REGULATION OF ACIAD BY LYMPHOCYTES WITH NK MARKERS

Summary

Principal Investigator: Joan Stein-Streilein
Affiliation: Harvard University
Country: USA
Abstract: Immunologists have known for decades that immunity is the result of the various contributions of cell-mediated and antibody-mediated responses. Within recent years the dichotomy of possible immune responses has been further defined by the knowledge that T helper cells can adopt one of two polar types of reactivity: T helper 1 (Th1) and T helper 2 (Th2). These counter responses can be differentiated by differences in the phenotype of cytokines (Th1, IFNgamma; Th2, IL4, IL10) and isotypes of antibodies (Th1: IgG2a; Th2: IgG1, IgE) they make. Th1 responses are associated with inflammation, while Th2 responses are associated with inflammation, while Th2 responses associated with hypersensitivity and protection against parasitic invasion. Because these two polar responses cross regulate each other it is possible that Th2 responses might be important in the prevention of inflammation in various organs including the eye. Apparently, in the health eye, it is very difficult to induce a Th1 response because of an unusual local regulatory mechanism in the anterior chamber. This research proposal will study the ocular regulatory mechanism known as Anterior Chamber Associated Immune Deviation (ACAID). ACAID is relevant to the up-regulation of Th2 responses and the down regulation of Th1 responses, i.e. inflammation, thereby preserving sight. In an animal model antigenic materials that are placed in the anterior chamber (a.c.) Of the eye evoke a systemic immune response that is distinctly unusual in there is a selective deficiency of delayed-type hypersensitivity (DTH, an indicator of a Th1, response). While this model is well studied, no one has looked at early mechanisms that might be invoked to produce and maintain an ocular Th2 response. We propose that two distinct subpopulations of lymphocytes expressing natural killer (NK) antigens may participate in the early regulation of the polar responses to antigens inoculated into the anterior chamber. Recent data from our laboratory show that ACID does not develop in CD1 deficient mice. This application will exploit this observation by studying the mechanisms and interaction of NKT cells and CD1. We will use a variety of methods to test the hypotheses including flow cytometry with simultaneous labeling of intracellular cytokines and surface markers, morphological analysis of cells in tissues and suspension, molecular biology techniques, including Rnase protection assay. In addition we will evaluate the role of NK antigen positive lymphocytes in whole animal models that are manipulated to prevent ACID and compare ACAID in naive and primed mice. Resents of the studies will generate new information toward understanding the cellular mechanisms of immune deviation in the eye and new insights into the interactions of NKT (innate immunity) and the adaptive immune response.
Funding Period: 1999-04-01 - 2002-12-31
more information: NIH RePORT

Top Publications

  1. pmc The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance
    Hsi Hsien Lin
    Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England, UK
    J Exp Med 201:1615-25. 2005
  2. doi Ly49 C/I-dependent NKT cell-derived IL-10 is required for corneal graft survival and peripheral tolerance
    C M Watte
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
    J Leukoc Biol 83:928-35. 2008
  3. ncbi NKT cell-derived urokinase-type plasminogen activator promotes peripheral tolerance associated with eye
    Koh Hei Sonoda
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
    J Immunol 179:2215-22. 2007
  4. ncbi Invariant NKT cells and tolerance
    Michael Nowak
    Institut fur Umweltmedizinische Forschung at Heinrich Heine University, Duesseldorf, Germany
    Int Rev Immunol 26:95-119. 2007
  5. ncbi B7+ iris pigment epithelial cells convert T cells into CTLA-4+, B7-expressing CD8+ regulatory T cells
    Sunao Sugita
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA
    Invest Ophthalmol Vis Sci 47:5376-84. 2006
  6. ncbi CD8+ T regulatory cells use a novel genetic program that includes CD103 to suppress Th1 immunity in eye-derived tolerance
    Hiroshi Keino
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA
    Invest Ophthalmol Vis Sci 47:1533-42. 2006
  7. ncbi Induction of eye-derived tolerance does not depend on naturally occurring CD4+CD25+ T regulatory cells
    Hiroshi Keino
    Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA
    Invest Ophthalmol Vis Sci 47:1047-55. 2006
  8. ncbi Modulation of ovalbumin-induced airway inflammation and hyperreactivity by tolerogenic APC
    Jie Zhang-Hoover
    Schepens Eye Research Institute, Boston, MA 02114, USA
    J Immunol 175:7117-24. 2005
  9. ncbi Mechanisms of peripheral tolerance following intracameral inoculation are independent of IL-13 or STAT6
    Takahiko Nakamura
    Ocular Immunology Group, Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA
    J Immunol 175:2643-6. 2005
  10. ncbi A privileged view of NKT cells and peripheral tolerance through the eye
    Joan Stein-Streilein
    Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA
    Ocul Immunol Inflamm 13:111-7. 2005

Scientific Experts

  • Joan Stein-Streilein
  • Hiroshi Keino
  • Takahiko Nakamura
  • J Wayne Streilein
  • Jie Zhang-Hoover
  • Hong Qiao
  • C M Watte
  • Koh Hei Sonoda
  • Michael Nowak
  • Sunao Sugita
  • Ania Terajewicz
  • Hsi Hsien Lin
  • Kenyatta Lucas
  • J R Ortaldo
  • T Nakamura
  • C H Lau
  • Peter Carmeliet
  • David Hart
  • Howard A Young
  • Sharmila Masli
  • Masahiko Usui
  • Manabu Mochizuki
  • Masaru Takeuchi
  • Shuji Sasaki
  • Osamu Taguchi
  • Yuri Futagami
  • Hiroshi Takase
  • Takeshi Kezuka
  • Takaaki Hattori
  • Patricia Finn
  • Siamon Gordon
  • Martin Stacey
  • Marilyn Kerley
  • Michael L Mucenski
  • Douglas E Faunce

Detail Information

Publications11

  1. pmc The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance
    Hsi Hsien Lin
    Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England, UK
    J Exp Med 201:1615-25. 2005
    ..Peripheral tolerance was restored in F4/80(-/-) mice by adoptive transfer of F4/80(+) APCs in both peripheral tolerance models, indicating a central role for the F4/80 molecule in the generation of efferent CD8(+) T reg cells...
  2. doi Ly49 C/I-dependent NKT cell-derived IL-10 is required for corneal graft survival and peripheral tolerance
    C M Watte
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
    J Leukoc Biol 83:928-35. 2008
    ....
  3. ncbi NKT cell-derived urokinase-type plasminogen activator promotes peripheral tolerance associated with eye
    Koh Hei Sonoda
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
    J Immunol 179:2215-22. 2007
    ..In conclusion, uPA derived from iNKT cells is required to induce peripheral tolerance via the eye...
  4. ncbi Invariant NKT cells and tolerance
    Michael Nowak
    Institut fur Umweltmedizinische Forschung at Heinrich Heine University, Duesseldorf, Germany
    Int Rev Immunol 26:95-119. 2007
    ..The roles of iNKT cell in anterior chamber-associated immune deviation (ACAID), oral tolerance, other tolerance systems, and autoimmune diseases is discussed...
  5. ncbi B7+ iris pigment epithelial cells convert T cells into CTLA-4+, B7-expressing CD8+ regulatory T cells
    Sunao Sugita
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA
    Invest Ophthalmol Vis Sci 47:5376-84. 2006
    ..To determine whether iris PE (IPE) promotes the generation of regulatory T-cells (Tregs) with cell contact via B7-2/CTLA-4 interactions...
  6. ncbi CD8+ T regulatory cells use a novel genetic program that includes CD103 to suppress Th1 immunity in eye-derived tolerance
    Hiroshi Keino
    Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA
    Invest Ophthalmol Vis Sci 47:1533-42. 2006
    ..The purpose of these studies was to determine the genes and molecules that are critical for CD8+ T regulatory cell (T reg) functions in ACAID...
  7. ncbi Induction of eye-derived tolerance does not depend on naturally occurring CD4+CD25+ T regulatory cells
    Hiroshi Keino
    Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA
    Invest Ophthalmol Vis Sci 47:1047-55. 2006
    ..The current study was conducted to investigate the possibility that these T regs express CD25 and are derived from natural CD4+CD25+ T cells...
  8. ncbi Modulation of ovalbumin-induced airway inflammation and hyperreactivity by tolerogenic APC
    Jie Zhang-Hoover
    Schepens Eye Research Institute, Boston, MA 02114, USA
    J Immunol 175:7117-24. 2005
    ..The ability of the tol-APC to induce peripheral tolerance and suppress existing Th2 immune inflammation may lead to novel therapies for pulmonary allergic inflammation and its related pathology...
  9. ncbi Mechanisms of peripheral tolerance following intracameral inoculation are independent of IL-13 or STAT6
    Takahiko Nakamura
    Ocular Immunology Group, Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA
    J Immunol 175:2643-6. 2005
    ....
  10. ncbi A privileged view of NKT cells and peripheral tolerance through the eye
    Joan Stein-Streilein
    Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA
    Ocul Immunol Inflamm 13:111-7. 2005
    ..The role of the iNKT cell in ACAID and its novel story is discussed in this mini-review...
  11. pmc Retinal laser burn disrupts immune privilege in the eye
    Hong Qiao
    Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA
    Am J Pathol 174:414-22. 2009
    ..The increased use of lasers in both the industrial and medical fields raises the risk of RLB-associated loss of immune regulation and an increased risk of immune inflammation in the eye...