Dynamics of APC recruitment at the site of injection following injection of vaccine adjuvants. Issue 12 (14th March 2017)

• Record Type: Journal Article
• Authors: van Aalst, Susan; Ludwig, Irene Stephanie; van Kooten, Peter Johannes Sylvester; van der Zee, Ruurd; van Eden, Willem; Broere, Femke
• Is Part Of: Vaccine. Volume 35:Issue 12(2017)
• Page Start: 1622
• Page End: 1629
• Publication Date: 2017-03-14
• Subjects: APC antigen presenting cell -- CFA Complete Freunds' Adjuvant -- CFSE 5, 6-carboxy-succinimidyl-fluoresceine-ester -- CL contralateral -- DC dendritic cell -- DDA dimethyldioctadecylammonium bromide -- dLN draining lymph node -- hPG human proteoglycan -- hpi hours post immunization -- i.m. intramuscular -- IL interleukin -- LPS lipopolysaccharide -- MPL monophosphoryl Lipid A -- PAM Pam3CSK4 -- SOI site of injection -- TDB trehalose-6, 6-dibehenate -- TDM trehalose 6, 6′-dimycolate -- TNF-α tumor necrosis factor alpha; Vaccine adjuvant -- Mechanism of action -- Innate immunity -- Site of injection -- Muscle immunity -- APC; Vaccines -- Periodicals; 615.372
• DOI: 10.1016/j.vaccine.2017.02.005
• Languages: English
• ISSNs: 0264-410X

Abstract

Highlights: Intramuscular adjuvant injection induces adjuvant-specific cell influx in muscle. Adjuvants induce a transient pro-inflammatory milieu in muscle. The capacity of muscle APC to load and present antigen is affected by the adjuvant. Abstract: Vaccines often contain adjuvants to strengthen the response to the vaccine antigen. However, their modes of action at the site of injection (SOI) are poorly understood. Therefore, we assessed the local effects of adjuvant on the innate immune system in mice. We investigated the safe, widely used adjuvants MF59 and aluminum hydroxide (alum), as well as trehalose-6, 6′-dibehenate (TDB), Complete Freund's Adjuvant (CFA) and the Toll-Like-Receptor-ligands lipopolysaccharide (LPS) and Pam3CysSerLys4 (Pam3 CSK4 ). We assessed muscle immune cell infiltration after adjuvant injection and observed 16 h post immunization (hpi) an increased influx with CFA, MF59 and TDB, but not with alum, LPS or Pam3 CSK4 . An elevated influx with the latter three became visible only 72 hpi. Contribution of granulocytes, macrophages and dendritic cells to the influx differed per adjuvant and in time. Adjuvants generally induced a local pro-inflammatory micro-milieu that was transient except for CFA and TDB. The gene expression of CXCL-1, CCL-2 and CCL-5, involved in recruitment of immune cells, varied per adjuvant and corresponded grossly with the observed influx of granulocytes and monocytes/macrophages. Muscles injected with CFA or MF59 (when co-injected with peptide) resulted in APC ex vivo capable to induce proliferation of peptide-specific T-cells. By adding in vitro an excess of peptide to the APC/T cell co-cultures, we observed an adjuvant-enhanced co-stimulation or antigen presentation by APC after CFA- but not MF59-injection. After TDB-injection this effect was observed only at 72 hpi, but not 24 hpi. Thus the cellular influx profile and the local cytokine and chemokine micro-milieu in the muscle were strongly influenced by the type of adjuvant. Additionally, the capacity of muscle APC to load and present antigen was affected by the adjuvant. These findings may assist the development of novel adjuvanted vaccines in a more rational manner.