Peritransplant tolerance induction in macaques: early events reflecting the unique synergy between immunotoxin and deoxyspergualin.

Academic Article

Abstract

  • BACKGROUND: Day of transplant T cell depletion with anti-CD3 immunotoxin or F(Ab)2 immunotoxin induces stable tolerance to renal allografts in rhesus monkeys given 15-deoxyspergualin (DSG), a NF-kappaB inhibitor that suppresses proinflammatory cytokine (PC) production. Because PC and NF-kappaB are involved in dendritic cell (DC) maturation, we asked if impaired DC maturation and Th2-type cytokine deviation might be related to the synergistic effect of DSG in this novel model. METHODS: Immunosuppression was initiated 4 hr before transplanting a major histocompatibility complex mismatched renal allograft. Some groups received a supplemental 5-day course of cyclosporine A or DSG or a 15-day course of DSG. Peripheral lymph nodes were sequentially examined for presence of mature DC. In vitro effects of DSG on PC-induced maturation of DC were also examined. RESULTS: Allografts survived without rejection in 87% of recipients given immunotoxin or F(Ab)2 immunotoxin with DSG x 15 days, in 50% with DSG x 5 days, and 0% with cyclosporine A. The longest DSG survivors are >1000 days with normal graft function and tolerance validated, including acceptance of challenge second donor kidneys without treatment. DSG-treated recipients were unique in developing polarized Th2-type plasma cytokines. In DSG recipients, mature DC were significantly reduced in day +5 lymph node biopsies, with complete repopulation by 30 days. In vitro studies verified an inhibitory effect of DSG on DC maturation. CONCLUSIONS: The study suggests DSG arrests DC maturation. The unusual synergy of immunotoxin and DSG apparently involves coincidental reduction in lymph node T cell mass and mature DC, a transient circumstance favoring development of stable tolerance.
  • Authors

    Published In

  • Transplantation  Journal
  • Keywords

  • Animals, CD3 Complex, Cell Count, Cellular Senescence, Chimera, Cytokines, Dendritic Cells, Graft Survival, Guanidines, Immune Tolerance, Immunoglobulin Fab Fragments, Immunosuppressive Agents, Immunotoxins, Kidney Transplantation, Lymph Nodes, Macaca mulatta, Male, Stem Cells, T-Lymphocytes, Cytotoxic
  • Authorlist

  • Thomas JM; Contreras JL; Jiang XL; Eckhoff DE; Wang PX; Hubbard WJ; Lobashevsky AL; Wang W; Asiedu C; Stavrou S
  • Start Page

  • 1660
  • End Page

  • 1673
  • Volume

  • 68
  • Issue

  • 11