title: Continuous stress disrupts immunostimulatory effects of IL-12.
abstract: Immune stimulation by biological response modifiers is a common approach in tumor immunotherapy. IL-12 was found effective in various animal studies, but clinical trials showed limited success. However, among other differences, animal models do not simulate psychological or physiological stress while employing IL-12, whereas cancer patients often experience distress while treated with immunostimulants. Thus, in the current study we assessed the impact of continuous stress on the efficacy of IL-12 immunostimulation. F344 rats were subjected to a pharmacological stress paradigm (continuous administration of a β-adrenergic agonist) or to a 20 h behavioral stress paradigm (wet cage exposure) commencing 2h before IL-12 administration. Twenty-six hours after stress initiation, we studied indices known to reflect IL-12 immunostimulatory impacts, including NK cell numbers and activity in different immune compartments, and in vivo resistance to MADB106 lung tumor colonization. The results indicated that both the pharmacological and behavioral stress paradigms significantly reduced the increase in the number and activity of marginating-pulmonary NK cells evident in non-stressed IL-12 treated animals. Additionally, stressed animals exhibited a lower IL-12-induced improvement of MADB106 lung clearance, an in vivo index that markedly depends on total marginating-pulmonary NK activity. These deleterious effects of stress were more prominent in males than in females. Overall, the findings demonstrate that prolonged stress exposure can disrupt the efficacy of simultaneous immunostimulatory treatments, irrespective of stress effects on baseline immune measures. Neuroendocrine and cellular mediating mechanisms are yet unknown, but the potential clinical ramifications of these findings warrant consideration in clinical trials employing immunostimulatory agents.
authors.affiliation: Neuroimmunology Research Unit, Department of Psychology, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Levi
authors.forename: Marganit
authors.initials: M
authors.lastname: Benish
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldfarb
authors.forename: Liat
authors.initials: L
authors.lastname: Sorski
authors.forename: Rivka
authors.initials: R
authors.lastname: Melamed
authors.forename: Ella
authors.initials: E
authors.lastname: Rosenne
authors.forename: Shamgar
authors.initials: S
authors.lastname: Ben-Eliyahu
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D058666:Adrenergic beta-2 Receptor Agonists; D000704:Analysis of Variance; D000818:Animals; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood; D004837:Epinephrine / Q000097:blood; D005260:Female; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008175:Lung Neoplasms / Q000150:complications / Q000276:immunology*; D008297:Male; D009921:Metaproterenol; D009374:Neoplasms, Experimental / Q000150:complications / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D013315:Stress, Psychological / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D058666:Adrenergic beta-2 Receptor Agonists; D018664:Interleukin-12; D009921:Metaproterenol; D003345:Corticosterone; D004837:Epinephrine