The Therapeutic Effect of Immune-Modifying Microparticles in an Acute Graft-Versus-Host Disease Model

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Introduction Inflammatory monocytes are recruited to target organs during acute Graft versus Host Disease (aGVHD). As seen in other autoimmune disorders, inflammatory monocytes play an important role in antigen presentation and cytokine production. These actions allow for a sustained activation and proliferation signal to T-cells. Objective Previous studies have shown that IMP treatment in mouse models of colitis, encephalitis, myocardial infarction and peritonitis markedly reduced monocyte accumulation in the affected end-organs – promoting tissue repair; reducing disease symptoms and increasing survival. Therefore, our objective was to test clinical outcomes after IMP treatment in a mouse model of aGVHD. Methods Murine aGVHD model: BALB/c mice were given 800 cGy total body irradiation, irradiated BALB/c mice were transplanted with 5 × 106 C57BL/6 bone marrow cells and 1 × 106 C57BL/6 spleen cells via tail vein. IMP treatment: IMPs were made with PLGA (Phosphorex Inc, Hopkinton MA) was administered to the recipient mice (1.4 mg/kg body weight) by IV daily starting from day 5 to day 10 after bone marrow transplantation (BMT). PBS at the same volume was used as vehicle control. In vivo bioluminescence imaging: Mice were given an intraperitoneal injection of luciferin (150 mg/kg body weight) and then anesthetized and imaged using the IVIS Imaging system (Xenogen). Imaging data were analyzed and quantified with Living Image Software (Xenogen). Results IMP treated mice had significantly less severe acute GVHD symptoms (average score of 2.48) than the untreated BM+Sp group (average score 3.96) starting at the time of IMP treatment (days 5-10) and remained with significantly reduced symptoms for the 30 day course (Figure 1). IMP treatment also rescued BM+Sp mice from aGVHD associated mortality with a 30-day overall survival of 62% compared to 4% in the untreated BM+Sp group (Figure 2). Intestinal tissue from the IMP treated mice compared to the BM+Sp mice demonstrated less evidence of aGVHD (an average score of 1.25 and 2.75, respectively). Hepatic tissue from the IMP treated mice compared to the BM+Sp mice demonstrated less evidence of aGVHD (an average score of 1.5 and 2.42, respectively) (Figure 3). IMP treatment also significantly reduced INF-γ levels in the intestinal tissues of treated mice compared to untreated BM+Sp mice. In the mice infused with lymphoma cells (A20-luc), IMP treatment reduced aGVHD symptoms and death while preserving the GVL effect. (Figure 4) Conclusions Our results demonstrate that IMPs significantly reduce symptoms and mortality in a murine model of aGVHD while preserving GVL. The reduction in inflammatory monocytes with IMPs leads to a reduction in inflammatory cytokines, hepatic lymphocyte infiltration and intestinal mucosal denudation. These findings highlight the potential of IMP therapy as a specific and potentially safe treatment in acute GVHD.