Immunogenicity profile in African green monkeys of a vaccine candidate based on a mutated form of human Interleukin-15.

Background: Interleukin (IL)-15 is a proinflammatory T-cell growth factor overexpressed in several autoimmune diseases such as rheumatoid arthritis. Our initial strategy to neutralize the increased levels of IL-15 consisted in a vaccine candidate based on the recombinant modified human IL-15 (mhIL-15) mixed with the alum adjuvant. A previous study in non-human primates Macaca fascicularis has shown that vaccination induces neutralizing antibodies against native IL-15, without affecting animal behavior, clinical status, or the percentage of IL-15-dependent cell populations.

d-Amino acid substitutions and dimerization increase the biological activity and stability of an IL-15 antagonist peptide.

Interleukin (IL)-15 plays an important role in several inflammatory diseases. We have previously identified an IL-15 antagonist called P8 peptide, which binds specifically to IL-15 receptor alpha subunit. However, the P8 peptide rapidly degraded by proteases, limiting its therapeutic application.

In vitro and in vivo characterization of an interleukin-15 antagonist peptide by metabolic stability, Tc-labeling, and biological activity assays.

Interleukin (IL)-15 is an inflammatory cytokine that constitutes a validated therapeutic target in some immunopathologies, including rheumatoid arthritis (RA). Previously, we identified an IL-15 antagonist peptide named [K6T]P8, with potential therapeutic application in RA. In the current work, the metabolic stability of this peptide in synovial fluids from RA patients was studied.

Obtention and characterization of the recombinant simian Interleukin-15 in Escherichia coli for the preclinical assessment of an IL-15-based therapeutic vaccine.

Recombinant simian IL-15 (siIL-15) was obtained for the preclinical assessment of an anti-human IL-15 vaccine. For this purpose, the cDNA from peripheral blood mononuclear cells of a Macaca fascicularis monkey was cloned into a pIL-2 vector. The siIL-15 was expressed in Escherichia coli strain W3110 as an insoluble protein which accounted for 13% of the total cellular proteins.

Active immunization with human interleukin-15 induces neutralizing antibodies in non-human primates.

Background: Interleukin-15 is an immunostimulatory cytokine overexpressed in several autoimmune and inflammatory diseases such as Rheumatoid Arthritis, psoriasis and ulcerative colitis; thus, inhibition of IL-15-induced signaling could be clinically beneficial in these disorders. Our approach to neutralize IL-15 consisted in active immunization with structurally modified human IL-15 (mhIL-15) with the aim to induce neutralizing antibodies against native IL-15. In the present study, we characterized the antibody response in Macaca fascicularis, non-human primates that were immunized with a vaccine candidate containing mhIL-15 in Aluminum hydroxide (Alum), Montanide and Incomplete Freund's Adjuvant.

Differential expression of pro-inflammatory cytokines IL-15Ralpha, IL-15, IL-6 and TNFalpha in synovial fluid from rheumatoid arthritis patients.

Background: Pro-inflammatory cytokines are directly implicated in the pathogenesis of Rheumatoid arthritis (RA). Variable clinical response to cytokine targeted therapies as TNFalpha and IL-6, strongly highlights the heterogeneity of inflammatory process in RA. Another cytokine, IL-15 has also been related to the inflammatory process in RA.

Proinflammatory soluble interleukin-15 receptor alpha is increased in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease in which many cytokines have been implicated. In particular, IL-15 is a cytokine involved in the inflammatory processes and bone loss. The aim of this study was to investigate the existence in synovial fluid of soluble IL-15Rα, a private receptor subunit for IL-15 which may act as an enhancer of IL-15-induced proinflammatory cytokines.

Enhancement of the inhibitory effect of an IL-15 antagonist peptide by alanine scanning.

IL-15 is a proinflammatory cytokine that acts early in the inflammatory response and has been associated with several autoimmune diseases including rheumatoid arthritis, where it had been proposed as a therapeutic target. We recently reported an IL-15 antagonist peptide corresponding to sequence 36-45 of IL-15 (KVTAMKCFLL) named P8, which specifically binds to IL-15Rα and inhibits IL-15 biological activity with a half maximal inhibitory concentration (IC50) of 130 µ m in CTLL-2 proliferation assay. In order to improve binding of peptide P8 to the receptor IL-15Rα, we used an Ala scan strategy to study contribution of each individual amino acid to the peptide's antagonist effect.