. In these HG after over 100 days of transplant, histological analysis showed the evidence of PTCAD (coronary artries stenosis ratio on day 200 ; 68.0(]SY.+-。[)16.0%, score of interstitial and pervascular fibrosis ; 3.67(]SY.+-。[)0.58). Permanent skin tolerance to AKR skin was induced in SC/200mg/kg CP-treated C3H mice, but not in SC/100mg/kg CP-treated C3H mice. Destruction of Milsreactive Vbeta6<@D1+@>D1CD4<@D1+@>D1 T cells in the periphery was observed in both groups, but permanent mixed chimerism was not induced in SC/100mg/kg CP-treated C3H mice. In both groups, AKR HG survived for more than 300 days (n=1.5), and both intimal hyperplasia and vascular fibrosis was remarkably limited. Discussion and Conclusion. Present study indicated the beneficial effect of CP-induced tolerance on PTCAD.Furthermore, our results indicated that profound degree of tolerance to induce permanent skin graft acceotance and/or mixed chimerism was not required to prevent PTCAD in murine heart transplant model.