Acquired systemic tolerance to rat cardiac allografts induced by intrathymic inoculation of synthetic polymorphic MHC class I allopeptides

被引:40
作者
Chowdhury, NC
Murphy, B
Sayegh, MH
Jin, MX
Roy, DK
Hardy, MA
Oluwole, SF
机构
[1] COLUMBIA UNIV COLL PHYS & SURG,DEPT SURG,NEW YORK,NY 10032
[2] HARVARD UNIV,BRIGHAM & WOMENS HOSP,SCH MED,LAB IMMUNOGENT & TRANSPLANTAT,BOSTON,MA 02115
关键词
D O I
10.1097/00007890-199612270-00034
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
This study extends the finding that intrathymic (IT) injection of 3M KCl extracts of T cells induces transplant tolerance to the use of well defined polymorphic MHC class I allopeptides derived from the hypervariable domain of RT1.A(u) (WF MHC class I). While three of the six synthetic RT1.A(u) peptides were immunogenic, three others were nonimmunogenic when tested in ACI responders. In our initial studies, we examined the effects of IT injection of a mixture of equal concentrations of the three nonimmunogenic RT1.A(u) peptides on WF cardiac allograft survival in ACI recipients. The results showed that a single IT injection of 100 and 300 mu g class I MHC allopeptides on day -7 relative to cardiac transplant did not significantly prolong graft survival in naive ACI recipients (MST of 9.8, and 12.3 days vs. 10.5 days in controls). In contrast, 600 mu g allopeptides injected IT resulted in modest prolongation of graft to an MST of 19.5 days. However, IT injection of 600 mu allopeptides combined with 0.5 ml ALS on day -7 led to permanent acceptance (>200 days) of cardiac allografts in 7/9 ACI recipients compared with survival of 24.2 days in ALS alone treated controls. In contrast, similar treatment led to acute rejection of third party (Lewis) cardiac allografts. Intravenous injection of 600 mu g allopeptides combined with ALS did not result in prolonged graft survival (26.8 days). The long-term unresponsive ACI recipients (>100 days) challenged with second-set cardiac grafts accepted permanently donor-type (WF) grafts while rejecting the third party (Lewis) grafts, a finding that confirms acquired systemic tolerance. These findings confirm the role of IT injection of synthetic polymorphic allopeptides in the induction of acquired thymic tolerance and provide the rational for testing this strategy in large animals and eventually in man.
引用
收藏
页码:1878 / 1882
页数:5
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