Didemnin B: A new immunosuppressive cyclic peptide with potent activity in vitro and in vivo

David W Montgomery, C. F. Zukoski

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Didemnin B (DB) is a 7-amino-acid, cyclic polypeptide with potent (10-7-10-10 M) antiproliferative effects in vivo and in vitro against a variety of viruses and tumor cell lines. Because lymphocyte blastogenesis is essential for many immune responses, DB appeared likely to exert immunosuppressive effects as well. Using primary cultures of murine (Balb/c) splenic mononuclear cells to evaluate this possibility, we found that DB was a potent (IC50 = 190 ng/ml) inhibitor of lymphocyte protein synthesis, although RNA synthesis and cell viability were unaffected. However, it markedly inhibited blastogenesis stimulated by concanavalin A (IC50 = 50 pg/ml), lipopolysaccharide (IC50 = < 100 pg/ml) and alloantigen (IC50 = < 10 pg/ml) when added to cultures immediately after stimulation. DB added later, at the time of thymidine labeling was much less potent (1/46-1/1430), suggesting that the lymphocyte activation process is particularly sensitive to this agent. Our finding that alloantigen-driven proliferation was exquisitely sensitive to DB (> 90% inhibition at 10 pg/ml) led us to test its effects in vivo using the Simonsen parental-to-F1 graft-versus-host reaction (GVHR). Treatment of graft recipients with 0.05, 0.10, and 0.20 mg DB/kg/day for 7 days produced 51%, 40%, and 60% inhibition of splenomegaly induced by the GVHR, and treatment with 0.3 mg/kg/day on days 1, 2, 4, and 6 inhibited 71%. These data show that the in vitro inhibition of alloantigen-driven blastogenesis by DB was reproduced by in vivo treatment as well, even across major histocompatibility differences. This leads us to conclude that DB has potent immunosuppressive activity both in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)49-56
Number of pages8
JournalTransplantation
Volume40
Issue number1
StatePublished - 1985

Fingerprint

didemnins
Cyclic Peptides
Immunosuppressive Agents
Lymphocyte Activation
Inhibitory Concentration 50
Transplants
Cyclic Amino Acids
Lymphocytes
Histocompatibility
Protein Synthesis Inhibitors
Isoantigens
Splenomegaly
Concanavalin A
Tumor Cell Line
Lipopolysaccharides
In Vitro Techniques
Cell Survival
RNA
Viruses

ASJC Scopus subject areas

  • Immunology
  • Transplantation

Cite this

Didemnin B : A new immunosuppressive cyclic peptide with potent activity in vitro and in vivo. / Montgomery, David W; Zukoski, C. F.

In: Transplantation, Vol. 40, No. 1, 1985, p. 49-56.

Research output: Contribution to journalArticle

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