Boosting Adaptive Immunity: A New Role for PAFR Antagonists

Abstract

We have previously shown that the Platelet-Activating Factor Receptor (PAFR) engagement in murine macrophages and dendritic cells (DCs) promotes a tolerogenic phenotype reversed by PAFR-antagonists treatment in vitro. Here, we investigated whether a PAFR antagonist would modulate the immune response in vivo. Mice were subcutaneously injected with OVA or OVA with PAFR-antagonist WEB2170 on days 0 and 7. On day 14, OVA–specific IgG2a and IgG1 were measured in the serum. The presence of WEB2170 during immunization significantly increased IgG2a without affecting IgG1 levels. When WEB2170 was added to OVA in complete Freund’s adjuvant, enhanced IgG2a but not IgG1 production was also observed, and CD4+ FoxP3+ T cell frequency in the spleen was reduced compared to mice immunized without the antagonist. Similar results were observed in PAFR-deficient mice, along with increased Tbet mRNA expression in the spleen. Additionally, bone marrow-derived DCs loaded with OVA were transferred into naïve mice and their splenocytes were co-cultured with fresh OVA-loaded DCs. CD4+ T cell proliferation was higher in the group transferred with DCs treated with the PAFR-antagonist. We propose that the activation of PAFR by ligands present in the site of immunization is able to fine-tune the adaptive immune response.

Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

“…In previous studies, we described the effect of the PAFR blockage in DCs during maturation induced by LPS. A pretreatment with a PAFR antagonist reduced the IL-10 and PGE 2 secretion by DCs and increased their ability in promoting T cell proliferation and Th1-like adaptive response in vitro and in vivo [6,8].…”

“…We have recently shown that mice that were immunized in the presence of a PAFR antagonist developed an enhanced antigen-specific adaptive immune response. We also observed that vaccination of mice with dendritic cells (DCs) that had been previously treated with PAFR antagonists and stimulated with lipopolysaccharide (LPS) also induced higher antigen-specific T cell proliferation, suggesting that the activation of this receptor in the site of immunization could adjust both innate and adaptive immunity responses [6].…”

Platelet activating factor receptor antagonists improve the efficacy of experimental chemo- and radiotherapy

“…The PAF/PAFR axis can also suppress the immune response by inducing tolerogenic dendritic cells 41 and proliferation of myeloid-derived suppressor cells 42 . In these cells, PAFR-mediated suppression involves IL10 and prostaglandin production 43 .…”

Progress in the Development of Platelet‐Activating Factor Receptor (PAFr) Antagonists and Applications in the Treatment of Inflammatory Diseases

“…Besides the well‐established pro‐inflammatory effects of PAF, in select cases, PAFr has also been implicated in damping the immune response, inducing immune suppression . Several in vitro and in vivo studies have reported that PAFr activation in macrophages and dendritic cells is able to shift these cells toward an anti‐inflammatory or tolerogenic phenotype . Thus, PAFr antagonists may have the ability to fine‐tune the innate and adaptive immunity with a potential role in immunization …”