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Ann-Charlott Schneider, Ann-Helen Willrodt, Cornelia Halin, Felix Bock; Antibody-mediated ALCAM blockade induces corneal allograft tolerance. Invest. Ophthalmol. Vis. Sci. 2017;58(8):976.
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© ARVO (1962-2015); The Authors (2016-present)
Activated leukocyte cell adhesion molecule (ALCAM) has been implicated in diverse pathophysiological processes, including T cell activation, leukocyte trafficking and (lymph)angiogenesis. Therefore, therapeutic blockade of ALCAM could represent a promising approach for treating immune-mediated inflammatory or vascular disorders. Here we use for the first time a blocking fusion protein (I/F8-Fc) against ALCAM to improve corneal graft survival after high risk keratoplasty.
Using the mouse model of high-risk keratoplasty I/F8-Fc was applied systemically as well as eye drops. The graft outcome was graded weekly for 8 weeks. In addition, induction of regulatory T cells was analysed by FACS analysis on CD4 and FoxP3. Furthermore, using the mouse model suture-induced corneal inflammation the influence of ALCAM blockade on corneal immune cells was assessed by immunofluorescence.
Treatment with I/F8-Fc leads to significant improvement of graft survival after high risk (inflamed/vascularised) keratoplasty up the level of low risk (naïve/avascular) keratoplasty. The frequency of CD4+CD25+FoxP3+ regulatory T cells was significantly increased. In the suture model the amount of CD11c+ dendritic cells was increased after two weeks treatment with I/F8-Fc.
Blockade of the leukocyte adhesion molecule ALCAM can improve graft survival by delaying the regress of antigen presenting cells from the side of transplantation. This leads to the generation of regulatory T cells similar to the amount of T regs found in the normal risk group. Thereby, blockade of ALCAM seems to restore the immune privilege of the cornea. Overall, our findings identify ALCAM as a completely novel therapeutic target for the intervention in (corneal) allograft rejection or other vascular diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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