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Integrin alpha 9 blockade suppresses lymphatic valve formation and promotes transplant survival

A technology of lymphatic vessels and integrins, which is applied in the field of LG pharmaceuticals and corneal flap generation in mammals, can solve the problems of less treatment of lymphatic vessel diseases and so on.

Pending Publication Date: 2019-07-05
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, few treatments currently exist for lymphatic disease

Method used

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  • Integrin alpha 9 blockade suppresses lymphatic valve formation and promotes transplant survival
  • Integrin alpha 9 blockade suppresses lymphatic valve formation and promotes transplant survival
  • Integrin alpha 9 blockade suppresses lymphatic valve formation and promotes transplant survival

Examples

Experimental program
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Effect test

Embodiment 1

[0207] summary

[0208] Objective. Lymphatic pathway mediates transplant rejection. We recently reported that lymphatic vessels develop luminal flaps in the cornea during lymphangiogenesis, and that these flaps express integrin alpha 9 (Itga-9) and play a key role in directing lymphatic flow. In this study, we used an allogeneic keratoplasty model to investigate whether blockade of Itga-9 could inhibit flap formation after transplantation and how this effect would affect graft outcome.

[0209] Methods. Orthotopic corneal transplantation was performed between fully mismatched C57BL / 6 (donor) and BALB / c (recipient) mice. Recipients were randomized to receive subconjunctival injections of Itga-9 blocking antibody or an isotype control twice weekly for 8 weeks. Corneal grafts were evaluated in vivo by ophthalmic slit lamp biomicroscopy and analyzed using Kaplan-Meier survival curves. Additionally, full-thickness corneas were evaluated in vitro by immunofluorescence microscopy ...

Embodiment 2

[0245] Further studies showed that combined blockade of ltga-9 and VEGFR-3 inhibited lymphatic valve and tube formation after high-risk keratoplasty (Fig. 6, tubes and valves are shown in green) and promoted graft survival ( Figure 6B , Kaplan-Meier survival curve).

Embodiment 3

[0247] Aim. We recently reported that corneal lymphatic vessels develop integrin alpha-9 (Itga-9) positive flaps during inflammatory lymphangiogenesis. The purpose of this study was to further investigate the role of Itga-9 in corneal lymphatic flap formation in vivo and lymphatic endothelial cell (LEC) function in vitro.

[0248] Methods. A standard murine suture placement model was used to study the effect of Itga-9 blockade on lymphatic flap formation in vivo using an Itga-9 neutralizing antibody. Whole corneas were collected for immunofluorescence microscopy analysis. Additionally, the human skin LEC culture system was used to examine the effect of Itga-9 gene knockdown on cell function using small interfering RNA (siRNA).

[0249] Results. Blockade of Itga-9 significantly reduced the number of lymphatic flaps formed in the inflamed cornea in vivo. Furthermore, Itga-9 knockdown in human LECs suppresses the cellular functions of proliferation, adhesion, migration, and tub...

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Abstract

In certain embodiments, the present invention provides methods of suppressing valvulogenesis (VG) in a lymphatic vessel in an inflamed or transplanted tissue or organ in a mammal in need thereof comprising administering an effective amount of an anti-integrin alpha 9 (Itga-9) therapeutic agent to the mammal, and optionally by administering VEGFR-3.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 62 / 413,863, filed October 27, 2016. The entire content of the above-mentioned application is hereby incorporated by reference herein. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with government support under EY017392 awarded by the National Institutes of Health and W81XWH-14-1-0496 awarded by the Department of Defense. The government has certain rights in the invention. [0005] Background of the invention [0006] The lymphatic network permeates most tissues and its dysfunction is associated with a wide range of conditions such as cancer metastasis, inflammation, transplant rejection, hypertension, obesity and lymphedema. After being neglected for centuries due to historical reasons and technical limitations, the study of lymphatic vessels has gained significant attention and significant progress in recent ye...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61B90/00A61B5/00
CPCC07K16/2839A61K2039/505C07K2317/73C07K2317/76A61P17/00A61P27/02A61P37/06A61P43/00A61K9/0019A61K9/0048A61K45/06C07K2317/54C07K2317/56C12N15/113C12N2310/14
Inventor 陈璐
Owner RGT UNIV OF CALIFORNIA
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