title: Optimized dosing of a CCR2 antagonist for amplification of vaccine immunity.
abstract: We have recently discovered that inflammatory monocytes recruited to lymph nodes in response to vaccine-induced inflammation can function as potent negative regulators of both humoral and cell-mediated immune responses to vaccination. Monocyte depletion or migration blockade can significantly amplify both antibody titers and cellular immune responses to vaccination with several different antigens in mouse models. Thus, we hypothesized that the use of small molecule CCR2 inhibitors to block monocyte migration into lymph nodes may represent a broadly effective means of amplifying vaccine immunity. To address this question, the role of CCR2 in monocyte recruitment to vaccine draining lymph nodes was initially explored in CCR2-/- mice. Next, a small molecule antagonist of CCR2 (RS102895) was evaluated in mouse vaccination models. Initial studies revealed that a single intraperitoneal dose of RS102895 failed to effectively block monocyte recruitment following vaccination. Pharmacokinetic analysis of RS102895 revealed a short half-life (approximately 1h), and suggested that a multi-dose treatment regimen would be more effective. We found that administration of RS102895 every 6 h resulted in consistent plasma levels of 20 ng/ml or greater, which effectively blocked monocyte migration to lymph nodes following vaccination. Moreover, administration of RS102895 with concurrent vaccination markedly enhanced vaccine responses following immunization against the influenza antigen HA1. We concluded that administration of small molecule CCR2 antagonists such as RS102895 in the immediate post-vaccine period could be used as a novel means of significantly enhancing vaccine immunity.
authors.affiliation: Animal Cancer Center, Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Leah A
authors.initials: LA
authors.lastname: Mitchell
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hansen
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Beaupre
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
authors.forename: Steven W
authors.initials: SW
authors.lastname: Dow
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage*; D002465:Cell Movement / Q000187:drug effects; D054796:Drug Dosage Calculations; D006207:Half-Life; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D023421:Models, Animal; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010880:Piperidines / Q000008:administration & dosage*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D048588:Benzoxazines; C515335:Ccr2 protein, mouse; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D010880:Piperidines; C573791:RS 102895; D054390:Receptors, CCR2; C493831:hemagglutinin HA1, influenza B virus