Abstract: TH-OR124

Absence of MFGE8 Promotes Rejection in a Murine Model of Transplant Vasculopathy

Session Information

Category: Transplantation

  • 1701 Transplantation: Basic and Experimental

Authors

  • Brilland, Benoit, CHU d'Angers, Angers, France
  • Thebault, Pamela, CHUM Research Center, Centre Hospitalier de l'Universite de Montreal, Montreal, Ontario, Canada
  • Chassé, Michaël, CHUM Research Center, Centre Hospitalier de l'Universite de Montreal, Montreal, Ontario, Canada
  • Qi, Shijie, CHUM Research Center, Centre Hospitalier de l'Universite de Montreal, Montreal, Ontario, Canada
  • Laplante, Patrick, CHUM Research Center, Centre Hospitalier de l'Universite de Montreal, Montreal, Ontario, Canada
  • Cailhier, Jean-Francois, CHUM Research Center, Centre Hospitalier de l'Universite de Montreal, Montreal, Ontario, Canada
Background

Transplant vasculopathy (TV) is the major cause of long-term allograft dysfunction in renal and heart transplantation. TV is characterized by persistent endothelial and epithelial apoptosis, leading to neointima formation and release of mediators in the microenvironment. Amongst them, we found that Milk Fat Globule Epidermal growth factor-8 (MFG-E8) can reprogram macrophages from a pro-inflammatory to a pro-repair phenotype. We hypothesize that MFG-E8 from the allograft is crucial to dampen local and systemic inflammation; attenuating the initial pro-inflammatory macrophage program resulting in better transplant outcomes.

Methods

We used a filly mismatched murine aortic transplant model. Abdominal aorta from MFG-E8 KO and WT mice (C57BL/6J background) were transplanted into Balb/C recipients. Following transplantation, each group received MFG-E8 or vehicle (PBS) twice a week. 4 groups (8-10 mice in each) were constituted (KO+PBS, KO+MFG-E8, WT+PBS, WT+MFG-E8). Isografts were performed between Balb/C mice as control.
Intimal proliferation of the transplant was evaluated at week 9. Leukocyte phenotypes and activation status were assessed by flow cytometry, weekly in blood and at week nine in spleen. Variation overtime was evaluated using mixed linear models to account for repeated measurement and time effect when appropriate.

Results

At week nine, intimal proliferation was higher in the KO+PBS group than in all the others groups. CD8+ T cell activation in spleen was higher in the KO+PBS group compared with the KO+MFG-E8 and with the WT+PBS.
In circulating blood, the variations over time of activated CD4+ T cells, regulatory T cells, B cells and plasmablasts were significantly different between groups.

Conclusion

The absence of MFG-E8 is associated with increased intimal proliferation in the transplant, increased activation of T cells in spleen and significant variation of T and B cells subpopulation in circulating blood. The addition of recombinant MFG-E8 dampened this proliferation and activation.

Funding

  • Private Foundation Support