EMBT 2019 | Immune-modifying micro-particles in an acute graft-versus-host disease model

Acute graft versus host disease (aGvHD) is often a complication of allogenic hematopoietic stem cell transplantation (allo-HSCT). Inflammatory monocytes have shown clinical significance in the pathogenesis of numerous inflammatory diseases, whereby organ infiltration by monocytes may be correlated with the severity of aGvHD. Therefore, targeting inflammatory monocytes may present a new option for the treatment of aGvHD.

On Wednesday 27 March 2019, Oral Session 10 (OS10) took place at the 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE. During that session, Abstract OS10-3 was presented by John Galvin from the University of Illinois Chicago, IL, United States, discussed whether clinical symptoms and mortality may reduce with the administration of IMPs in murine models of aGvHD.

Dr. Galvin explained that biodegradable micro-particles derived from polymers such as poly(lactic-co-glycolic) acid (PLGA), have been shown to be taken up by inflammatory monocytes. These immune-modifying micro-particles (IMPs) divert monocytes from the site of inflammation, instead, they fuse with monocytes and cause apoptotic cell clearance via the spleen.

Methods

Murine aGvHD model:

• Bagg Albino Mice (BALB/c mice) were given 800 cGy total body irradiation
• The irradiated BALB/c mice were transplanted with 5×10⁶C57BL/6 bone marrow cells and 1×10⁶ C57BL/6 spleen cells via tail vein

IMP treatment:

• IMPs were made with an FDA approved copolymer PLGA
• PLGA was administered to the recipient mice (1.4 mg/kg body weight) by IV daily beginning at day 5 to day 10 after bone marrow transplantation (BMT)
• Phosphate-buffered saline (PBS) 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

Results

• Mice treated with IMPs had significantly less aGvHD:
  • Average clinical score 2.48 compared to 3.96 untreated mice
  • IMPs treatment rescued mice from lethal aGvHD: Overall survival (OS) at day 30: 62% in treated mice vs 4% in untreated mice
• Intestinal tissue and hepatic tissue from the IMPs treated demonstrated less evidence of aGvHD
• IMPs treatment reduced INF-y levels and increased numbers of T-regulatory cells in treated mice

Conclusion

Dr. Galvin concluded the session by demonstrating that in murine models, IMPs significantly reduced symptoms and mortality of aGvHD while preserving the graft-versus-tumor effect (GVT). The model also demonstrated a reduction in circulating inflammatory monocytes, as well as a reduction in hepatic lymphocyte infiltration and intestinal mucosal denudation. Dr. Galvin highlighted the potential of using IMP therapy for inhibiting inflammatory monocyte-mediated pathology in aGvHD.