NEUROIMMUNOMODULATION WITHIN THE EYE

Summary

Principal Investigator: Andrew W Taylor
Affiliation: Boston University
Country: USA
Abstract: The eye normally possesses a unique physiological adaptation that regionally modifies the expression of immunity. This physiological adaptation is part of ocular immune privilege. The physiological role of immune privilege is to impart upon the eye immune protection that avoids the destructive side effects of immunogenic inflammation. Immunogenic inflammation associated with delayed hypersensitivity reactions can grossly distort the visual axis resulting in blindness. Consequently, immune protection within the eye involves a selective deficiency of delayed type hypersensitivity T-cells. To control immunogenic inflammation, the cells and neurons within the ocular microenvironment produce immunomodulating factors that regionally suppress T-cell inflammatory-mediating activities. A biochemical examination of aqueous humor has shown that some of its immunosuppressive activity is associated with alpha-melanocyte stimulating hormone (alpha-MSH). Through alpha-MSH, aqueous humor suppresses IFN-gamma production but promotes proliferation of TGF-beta-producing effector T cells. These effector T cells act as regulatory T cells in that they can suppress immunogenic inflammation mediated by other inflammatory T cells. Moreover, if such regulatory T cells respond specifically to ocular autoantigens, they can suppress the severity and incidence of autoimmune retinitis. The induction of regulatory T cells is a result of alpha-MSH influencing the ability of antigen presenting cells (APC) to activate T cells and directly on T cells responding to presented antigen. It is our plan to characterize the effects of alpha-MSH on the mechanisms of T cell activation. We will also test the possibility that an injection of either alpha-MSH itself or alpha-MSH-induced regulatory T cells can suppress the incidence and severity of ocular autoimmune disease. The results of this project will allow us to understand the molecular and cellular features of immunity within the normal eye. By understanding the activity of intraocular immunomodulatory factors, such as alpha-MSH, it will be possible to induce an immune response that promotes the elimination of pathogens and tumors without the blinding consequences of immunogenic inflammation, that prevents or cures autoimmune diseases of the eye, and that promotes success of corneal, retinal and other tissue transplants.
Funding Period: 1995-04-01 - 2006-11-30
more information: NIH RePORT

Top Publications

  1. pmc Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice
    Darren J Lee
    Department of Ophthalmology, Boston University School of Medicine, Boston, MA 02118
    J Immunol 191:4103-11. 2013
  2. pmc The neuropeptides α-MSH and NPY modulate phagocytosis and phagolysosome activation in RAW 264.7 cells
    Toan A Phan
    Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA
    J Neuroimmunol 260:9-16. 2013
  3. pmc Following EAU recovery there is an associated MC5r-dependent APC induction of regulatory immunity in the spleen
    Darren J Lee
    Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    Invest Ophthalmol Vis Sci 52:8862-7. 2011
  4. pmc The alpha-melanocyte stimulating hormone induces conversion of effector T cells into treg cells
    Andrew W Taylor
    Department of Ophthalmology, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
    J Transplant 2011:246856. 2011
  5. pmc Ocular immune privilege in the year 2010: ocular immune privilege and uveitis
    Andrew W Taylor
    Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, USA
    Ocul Immunol Inflamm 18:488-92. 2010
  6. pmc Inflammatory cytokines in eyes with uveal melanoma and relation with macrophage infiltration
    Long V Ly
    Departments of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
    Invest Ophthalmol Vis Sci 51:5445-51. 2010
  7. ncbi Ocular immune privilege
    A W Taylor
    Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
    Eye (Lond) 23:1885-9. 2009
  8. pmc Diminishment of alpha-MSH anti-inflammatory activity in MC1r siRNA-transfected RAW264.7 macrophages
    Dayu Li
    Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114, USA
    J Leukoc Biol 84:191-8. 2008
  9. pmc The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) therapy
    Andrew W Taylor
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
    Brain Behav Immun 22:639-46. 2008
  10. ncbi In vitro generated autoimmune regulatory T cells enhance intravitreous allogeneic retinal graft survival
    Tat Fong Ng
    Schepens Eye Research Institute, Boston, MA 02114, USA
    Invest Ophthalmol Vis Sci 48:5112-7. 2007

Scientific Experts

  • A W Taylor
  • Darren J Lee
  • Tat Fong Ng
  • D J Biros
  • Nobuyoshi Kitaichi
  • Toan A Phan
  • Norikuni Kawanaka
  • Long V Ly
  • Pedram Hamrah
  • Chun H Lau
  • D J Lee
  • Dayu Li
  • M Reza Dana
  • Joan Stein-Streilein
  • Linling Shen
  • Parisa Zamiri
  • Inge H G Bronkhorst
  • Johannes Vrolijk
  • Gregorius P M Luyten
  • Martine J Jager
  • Mieke Versluis
  • Els van Beelen
  • Zdenka Haskova
  • Bruce R Ksander
  • Qiang Zhang
  • Erin Lavik
  • Hiroshi Keino
  • Robert S Langer
  • Michael J Young
  • Stefano Barabino
  • Sharmila Masli
  • K Namba
  • J Wayne Streilein
  • Kenichi Namba

Detail Information

Publications24

  1. pmc Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice
    Darren J Lee
    Department of Ophthalmology, Boston University School of Medicine, Boston, MA 02118
    J Immunol 191:4103-11. 2013
    ....
  2. pmc The neuropeptides α-MSH and NPY modulate phagocytosis and phagolysosome activation in RAW 264.7 cells
    Toan A Phan
    Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA
    J Neuroimmunol 260:9-16. 2013
    ..This suppression corresponds to neuropeptide modulation of macrophage functionality within the ocular microenvironment to suppress the activation of immunogenic inflammation...
  3. pmc Following EAU recovery there is an associated MC5r-dependent APC induction of regulatory immunity in the spleen
    Darren J Lee
    Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    Invest Ophthalmol Vis Sci 52:8862-7. 2011
    ..Therefore, the authors investigated whether dependence on the expression of MC5r was with the T cells or with the APCs mediating protective regulatory immunity in the EAU-recovered mouse spleen...
  4. pmc The alpha-melanocyte stimulating hormone induces conversion of effector T cells into treg cells
    Andrew W Taylor
    Department of Ophthalmology, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
    J Transplant 2011:246856. 2011
    ..Therefore, α-MSH converts effector T cells into Treg cells, which suppress immunity targeting specific antigens and tissues...
  5. pmc Ocular immune privilege in the year 2010: ocular immune privilege and uveitis
    Andrew W Taylor
    Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, USA
    Ocul Immunol Inflamm 18:488-92. 2010
    ..It may be idiopathic or associated with systemic disease or infection. Understanding the biochemistry of immune privilege has the potential to identify its weaknesses that allow for immunity to break through...
  6. pmc Inflammatory cytokines in eyes with uveal melanoma and relation with macrophage infiltration
    Long V Ly
    Departments of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
    Invest Ophthalmol Vis Sci 51:5445-51. 2010
    ..This study was conducted to determine whether the aqueous humor (AqH) from eyes with uveal melanoma contains inflammatory cytokines and whether their presence is associated with inflammation...
  7. ncbi Ocular immune privilege
    A W Taylor
    Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
    Eye (Lond) 23:1885-9. 2009
    ..Success in translating the lessons of ocular immune privilege to other tissues has the potential to drastically change the therapy and clinical outcomes of autoimmune diseases and allograft survival...
  8. pmc Diminishment of alpha-MSH anti-inflammatory activity in MC1r siRNA-transfected RAW264.7 macrophages
    Dayu Li
    Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114, USA
    J Leukoc Biol 84:191-8. 2008
    ..The results imply that although all of the MCr are G-coupled proteins, they may not necessarily function through the same intracellular pathways in macrophages...
  9. pmc The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) therapy
    Andrew W Taylor
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
    Brain Behav Immun 22:639-46. 2008
    ....
  10. ncbi In vitro generated autoimmune regulatory T cells enhance intravitreous allogeneic retinal graft survival
    Tat Fong Ng
    Schepens Eye Research Institute, Boston, MA 02114, USA
    Invest Ophthalmol Vis Sci 48:5112-7. 2007
    ..They examined the possibility of using these ocular autoantigen-specific Treg cells to promote the survival of a retinal allograft placed in the mouse vitreous...
  11. ncbi Alpha-MSH regulates protein ubiquitination in T cells
    D J Biros
    The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
    Cell Mol Biol (Noisy-le-grand) 52:33-8. 2006
    ..Our results demonstrate that one of the mechanisms by which alpha-MSH regulates T cell activity is through mediating a change in the pattern of protein ubiquitination in T cells...
  12. ncbi Melanocortin 5 receptor and ocular immunity
    A W Taylor
    Schepens Eye Research Institute and the Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
    Cell Mol Biol (Noisy-le-grand) 52:53-9. 2006
    ..However, protection of the retina from the inflammatory damage of EAU and the induction of ocular autoantigen-responsive CD4+ Treg cells in the post EAU spleen requires expression of MC5r...
  13. ncbi Pigment epithelial growth factor suppresses inflammation by modulating macrophage activation
    Parisa Zamiri
    Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Invest Ophthalmol Vis Sci 47:3912-8. 2006
    ....
  14. ncbi An eye's view of T regulatory cells
    Joan Stein-Streilein
    Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
    J Leukoc Biol 81:593-8. 2007
    ..The purpose of this mini-review is to condense and summarize reports of Treg cells dependent on the eye in the context of the Treg literature in general...
  15. ncbi Ocular immunosuppressive microenvironment
    Andrew W Taylor
    Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA
    Chem Immunol Allergy 92:71-85. 2007
    ..This ocular system of immunoregulation and immunosuppression through alpha-MSH not only suppresses immunogenic inflammation, but also actively manipulates immunity to make the immune response itself immunosuppressive...
  16. ncbi Creating an immune-privileged site using retinal progenitor cells and biodegradable polymers
    Tat Fong Ng
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, Massachusetts 02114, USA
    Stem Cells 25:1552-9. 2007
    ..This technology may be used to promote the survival of nonprivileged grafts (e.g., pancreas, liver, or skin). Disclosure of potential conflicts of interest is found at the end of this article...
  17. ncbi Effect of the ocular microenvironment in regulating corneal dendritic cell maturation
    Linling Shen
    Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA
    Arch Ophthalmol 125:908-15. 2007
    ..To determine whether the ocular anterior segment (aqueous humor and cornea) actively inhibits dendritic cell (DC) maturation...
  18. pmc Localized retinal neuropeptide regulation of macrophage and microglial cell functionality
    Norikuni Kawanaka
    Schepens Eye Research Institute and the Department of Ophthalmology Harvard Medical School, United States
    J Neuroimmunol 232:17-25. 2011
    ..Similar co-expressing cells were found within healthy, but not in wounded retinas. Therefore, the healthy retina regulates macrophage functionality to the benefit of ocular immune privilege...
  19. pmc Injection of an alpha-melanocyte stimulating hormone expression plasmid is effective in suppressing experimental autoimmune uveitis
    D J Lee
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, USA
    Int Immunopharmacol 9:1079-86. 2009
    ..We evaluated the potential to suppress ocular autoimmune disease (uveitis) by augmenting the expression of alpha-MSH through subconjunctival injections of naked adrenocorticotropic hormone amino acids 1-17 (ACTH1-17) plasmid...
  20. pmc Applications of the role of α-MSH in ocular immune privilege
    Andrew W Taylor
    Schepens Eye Research Institute, Boston, MA 02114, USA
    Adv Exp Med Biol 681:143-9. 2010
    ....
  21. doi The immune privileged retina mediates an alternative activation of J774A.1 cells
    Chun H Lau
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02116, USA
    Ocul Immunol Inflamm 17:380-9. 2009
    ..We further assessed the possibility that the RPE is alternatively activating macrophages...
  22. pmc Local treatment with alpha-melanocyte stimulating hormone reduces corneal allorejection
    Pedram Hamrah
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
    Transplantation 88:180-7. 2009
    ..The purpose of this study was to determine the role of local therapy with alpha-MSH on corneal allograft survival, and the mechanisms by which it may influence graft outcome...
  23. pmc Review of the activation of TGF-beta in immunity
    Andrew W Taylor
    Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114, USA
    J Leukoc Biol 85:29-33. 2009
    ..A mechanistic understanding of the process activating TGF-beta can lead to regulating multiple biological systems by enhancing or inhibiting TGF-beta activation...
  24. pmc Inducible immune regulation following autoimmune disease in the immune-privileged eye
    Nobuyoshi Kitaichi
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
    J Leukoc Biol 77:496-502. 2005
    ....