Immunobiology of Corneal Transplants

Immune Privilege and Retinal Transplantation

Effects of Ultraviolet-B on Contact Hypersensitivity

Current Research Projects:

Ocular Immune Privilege

Immunologic privilege is extended to foreign antigens and grafts placed in the anterior chamber of the eye. This laboratory has determined that privilege results in part from induction of a deviant form of systemic immunity, termed Anterior Chamber Associated Immune Deviation (ACAID). In ACAID, effectors of immunogenic inflammation (delayed hypersensitivity T cells, complement-fixing antibodies) are selectively suppressed, whereas other effectors (precursor cytotoxic T cells, non-complement fixing antibodies) are preserved. ACAID is initiated by an antigen-specific signal generated within the anterior chamber via intraocular dendritic cells and macrophages. Under the influence of immunoregulatory factors in aqueous hn8umor, these cells capture antigen, process it uniquely, and migrate across the trabecular meshwork into the blood and thence to the spleen. Current research is aimed at (a) determining which genes are differentially regulated in eye-derived antigen presenting cells and in the regulatory T cells that are activated by these cells in the spleen; (b) determining the mechanisms by which pigment epithelial cells create an immunomodulatory ocular microenvironment and convert potential T effector cells into regulatory cells; and (c) understanding the extent to which persistence of immune privilege in the eye is maintained in the face of different types of intraocular inflammation. The overall goal is to use the principles of ocular immune privilege to inhibit intraocular inflammation and autoimmune eye diseases.

Expression of select genes in antigen presenting cells treated with thrombospondin and interferon-beta.

Grant Support
NIH EY05678, “Immune Responses to Ocular Antigens”

Current Collaborators
Sharmila Masli, Ph.D., Andrew W. Taylor, Ph.D., Jacqueline M. Doherty, Ph.D.

Current Postdoctoral Fellows
Jun Song Mo, M.D., Ph.D.
Hiroshi Keino, M.D., Ph.D.
Sunao Sugita, M.D., Ph.D.

Medical Student
Paiman Ghafoori

Papers Published/In Press since January 1, 2000.

IMMUNE PRIVILEGE AND ANTERIOR CHAMBER-ASSOCIATED IMMUNE DEVIATION

Perez, V.L. and Streilein, J.W. In vivo impaired T helper cell 1 development due to IL-12 deficiency following antigen injection into the anterior chamber of the eye. Ocular Immunity and Inflammation 8: 9 – 24, 2000.

Kezuka, T., and Streilein, J.W. Evidence for multiple CD95-CD95Ligand interactions in anterior chamber associated immune deviation (ACAID) induced by soluble protein antigen. Immunology 99:451 – 457, 2000.

Wenkel, H., Streilein, J.W., and Young, Michael J. Systemic immune deviation in the brain that does not depend on the integrity of the blood-brain barrier. J. Immunology 164: 5125 – 5131, 2000.

Streilein, J.W., Okamoto, S., Sano, Y., and Taylor, A.W. Neural Control of Ocular Immune Privilege. ANNALS N.Y. ACAD. SCI 917: 297-306, 2000.

Streilein, J.W., and Stein-Streilein, J. Does innate immune privilege exist? J. Leukocyte Biology 67: 479 – 487, 2000.

Kezuka, T., Sakai, J., Usui, N., Streilein, J.W., and Usui, M. Evidence for antigen-specific immune deviation in patients with acute retinal necrosis. Arch. Ophthal. 119:1044 – 1049, 2001.

Streilein, J. W. Ocular Immune Privilege – Protection That Preserves Sight. Karger Gazette 64: 5 – 8, 2001.

Stein-Streilein, J., and Streilein, J.W. Anterior chamber associated immune deviation (ACAID): regulation, biological relevance, and implications for therapy. in International Reviews of Immunology: The Eye – Immunity and Autoimmunity, R. Caspi, Ed., Gordon and Breach Publishing (IN PRESS).

Katagiri, K., Zhang-Hoover, J., Mo, J-S., Stein-Streilein, J., and Streilein, J.W. Using tolerance induced via the anterior chamber of the eye to inhibit Th2-dependent pulmonary pathology. J. Immunol.(IN PRESS).

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Effects of exogenous active TGFb on antigen presenting cells that enables them, primarily through production of thrombospondin, to induce responding T cells to be regulators that promote tolerance.

CELLULAR AND MOLECULAR BASIS OF ANTERIOR CHAMBER-ASSOCIATED IMMUNE DEVIATION

Kezuka, T., and Streilein, J.W. Analysis of in vivo regulatory properties of T cells activated in vitro by TGFß-2-treated antigen presenting cells. Invest. Ophthal. Vis. Sci. 41: 1410 – 1421, 2000.

Kezuka, Takeshi, and Streilein, J.W. In vitro generation of regulatory CD8+ T cells similar to those found in mice with Anterior Chamber Associated Immune Deviation. Invest. Ophthal. Vis Sci. 41: 1803 – 1811, 2000.

Masli, S. and Streilein, J.W. Expression of thrombospondin in TGFb-treated antigen presenting cells and its relevance to their immune deviation-promoting properties. J. Immunol 168: 2264 – 2273, 2002.
Streilein, J. W., Masli, S., Takeuchi, M., and Kezuka, T. The eye’s view of antigen presentation. Human Immunology (IN PRESS).

OCULAR IMMUNOSUPPRESSIVE MICROENVIRONMENT

Yoshida, Munenori, Takeuchi, M., and Streilein, J. W. Participation of pigment epithelium of iris and ciliary body in ocular immune privilege. I. Inhibition of T cell activation in vitro by direct cell contact. Invest. Ophthal. Vis. Sci. 41: 811 – 821, 2000.

Yoshida, M., Kezuka, T., and Streilein, J.W. Participation of pigment epithelium of iris and ciliary body in ocular immune privilege. 2. Generation of regulatory T cells that suppress bystander T cells via TGFb. Invest. Ophthal. Vis. Sci. 41: 3862 – 3870, 2000.

Streilein, J.W. , and Taylor, A.W. Local Immunosuppression: The Eye. in THERAPEUTIC IMMUNOSUPPRESSION, A.A. Thomson, ed., Immunology & Medicine Series, Khwer Academic Publishers, Dordrecht, The Netherlands, 2001, pp. 275 - 322.

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Schema by which antigen placed in the anterior chamber of the eye is carried to the marginal zone of the spleen and initiates a sequence of multicellular interactions that culminate in the phenomenon of Anterior Chamber Associated Immune Deviation (ACAID).

IMMUNE PRIVILEGE AND INTRAOCULAR INFLAMMATION

Ohta, K., Wiggert, B., Yamagami, S., Taylor, A.W., and Streilein, J.W. Analysis of immunomodulatory activities of aqueous humor from eyes of mice with experimental autoimmune uveitis. J. Immunol. 164: 1185 – 1192, 2000.

Ohta, K., Yamagami, S., Taylor, A.W., and Streilein, J.W. IL-6 antagonizes TGF-b and abolishes immune privilege in eyes with endotoxin-induced uveitis. Invest. Ophthal. Vis. Sci. 41: 2591 – 2599, 2000.

Mo, J. S. and Streilein, J.W. Immune privilege persists in eyes with extreme inflammation induced by intravitreal LPS. Eur. J. Immunol., 31: 3806 – 3815, 2001.

Streilein, J. W., Mo, Jun Song, and Ohta, K. On the relationship between ocular inflammation and immune privilege. In UVEITIS IN THE THIRD MILLENIUM, Proceedings of the Fifth International Symposium on Uveitis, E.M. Dodds and C.A. Couta, eds., Elsevier, The Netherlands (IN PRESS).

Streilein, J. W., Ohta, K., Mo, J. S., and Taylor, A. W. Ocular immune privilege and the impact of intraocular inflammation. DNA and Cell Biology (IN PRESS).