IMMUNOLOGY, PHARMACOLOGY AND TOXICOLOGY OF THE IMMUNOSUPPRESSIVE CYCLIC PEPTIDE, DIDEMNIN B.

Persistent Link:
http://hdl.handle.net/10150/183982
Title:
IMMUNOLOGY, PHARMACOLOGY AND TOXICOLOGY OF THE IMMUNOSUPPRESSIVE CYCLIC PEPTIDE, DIDEMNIN B.
Author:
MONTGOMERY, DAVID WESLEY.
Issue Date:
1986
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Didemnin B (DB) is a seven amino acid cyclic polypeptide (NSC-325319), MW 1112, isolated from a Caribbean tunicate of the family didemnidae (Trididemnum genus). In vitro assays of murine splenic mononuclear cell (MNC) proliferation showed that DB potently inhibited the mixed lymphocyte reaction (IC₅₀ = < 10 pg/ml), concanavalin A (Con A; IC₅₀ = 50 pg/ml) and lipopolysaccharide (IC₅₀ = < 100 pg/ml) mitogenesis. Proliferation induced by phorbol esters, calcium ionophore and Con A were equipotently inhibited by DB, suggesting that the drug acts upon an intracellular pathway common to these mitogens. Since DB did not produce lymphocytotoxicity, nor inhibit ongoing DNA, RNA or protein synthesis at immunosuppressive concentrations, it was concluded that this agent may affect lymphocyte activation processes. Investigation of the mechanisms of DB action showed that it failed to alter interleukin 2 (Il-2) production by MNC in vitro. However DB was found to block binding of the hormone prolactin (PRL) to both human lymphocytes and a PRL-dependent cell line, the Nb 2 node lymphoma. As PRL plays an important regulatory role in the immune response, abrogation of PRL-MNC interaction may represent a site of DB immunosuppressive action. In vivo, DB demonstrated a potent, inhibitory effect upon alloantigen-driven proliferation in the murine graft-versus-host reaction but hemagglutinating antibody responses in mice to sheep red blood cells were strongly enhanced by DB treatment (4.6-fold). Further, DB treatment of mice in vivo was not bone marrow suppressive, but increased organ cellularity, ongoing DNA synthesis and circulating levels of lymphocytes and granulocytes. DB also exerted significant toxicity in vivo. High doses caused losses in body weight (18%) and mortality (20%), but no mortality occurred at doses of 0.1 mg/kg/day x 7 days. DB did not significantly alter indices of renal function but high dose treatment produced significant but reversible hepatotoxicity. DB also induced ornithine decarboxylase activity in various rat tissues, with adrenal > liver > kidney = spleen > thymus > heart. This correlated with increased organ to body weight ratios for liver and spleen, suggesting a trophic response of these organs to DB. The data presented here show that DB exerts potent inhibitory activity toward cell mediated immunity in vivo and in vitro suggesting that DB might also inhibit rejection of solid organ grafts. In addition, humoral responses and bone marrow function are markedly enhanced by DB treatment in vivo, suggesting that resistance to infectious organisms might be increased by this drug.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Immunosuppressive agents.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology; Graduate College
Degree Grantor:
University of Arizona

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleIMMUNOLOGY, PHARMACOLOGY AND TOXICOLOGY OF THE IMMUNOSUPPRESSIVE CYCLIC PEPTIDE, DIDEMNIN B.en_US
dc.creatorMONTGOMERY, DAVID WESLEY.en_US
dc.contributor.authorMONTGOMERY, DAVID WESLEY.en_US
dc.date.issued1986en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractDidemnin B (DB) is a seven amino acid cyclic polypeptide (NSC-325319), MW 1112, isolated from a Caribbean tunicate of the family didemnidae (Trididemnum genus). In vitro assays of murine splenic mononuclear cell (MNC) proliferation showed that DB potently inhibited the mixed lymphocyte reaction (IC₅₀ = < 10 pg/ml), concanavalin A (Con A; IC₅₀ = 50 pg/ml) and lipopolysaccharide (IC₅₀ = < 100 pg/ml) mitogenesis. Proliferation induced by phorbol esters, calcium ionophore and Con A were equipotently inhibited by DB, suggesting that the drug acts upon an intracellular pathway common to these mitogens. Since DB did not produce lymphocytotoxicity, nor inhibit ongoing DNA, RNA or protein synthesis at immunosuppressive concentrations, it was concluded that this agent may affect lymphocyte activation processes. Investigation of the mechanisms of DB action showed that it failed to alter interleukin 2 (Il-2) production by MNC in vitro. However DB was found to block binding of the hormone prolactin (PRL) to both human lymphocytes and a PRL-dependent cell line, the Nb 2 node lymphoma. As PRL plays an important regulatory role in the immune response, abrogation of PRL-MNC interaction may represent a site of DB immunosuppressive action. In vivo, DB demonstrated a potent, inhibitory effect upon alloantigen-driven proliferation in the murine graft-versus-host reaction but hemagglutinating antibody responses in mice to sheep red blood cells were strongly enhanced by DB treatment (4.6-fold). Further, DB treatment of mice in vivo was not bone marrow suppressive, but increased organ cellularity, ongoing DNA synthesis and circulating levels of lymphocytes and granulocytes. DB also exerted significant toxicity in vivo. High doses caused losses in body weight (18%) and mortality (20%), but no mortality occurred at doses of 0.1 mg/kg/day x 7 days. DB did not significantly alter indices of renal function but high dose treatment produced significant but reversible hepatotoxicity. DB also induced ornithine decarboxylase activity in various rat tissues, with adrenal > liver > kidney = spleen > thymus > heart. This correlated with increased organ to body weight ratios for liver and spleen, suggesting a trophic response of these organs to DB. The data presented here show that DB exerts potent inhibitory activity toward cell mediated immunity in vivo and in vitro suggesting that DB might also inhibit rejection of solid organ grafts. In addition, humoral responses and bone marrow function are markedly enhanced by DB treatment in vivo, suggesting that resistance to infectious organisms might be increased by this drug.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectImmunosuppressive agents.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.identifier.proquest8708564en_US
dc.identifier.oclc698377057en_US
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