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

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.

Duke Scholars

Author Roger Keith Reeves Surgery, Surgical Sciences

Author Georgia Doris Tomaras Surgery, Surgical Sciences

Author Cordelia Manickam Surgery, Surgical Sciences