Myeloid cell recruitment and activation through systemic and mucosae-directed cytokine therapy.

Abstract

Myeloid cells play critical roles as Fc effector cells in antibody-mediated immunity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that promotes the recruitment and activation of multiple myeloid populations and has been used in combination with vaccines/treatments against infectious diseases, inflammatory conditions and cancers. To evaluate GM-CSF-mediated kinetics of immune cell expansion and immune outcomes, we compared subcutaneous (subQ) and topical hypoosmolar (intravaginal/intrarectal) administration in vivo using rhesus macaques (RM), as they provide easy access to longitudinal mucosal tissue sampling and are a critical model species for vaccines/therapeutics development. While topical GM-CSF did not result in a major change, neutrophils, eosinophils and monocytes were elevated within 1-3 days of subQ GM-CSF administration, with peak eosinophil and neutrophil enrichment in blood at days 7 and 8, respectively. Corresponding elevations of neutrophils, eosinophils, total CD64⁺ and total CD32⁺ were observed at days 7 and 14 in rectal biopsies, indicating general Fc effector cell accumulation in these animals. Histological evaluations of vaginal biopsies showed myeloid cell infiltration at day 14 of subQ GM-CSF treatment. Further, subQ GM-CSF administration resulted in myeloid cell activation and trafficking, as evidenced by elevated levels of cytokines (CXCL13, MCP-1, IL-1RA). Importantly, neither subQ nor topical GM-CSF administration induced overt systemic inflammation or adverse clinical impacts. Overall, our findings delineate the kinetics of systemic and mucosal myeloid cell expansion, activation and trafficking achieved by subQ GM-CSF administration in RM. These findings will inform the use of GM-CSF as an adjuvant in clinical applications where myeloid cell mobilization is advantageous.