Immune-Modifying Microparticles for Treatment of Acute Graft-Versus-Host-Disease 1

Abstract Background: Acute Graft versus host disease (aGVHD) is one of the most common complication of allogeneic hematopoietic stem cell transplant. We have previously shown that infused immune-modifying particles (IMPs) can reduce clinical symptoms and improve survival in inflammatory conditions. IMPs are taken up by inflammatory monocytes (θIM) via the macrophage receptor with collagenous structure (MARCO) and then undergo splenic sequestration. Given these findings, IMPs may be an effective method of reducing inflammation in aGVHD. Methods: We tested the efficacy of IMP in an established aGVHD murine model. We also explored the changes in immune cell subsets and serum cytokines. To assess impact of IMP on graft-versus-tumor (GVT), we infused host mice with A20 lymphoma cells. Results: We demonstrated that treatment with IMPs effectively rescues mice in a lethal aGVHD model. Treatment with IMPs also significantly improved clinical and target organ histopathological scores. IMP treatment resulted in increased splenic and intestinal CD4 +CD25 +Foxp3 +Tregs. IMP treated mice had lower numbers of colonic CD11b +Ly6c hiθIM and a lower peak of serum inflammatory cytokines. Maintenance of GVT effect was demonstrated by comparable survival rates in host mice with co-infusion of A20 lymphoma cells. Conclusion: Systemic IMP was effective at rescuing mice in this lethal aGVHD model. This demonstrates that targeting θIMs with IMPs could be an effective strategy to treat aGVHD. Further investigation of the mechanisms by which IMPs ameliorate aGVHD is warranted, as is investigation of the use of IMPs to treat aGVHD in the clinical setting. Supported by Nanoparticle Tolerance Research Fund