Integrin Alpha 9 Blockade Suppresses Lymphatic Valve Formation and Promotes Transplant Survival.
OBJECTIVE
The lymphatic pathway mediates transplant rejection. We recently reported that lymphatic vessels develop luminal valves in the cornea during lymphangiogenesis, and these valves express integrin alpha 9 (Itga-9) and play a critical role in directing lymph flow. In this study, we used an allogeneic corneal transplantation model to investigate whether Itga-9 blockade could suppress valvulogenesis after transplantation, and how this effect would influence the outcomes of the transplants.


METHODS
Orthotopic corneal transplantation was performed between fully mismatched C57BL/6 (donor) and BALB/c (recipient) mice. The recipients were randomized to receive subconjunctival injections of either Itga-9 blocking antibody or isotype control twice a week for 8 weeks. Corneal grafts were assessed in vivo by ophthalmic slit-lamp biomicroscopy and analyzed using Kaplan-Meier survival curves. Additionally, whole-mount full-thickness corneas were evaluated ex vivo by immunofluorescent microscopy on both lymphatic vessels and valves.


RESULTS
Anti-Itga-9 treatment suppressed lymphatic valvulogenesis after transplantation. Our treatment did not affect lymphatic vessel formation or their nasal polarized distribution in the cornea. More importantly, Itga-9 blockade led to a significant promotion of graft survival.


CONCLUSIONS
Lymphatic valvulogenesis is critically involved in transplant rejection. Itga-9 targeting may offer a new and effective strategy to interfere with the immune responses and promote graft survival.
Vision Science Graduate Group, University of California, Berkeley, California, United States 2Center for Eye Disease and Development, Program in Vision Science and School of Optometry, University of California, Berkeley, California, United States.
Gyeong Jin
GJ
Kang
Vision Science Graduate Group, University of California, Berkeley, California, United States 2Center for Eye Disease and Development, Program in Vision Science and School of Optometry, University of California, Berkeley, California, United States.
Tan
T
Truong
Vision Science Graduate Group, University of California, Berkeley, California, United States 2Center for Eye Disease and Development, Program in Vision Science and School of Optometry, University of California, Berkeley, California, United States.
Eric
E
Huang
Vision Science Graduate Group, University of California, Berkeley, California, United States 2Center for Eye Disease and Development, Program in Vision Science and School of Optometry, University of California, Berkeley, California, United States.
Valerie
V
Su
Vision Science Graduate Group, University of California, Berkeley, California, United States 2Center for Eye Disease and Development, Program in Vision Science and School of Optometry, University of California, Berkeley, California, United States.
Shaokui
S
Ge
Vision Science Graduate Group, University of California, Berkeley, California, United States 2Center for Eye Disease and Development, Program in Vision Science and School of Optometry, University of California, Berkeley, California, United States.
Lu
L
Chen
D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D016510:Corneal Neovascularization / Q000188:drug therapy* / Q000276:immunology; D016039:Corneal Transplantation; D004195:Disease Models, Animal; D039001:Integrin alpha Chains / Q000037:antagonists & inhibitors* / Q000276:immunology; D053208:Kaplan-Meier Estimate; D042583:Lymphangiogenesis / Q000276:immunology*; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011897:Random Allocation
D057134:Antibodies, Neutralizing; D039001:Integrin alpha Chains; C084613:integrin alpha9