This is a competitive renewal application to further characterize the molecular and cellular facets of host immunity in high-risk corneal transplants, distinguished by their rapid and high-frequency rejection. The goal of these studies is to gain new insights into the mechanisms that distinguish high-risk vs. low-risk transplant immunity. Our overarching hypothesis is that high-risk corneal grafts are characterized by a microenvironment which at once abrogates the tolerogenic potential of corneal antigen-presenting cells while also rendering the host regulatory T cells dysfunctional. To test this concept, we have generated specific hypotheses: 1. The subverted immune homeostasis in high-risk grafts can be restored by (a) expansion of host regulatory T cells (Tregs) through enhanced CD25/IL-2R signaling (Aim 1), and (b) generation of tolerogenic antigen-presenting cells in the graft (Aim 2);and 2. The defective Treg function in high-risk grafts overrides the physiologic angiogenic privilege of the cornea, thus further amplifying the immune response against the graft (Aim 3). To test these specific hypotheses, we will pursue the following specific aims:
In Aim 1 A, we will investigate the differential frequencies and functional characteristics of 'natural'and 'induced'Tregs in low- and high-risk grafts, and determine the molecular bases for Treg dysfunction that we have established in high-risk transplants.
In Aim 1 B we will determine the efficacy of amplified CD25 signaling through low-dose interleukin-2 treatment in expanding and restoring Treg function in high-risk grafted hosts.
In Aim 2 we plan to continue our work enriching corneal donor buttons with tolerogenic antigen-presenting cells (tolAPC) through ex vivo conditioning, and to determine the effect of transplanting these tolAPC-enriched grafts on host sensitization, Treg frequency and function, and high-risk graft survival.
In Aim 3 we will evaluate the contribution of adaptive T cell-mediated immunity to corneal angiogenesis and lymphangiogenesis by comparing the function of effector T helper-1 cells vs. Tregs in abrogating vs. promoting corneal angiogenic privilege. Our study design relies on using the expertise of our laboratory along with use of well-characterized mouse models of corneal transplantation in conjunction with in vitro immunological and cell proliferation assays, and use of transgenic mice permitting us to monitor the differentiation and fate of Tregs so as to gain mechanistic insights into the molecular regulation of corneal alloimmunity. The overall health relevance of this research is that corneal grafting represents the number one form of transplantation performed in the United States. However, while most high-risk corneal transplant patients rapidly reject their grafts, there has been no significant change in the management or prognosis of high-risk transplantation in decades. The long-term objective is to use the data derived from these aims to develop new strategies to promote high-risk graft acceptance without the use of systemic immunosuppressive regimens which can be highly toxic.

Public Health Relevance

High-risk corneal transplantation, performed in inflamed host graft beds, is characterized by swift and often irreversible immune rejection. While tens of thousands of these are performed annually on a global basis, there has been no significant change in the prognosis of high-risk grafts for decades. This grant proposes to study the mechanisms that are involved in induction of immunity to high-risk corneal transplants and develop novel strategies to promote tolerance and long-term survival of these grafts without use of toxic immunosuppressive medications.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01EY012963-15
Application #
8629851
Study Section
(DPVS)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Schepens Eye Research Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02114
Tahvildari, Maryam; Omoto, Masahiro; Chen, Yihe et al. (2016) In Vivo Expansion of Regulatory T Cells by Low-Dose Interleukin-2 Treatment Increases Allograft Survival in Corneal Transplantation. Transplantation 100:525-32
Inomata, Takenori; Hua, Jing; Di Zazzo, Antonio et al. (2016) Impaired Function of Peripherally Induced Regulatory T Cells in Hosts at High Risk of Graft Rejection. Sci Rep 6:39924
Di Zazzo, Antonio; Tahvildari, Maryam; Subbarayal, Brinda et al. (2016) Proangiogenic Function of T Cells in Corneal Transplantation. Transplantation :
Hua, Jing; Stevenson, William; Dohlman, Thomas H et al. (2016) Graft Site Microenvironment Determines Dendritic Cell Trafficking Through the CCR7-CCL19/21 Axis. Invest Ophthalmol Vis Sci 57:1457-67
Dohlman, Thomas H; Di Zazzo, Antonio; Omoto, Masahiro et al. (2016) E-Selectin Mediates Immune Cell Trafficking in Corneal Transplantation. Transplantation 100:772-80
Hattori, Takaaki; Takahashi, Hiroki; Dana, Reza (2016) Novel Insights Into the Immunoregulatory Function and Localization of Dendritic Cells. Cornea 35 Suppl 1:S49-S54
ÄŒrnej, Alja; Omoto, Masahiro; Dohlman, Thomas H et al. (2016) Effect of Penetrating Keratoplasty and Keratoprosthesis Implantation on the Posterior Segment of the Eye. Invest Ophthalmol Vis Sci 57:1643-8
Amouzegar, Afsaneh; Chauhan, Sunil K; Dana, Reza (2016) Alloimmunity and Tolerance in Corneal Transplantation. J Immunol 196:3983-91
Mashaghi, Alireza; Marmalidou, Anna; Tehrani, Mohsen et al. (2016) Neuropeptide substance P and the immune response. Cell Mol Life Sci 73:4249-4264
Chauhan, Sunil K; Lee, Hyung Keun; Lee, Hyun Soo et al. (2015) PTK7+ Mononuclear Cells Express VEGFR2 and Contribute to Vascular Stabilization by Upregulating Angiopoietin-1. Arterioscler Thromb Vasc Biol 35:1606-15

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