Cytokines

Abstract

Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. An overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for evaluating these important entities was presented at this symposium. Cytokines play a broad role to help the immune system respond to diseases, and drugs which modulate their effect have led to some amazing therapies. Cytokines may be "good" when stimulating the immune system to fight a foreign pathogen or attack tumors. Other "good" cytokine effects include reduction of an immune response, for example interferon β reduction of neuron inflammation in patients with multiple sclerosis. They may be "bad" when their expression causes inflammatory diseases, such as the role of tumor necrosis factor α in rheumatoid arthritis or asthma and Crohn's disease. Therapeutic modulation of cytokine expression can help the "good" cytokines to generate or quench the immune system and block the "bad" cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody therapeutics can cause "ugly" cytokine release which can be deadly. Well-designed toxicology studies should incorporate careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discussed lessons learned in cytokine toxicology using case studies and suggested future directions.

Effects of Glycated Whey Protein Concentrate on Pro-inflammatory Cytokine Expression and Phagocytic Activity in RAW264.7 Macrophages

“…52) This immune response serves as the body's first line of defense against invasion, and inflammation by these inflammatory cytokines accompanies a wide range of effects, including (1) induction of vascular endothelial receptors required for moving of immune cells out of the circulation and into the local site of inflammation, and (2) drawing and activating additional leukocytes to assist in the destruction. 53) However, it should be noted that imbalances due to over-production of pro-inflammatory cytokines can cause pathological condition including rheumatoid arthritis. 54) Phagocytic Activity of RAW264.7 Cells Treated with G-WPC One of the critical activities of macrophages is phagocytosis, which serves as a primary immune defense against pathogens.…”

Host pathogen interactions in Helicobacter pylori related gastric cancer

“…It takes part in the regulation of immune cell activity, fever induction, apoptotic cell death, cachexia, inflammation, inhibition of tumorigenesis and viral replication. It is also involved in the cytokine response during sepsis[212,213]. The elevated secretion of TNF-α is observed in the gastric mucosa of H. pylori infected patients where this cytokine induces cell apoptosis[214].…”

“…This cytokine downregulates the production of pro-inflammatory cytokines by inhibition of Th 1 lymphocytes and stimulation of B, as well as Th 2, lymphocytes and thus downregulates the inflammatory response[212,213]. Since 2003 researchers have consistently reported associations between IL-10-592 A/C SNP and susceptibility to gastric cancer but with mixed or conflicting results[217].…”

Biomarkers for nonclinical infusion reactions in marketed biotherapeutics and considerations for study design

“… For small species with TK cohorts, sample from TK, Main study, and Recovery groups Positive 2-4 h after IR or prior to termination in all animals CIC serum or plasma 0.5–1 Method dependent 48 , 49 Positive/Increased Complement ∗∗2 , ∗∗5 , ∗6 , 18 , 19 , ∗∗51 CH50 serum 0.5–1.8 Process and freeze immediately. Minimize freeze/thaw cycles Decreased 2-4 h after IR C3a serum or plasma 0.5–1.8 Increased C5a Increased Bb Increased Sc5b-9 Increased Cytokines ∗∗2 , ∗∗5 , 10 , 12 , 19 , ∗50 , ∗∗51 Multi-plexed assay (cytokines most commonly observed listed) IL-6, TNF-α, IFNγ, IL1-b, IL-2 serum or plasma 0.5–1.0 Process and freeze immediately. Minimize freeze/thaw cycles Increased 2-4 h after IR Coagulation ∗∗2 , ∗∗4 , ∗∗5 APTT plasma 1–1.8 Samples taken by different routes or in the presence of anesthetics may impact biomarker modulation [63] Increased 2-4 h after IR PT Increased Fibrinogen c , e Decreased or increased D-dimer Increased Hematology ∗∗2 , …”

“…For cytokines, most CROs have multiplexed assays; however, IL-6 appears to be the cytokine most commonly elevated for both first dose and delayed IRs 10 , 12 , 19 . Cytokines in general can be increased following a drug-induced, immune-mediated IR 7 , ∗50 . Complement can be activated by immune complexes.…”