title: Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.
abstract: TNF-alpha mediates both protective and detrimental manifestations of the host immune response. Our previous work has shown thalidomide to be a relatively selective inhibitor of TNF-alpha production in vivo and in vitro. Additionally, we have recently reported that thalidomide exerts a costimulatory effect on T cell responses. To develop thalidomide analogues with increased anti-TNF-alpha activity and reduced or absent toxicities, novel TNF-alpha inhibitors were designed and synthesized. When a selected group of these compounds was examined for their immunomodulatory activities, different patterns of cytokine modulation were revealed. The tested compounds segregated into two distinct classes: one class of compounds, shown to be potent phosphodiesterase 4 inhibitors, inhibited TNF-alpha production, increased IL-10 production by LPS-induced PBMC, and had little effect on T cell activation; the other class of compounds, similar to thalidomide, were not phosphodiesterase 4 inhibitors and markedly stimulated T cell proliferation and IL-2 and IFN-gamma production. These compounds inhibited TNF-alpha, IL-1beta, and IL-6 and greatly increased IL-10 production by LPS-induced PBMC. Similar to thalidomide, the effect of these agents on IL-12 production was dichotomous; IL-12 was inhibited when PBMC were stimulated with LPS but increased when cells were stimulated by cross-linking the TCR. The latter effect was associated with increased T cell CD40 ligand expression. The distinct immunomodulatory activities of these classes of thalidomide analogues may potentially allow them to be used in the clinic for the treatment of different immunopathological disorders.
authors.affiliation: Celgene Corporation, Warren, NJ 07059, USA. corrall@rockvax.rockefeller.edu
authors.forename: L G
authors.initials: LG
authors.lastname: Corral
authors.forename: P A
authors.initials: PA
authors.lastname: Haslett
authors.forename: G W
authors.initials: GW
authors.lastname: Muller
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: L M
authors.initials: LM
authors.lastname: Wong
authors.forename: C J
authors.initials: CJ
authors.lastname: Ocampo
authors.forename: R T
authors.initials: RT
authors.lastname: Patterson
authors.forename: D I
authors.initials: DI
authors.lastname: Stirling
authors.forename: G
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives / Q000145:classification* / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D016207:Cytokines; D007527:Isoenzymes; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; D013792:Thalidomide; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4