Myeloid Cell-Targeting PLGA Nanoparticles Ameliorate Acute Graft-Versus-Host Disease

Area of Science:

• Immunology
• Transplantation Biology
• Nanomedicine

Background:

• Graft-versus-host disease (GVHD) is a severe complication following allogeneic hematopoietic stem cell transplant.
• Current GVHD treatments face limitations including steroid toxicity, broad immunosuppression, and potential suppression of the graft-versus-tumor (GVT) effect.
• Immune-modifying microparticles (IMPs) composed of carboxylated poly-lactic-co-glycolic acid have previously shown efficacy in inflammatory conditions by targeting monocytes via the MARCO receptor.

Purpose of the Study:

• To investigate the potential of systemically infused IMPs to mitigate acute GVHD manifestations.
• To evaluate the therapeutic efficacy and underlying mechanisms of IMPs in a murine model of GVHD.
• To assess the impact of IMPs on GVT activity.

Main Methods:

• Acute GVHD was induced in an MHC-mismatched murine transplant model.
• Mice received daily infusions of IMPs or saline control for five days.
• Outcomes assessed included organ histopathology, immune cell populations (spleen, intestine), serum cytokine levels, and GVT effect in a lymphoma model.

Main Results:

• IMP treatment significantly improved clinical GVHD scores, histopathology, and survival rates compared to controls.
• IMP-treated mice exhibited increased regulatory T-cells and decreased colonic inflammatory monocytes and pro-inflammatory cytokines (IL-6, IFN-γ).
• Therapeutic effects were dependent on MARCO receptor expression, and importantly, GVT activity was preserved, leading to improved survival in a lymphoma model.

Conclusions:

• Systemic administration of IMPs effectively reduces GVHD severity and enhances survival.
• The mechanism involves MARCO-mediated reduction of inflammatory monocytes and expansion of regulatory T-cells.
• IMPs represent a promising targeted therapy for GVHD, maintaining crucial GVT activity.