This is a competitive renewal application to further characterize the immunoregulatory function of mesenchymal stem cells (MSCs) in ocular inflammation. Renowned for promoting tissue regeneration and immune quiescence, studies have demonstrated the therapeutic potential of MSCs in human disease. Nevertheless, fundamental questions remain unanswered regarding their immunomodulatory mechanisms. This proposal employs a well-characterized transplant model of the murine cornea to systematically investigate how MSCs directly interact with T cells to suppress alloimmunity. Over recent years the work of several laboratories, including our own, has made substantial progress in understanding how MSCs regulate ocular inflammation. With respect to corneal transplantation, we and others have shown that exogenous administration of MSCs suppresses alloimmunity and promotes graft survival. Reports from our lab provide evidence that MSCs: (i) specifically home to the ocular surface following corneal transplantation, where they act to (ii) limit antigen-presenting cell (APC) maturation, and (iii) decrease graft-destroying IFN? + T helper-1 (Th1) cell responses. Moreover, our preliminary data and reports from other groups indicate that administration of MSCs following transplantation induces Foxp3+ regulatory T cells (Tregs). Despite these observations, the exact mechanisms by which MSCs suppress Th1 generation and induce Tregs are not known. Our preliminary investigations indicate that, in addition to indirect modulation via APCs, MSCs exert a direct immunomodulatory effect on alloreactive T cells. We define 3 specific aims to answer the following questions:
Aim 1 : What are the mechanisms by which MSCs inhibit generation of alloreactive Th1 cells? Aim 2: What are the mechanisms by which MSCs inhibit effector function of alloreactive Th1 cells? And finally Aim 3: How do MSCs promote the generation of tolerance-inducing Tregs? Our preliminary data implicate specific soluble and surface-bound immunoregulatory molecules. Based on these data, we propose 3 hypotheses: (1) MSCs negatively regulate early T cell activation via the surface-bound molecule ALCAM, resulting in decreased generation of Th1 cells; (2) MSC-secreted IL11 suppresses Th1 function by antagonizing IFN? and Tbet expression; and (3) MSCs skew the differentiation of nave T cells toward Foxp3+ Tregs via CD80/CTLA-4 interaction. The principal objective of this project is to define the molecular mechanisms by which MSCs directly interact with T cells to regulate alloimmunity. Given the considerable expense of delivering MSC-based cell therapies, identifying the factors that mediate the immunoregulatory activity of MSCs is a research priority. It is anticipated that completion of these entirely novel aims will elucidate as-yet-unknown mechanisms by which MSCs regulate T cell responses, and may conceivably provide a framework for the development of new therapeutic approaches in transplantation and other T cell-mediated inflammatory disorders.
The tremendous promise of mesenchymal stem cells (MSCs) to regulate inflammation is evident in corneal transplantation, where treatment of graft recipients with MSCs has been shown to decrease immune rejection of the donor tissue. However, the precise mechanisms by which MSCs regulate immune cell responses have not been defined. We propose to determine the cellular and molecular interactions by which MSCs modulate immunity in corneal transplantation, anticipating that improved understanding of these mechanisms will yield therapeutic targets that could be useful not only in tissue grafting but in a wide variety of inflammatory and autoimmune disorders.
| Foulsham, William; Coco, Giulia; Amouzegar, Afsaneh et al. (2018) When Clarity Is Crucial: Regulating Ocular Surface Immunity. Trends Immunol 39:288-301 |
| Mittal, Sharad K; Mashaghi, Alireza; Amouzegar, Afsaneh et al. (2018) Mesenchymal Stromal Cells Inhibit Neutrophil Effector Functions in a Murine Model of Ocular Inflammation. Invest Ophthalmol Vis Sci 59:1191-1198 |
| Mashaghi, Alireza; Hong, Jiaxu; Chauhan, Sunil K et al. (2017) Ageing and ocular surface immunity. Br J Ophthalmol 101:1-5 |
| Amouzegar, Afsaneh; Chauhan, Sunil K (2017) Effector and Regulatory T Cell Trafficking in Corneal Allograft Rejection. Mediators Inflamm 2017:8670280 |
| 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 |
| 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 |
| 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 |
| Mittal, Sharad K; Omoto, Masahiro; Amouzegar, Afsaneh et al. (2016) Restoration of Corneal Transparency by Mesenchymal Stem Cells. Stem Cell Reports 7:583-590 |
| Amouzegar, Afsaneh; Chauhan, Sunil K; Dana, Reza (2016) Alloimmunity and Tolerance in Corneal Transplantation. J Immunol 196:3983-91 |
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