A new approach to vaccine adjuvants. Immunopotentiation by intracellular T-helper-like signals transmitted by loxoribine.
Loxoribine is a potent new immunostimulant with a relatively broad spectrum of immunobiological activities. Both loxoribine and its analogues function as agonists of immune responses in a variety of species, including humans. They upregulate the activity of B cells, T cells, NK cells, macrophages, and LAK cells. Induction of enhanced cytokine secretion has been found to involve IFN-alpha/beta, IFN-gamma, TNF-alpha, TNF-beta, IL-1, IL-6, and the 40 kDa chain of IL-12. Evaluation of in vivo activity has been undertaken only for antibody production, NK cell-mediated cytotoxicity, induction of certain cytokines, and LAK cell-mediated cytotoxicity; all four types of activity are markedly upregulated by loxoribine in vivo. Augmentation of antibody production has been observed for protein, recombinant protein, and synthetic peptide antigens, among others. Because loxoribine and its analogues transmit a T-helper-like signal to antibody-producing B cells, it is a highly effective adjuvant even for synthetic peptides that lack T-cell epitopes, effectively replacing the function of T-helper cells in this milieu. It thus provides an alternative, T-cell-independent vaccination strategy if it becomes desirable to avoid untoward T-cell-mediated effects, or in patients with functional or absolute T-cell deficiency. There are a number of features unique to loxoribine that are highly advantageous under specific circumstances: (1) T cell independence; (2) loxoribine augments antibody responses from an intracellular location (rather than at the surface membrane), independently of protein kinase C involvement; this may be particularly relevant for patients with membrane receptor/signal transduction defects; (3) adjuvanticity of loxoribine is essentially free of cytokine dependency; this may be of particular value for organ transplantation patients whose cytokine-dependent immunity is pharmacologically suppressed; (4) loxoribine bypasses functional immunological immaturity, rendering it particularly useful for vaccines in infants. In preclinical safety studies, the drug has exhibited a relatively benign profile. Phase I clinical studies to date have produced no toxicity higher than grade 1. The drug appears to be quite stable, and compares very favorably in direct evaluations with a number of other immunostimulators. A number of clinical trials have been planned for the future.
Goodman
M G
MG
Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D006151:Guanosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D014612:Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*
D000276:Adjuvants, Immunologic; D014612:Vaccines; D006151:Guanosine; C068562:loxoribine