Abstract
Purpose :
Dendritic cells are the most potent antigen presenting cells and are crucial in the induction of allo-sensitization. Lymphatic vessel are the main route for exit of antigen presenting cells from sensitized tissues and are known to be a main risk factor for corneal graft rejection. Dendritic cells, amongst others, interact with the lymphatic endothelial cells, amongst others, via the hyaluronan glyocalyx on the DCs and the hyaluronan receptor Lyve-1 on the LECs. The purpose of this study was to analyze whether a specific blockade of this interaction leads to less corneal DC emigration under inflammation.
Methods :
Three different anti-Lyve-1 antibodies, B1/10, mAb2125 and C1/8, were compared. We used the murine models of suture-induced corneal neovascularization in combination with the intrastromal application of FITC-dextran to analyze the emigration of CD103+Fitc dextran+ DCs by flow cytometry 24h after suture placement. The effect on the growth of blood and lymphatic vessels was assessed by immune fluorescence of CD31 and Lyve-1 positive vessels 14 days after suture placement. To analyze corneal graft survival we used the mouse model of high risk corneal transplantation. After eight weeks, immune cells including CD4+CD25+FoxP3+ T regs in the draining lymph nodes were quantified by flow cytometry.
Results :
We could show that the trafficking of corneal DCs to the draining lymph nodes was impaired by the LYVE-1 mAbs to different degrees with the C1/8 being the most potent one. 2 weeks after corneal transplantation, again the LYVE-1 mAb C1/8 inhibited corneal lymphangiogenesis most effectively. Also, corneal graft survival and the generation of Tregs after 8 weeks was most potently induced by the C1/8 antibody.
Conclusions :
Here we show that the lymphatic hyaluronan receptor Lyve-1 regulates the emigration of dendritic cells from inflamed corneas and is thereby a key factor for the induction of corneal graft rejection. With this new approach, avascular graft survival could be improved not only in the cornea but possibly in other tissues also.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.