Sanglifehrin A blocks key dendritic cell functions in vivo and promotes long-term allograft survival together with low-dose CsA

H. Hackstein, C. Steinschulte, S. Fiedel, A. Eisele, V. Rathke, T. Stadlbauer, Timucin Taner, A. W. Thomson, H. Tillmanns, G. Bein, H. Hölschermann

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Sanglifehrin A (SFA) is a novel compound with unsurpassed cyclophilin-binding affinity, but relatively low direct antilymphocytic activity. Here, we report the capacity of SFA to selectively inhibit key dendritic cell (DC) functions in vivo and to suppress acute and chronic heart allograft rejection. We show that in vivo, SFA profoundly decreases DC receptor-mediated endocytosis and macropinocytosis and DC-T-cell allostimulatory activity. Furthermore, SFA abrogates >90% of IL-12p70 production in vivo while having no significant effect on IL-10 and TNF-α production. In a rat vascularized heart transplant model, SFA alone did not prevent graft rejection and rejection occurred within 23 days after low-dose CsA, whereas addition of SFA to low-dose CsA promoted long-term graft survival (median survival time >100 days; p = 0.0007). With respect to chronic rejection, SFA + CsA almost completely prevented graft arteriosclerosis compared to animals treated with CsA alone and controls. We propose that SFA represents a novel class of immunophilin-binding immunosuppressants with high activity against DCs and the development of graft vasculopathy in CsA-treated recipients.

Original languageEnglish (US)
Pages (from-to)789-798
Number of pages10
JournalAmerican Journal of Transplantation
Volume7
Issue number4
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

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Dendritic Cells
Allografts
Transplants
Immunophilins
Cyclophilins
sanglifehrin A
Arteriosclerosis
Graft Rejection
Graft Survival
Immunosuppressive Agents
Endocytosis
Interleukin-10
T-Lymphocytes

Keywords

  • Antigen presentation
  • Immunosuppression

ASJC Scopus subject areas

  • Immunology

Cite this

Sanglifehrin A blocks key dendritic cell functions in vivo and promotes long-term allograft survival together with low-dose CsA. / Hackstein, H.; Steinschulte, C.; Fiedel, S.; Eisele, A.; Rathke, V.; Stadlbauer, T.; Taner, Timucin; Thomson, A. W.; Tillmanns, H.; Bein, G.; Hölschermann, H.

In: American Journal of Transplantation, Vol. 7, No. 4, 01.04.2007, p. 789-798.

Research output: Contribution to journalArticle

Hackstein, H, Steinschulte, C, Fiedel, S, Eisele, A, Rathke, V, Stadlbauer, T, Taner, T, Thomson, AW, Tillmanns, H, Bein, G & Hölschermann, H 2007, 'Sanglifehrin A blocks key dendritic cell functions in vivo and promotes long-term allograft survival together with low-dose CsA', American Journal of Transplantation, vol. 7, no. 4, pp. 789-798. https://doi.org/10.1111/j.1600-6143.2006.01729.x
Hackstein, H. ; Steinschulte, C. ; Fiedel, S. ; Eisele, A. ; Rathke, V. ; Stadlbauer, T. ; Taner, Timucin ; Thomson, A. W. ; Tillmanns, H. ; Bein, G. ; Hölschermann, H. / Sanglifehrin A blocks key dendritic cell functions in vivo and promotes long-term allograft survival together with low-dose CsA. In: American Journal of Transplantation. 2007 ; Vol. 7, No. 4. pp. 789-798.
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