FK506 inhibits graft-versus-host disease and bone marrow graft rejection in murine recipients of MHC disparate donor grafts by interfering with mature peripheral T cell expansion post-transplantation

Bruce R. Blazar, Patricia A. Taylor, William E. Fitzsimmons, Daniel A. Vallera

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25 Scopus citations

Abstract

FK506 was evaluated as the sole graft-vs-host disease (GVHD) preventive agent in murine recipients of fully allogeneic donor grafts. FK506 (36 mg/kg given as a suspension on days 0 through 13, then three times per wk through day 29 post-bone marrow transplantation (BMT) reproducibly led to 50 to 90% of FK506-treated recipients surviving a 60- to 103-day observation period. High doses of cyclosporin A did not protect mice from lethal GVHD. A kinetic study performed in mice that received FK506 demonstrated that mature donor CD3+, CD4+, and CD8+ T cells in the spleen were each reduced by ≥64%, as compared with vehicle-treated control mice, although this effect was short lived. Thymic reconstitution studies revealed a remarkable decrease in mature CD4+ cells and cells expressing the activation Ag, CD69. In contrast, less mature CD4+8+ thymocytes were not reduced significantly and total thymocyte numbers were only marginally decreased. The fact that peripheral reconstitution of CD4+8- or CD8+4- T cells was impaired significantly at this time indicated that FK506 had a major effect on thymic maturation and/or thymic emigration. In two models specifically designed to study alloengraftment, recipients of pan-T cell-depleted (TCD) donor marrow and FK506 were noted to have accelerated hemopoietic recovery and augmented long- term multilineage peripheral blood alloengraftment, in marked contrast to controls (86 to 97% mean donor cells vs 0% in controls for all lineages). These data demonstrate that FK506 prevents GVHD and graft rejection in vivo by inhibiting mature T cell expansion post-BMT.

Original languageEnglish (US)
Pages (from-to)1836-1846
Number of pages11
JournalJournal of Immunology
Volume153
Issue number4
StatePublished - Aug 15 1994

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