Patients suffering from ocular injury and inflammation are at risk for development of chronic uncontrolled immune activation and tissue injury. Many of these conditions are commonly treated with non-specific anti- inflammatory drugs such as corticosteroids, which non-discriminately suppress host immunity, including both pathogenic and regulatory cells of the immune system. There is thus a pressing need for developing more effective and safe immunomodulatory strategies which not only downregulate specific pathogenic immune cells, but importantly also promote regulatory immune cells, namely myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). Interestingly, non-hematopoietic bone marrow-derived mesenchymal stem cells (BM-MSC) have shown significant immunomodulatory promise. Our preliminary studies demonstrate that BM- MSC can indeed promote MDSC and Treg function, and can be used to reestablish immune quiescence in ocular inflammation. However, very little is known regarding the mechanisms by which BM-MSC promote the function of these immunoregulatory cells. We specifically hypothesize that BM-MSC (i) skew differentiation of immature myeloid progenitor cells toward MDSC and away from macrophages; and (ii) provide direct support for Treg function via both cell-to-cell contact and paracrine mechanisms. To validate these hypotheses, we propose to pursue two specific aims:
In Aim 1, we will define the mechanisms by which BM-MSC promote generation of myeloid-derived suppressor cells and control ocular inflammation. We will specifically investigate i) which functional subset of MDSC is promoted by BM-MSC; and ii) determine BM-MSC-expressed factors that promote MDSC generation.
In Aim 2 we plan to determine the mechanisms by which BM-MSC directly enhance regulatory T cell function. In particular, we will investigate i) how BM-MSC-secreted hepatocyte growth factor promotes Treg function; and ii) the BMMSC cell surface-expressed molecules that promote Treg function through cell-cell interactions. The methodology we propose has been designed to utilize our laboratory's expertise in immunological assays along with a well-characterized murine cornea model of transplant-induced ocular inflammation and immunity. We anticipate that delineation of the mechanisms by which BM-MSC control ocular inflammation will identify critical immunomodulatory factors which can be utilized to develop new therapeutic strategies. The overall impact of this research will be significant, given the high prevalence of ocular inflammatory disorders and the potential benefit of therapeutic strategies that promote immunoregulatory cells while also inhibiting pathogenic immune cells.

Public Health Relevance

Millions of Americans suffer each year from ocular inflammatory disorders for which there are currently limited therapeutic options that are both safe and effective. Mesenchymal stem cells are adult stem cells that possess extraordinary capacity to modulate tissue inflammation and regeneration. The aim of this project is to determine the mechanisms and factors by which mesenchymal stem cells regulate the immune response in inflamed ocular tissues, and in so doing, identify novel therapeutic strategies for more effective and safe treatment of ocular inflammatory disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024602-04
Application #
9457462
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Schepens Eye Research Institute
Department
Type
DUNS #
073826000
City
Boston
State
MA
Country
United States
Zip Code
02114
Ji, Y W; Mittal, S K; Hwang, H S et al. (2017) Lacrimal gland-derived IL-22 regulates IL-17-mediated ocular mucosal inflammation. Mucosal Immunol 10:1202-1210
Amouzegar, Afsaneh; Mittal, Sharad K; Sahu, Anuradha et al. (2017) Mesenchymal Stem Cells Modulate Differentiation of Myeloid Progenitor Cells During Inflammation. Stem Cells 35:1532-1541
Omoto, Masahiro; Suri, Kunal; Amouzegar, Afsaneh et al. (2017) Hepatocyte Growth Factor Suppresses Inflammation and Promotes Epithelium Repair in Corneal Injury. Mol Ther 25:1881-1888
Mashaghi, Alireza; Hong, Jiaxu; Chauhan, Sunil K et al. (2017) Ageing and ocular surface immunity. Br J Ophthalmol 101:1-5
Foulsham, William; Coco, Giulia; Amouzegar, Afsaneh et al. (2017) When Clarity Is Crucial: Regulating Ocular Surface Immunity. Trends Immunol :
Dohlman, Thomas H; Ding, Julia; Dana, Reza et al. (2017) T Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Contributes to Dry Eye Disease Pathogenesis by Promoting CD11b+ Myeloid Cell Maturation and Migration. Invest Ophthalmol Vis Sci 58:1330-1336
Amouzegar, Afsaneh; Chauhan, Sunil K; Dana, Reza (2016) Alloimmunity and Tolerance in Corneal Transplantation. J Immunol 196:3983-91
Mittal, Sharad K; Omoto, Masahiro; Amouzegar, Afsaneh et al. (2016) Restoration of Corneal Transparency by Mesenchymal Stem Cells. Stem Cell Reports 7:583-590
Singh, Vivek; Shukla, Sachin; Ramachandran, Charanya et al. (2015) Science and Art of Cell-Based Ocular Surface Regeneration. Int Rev Cell Mol Biol 319:45-106