The eye has interactions with the systemic immune system that differ from those at other anatomic sites. The anterior chamber has been known to be a privileged site since the finding that allogeneic tissue implants placed there survive longer than at other sites. This has allowed of the clinical use of corneal allotransplants, although rejection can occur if vascularization of the allograft ensues. The ability of the eye to serve as an organ for the induction of immune responses has been examined in animal models by the placement of immunogenic haptens coupled to syngeneic cells, allografts, or certain tumor cells into sites in the eye. Although this approach has yielded significant information, it has not elucidated the mechanisms by which resident cells function in the eye to initiate or regulate an immune response. This application proposes to examine the ability of various populations of ocular cells (OC) from the interior of the eye to serve as antigen presenting cells for the induction of immunity and/or immunologic suppression in a murine system. Preliminary studies have shown that a mixed population of OC (MOC) from inside the anterior murine eye are capable of inducing T suppressor (Ts) cells in a hapten system. This activity appears to reside in cells bearing the I-A antigen. Proposals outlined in this application are to phenotypically characterize the subsets of MOC involved in the activation of Ts cells and to determine in what anatomic sites they reside, to examine the ability of OC from various ocular compartments to present antigens in vitro to primed and unprimed T cells and for the induction of in vivo immunity, and to determine the morphologic and immunohistologic characteristics of OC in situ. By comparing immunohistochemical data with the surface phenotype of cell subsets involved in the activation of suppression or immunity obtained from functional studies, the cellular and anatomic identity of these subsets may be elucidated. Other studies will examine the ability of populations of OC to produce interleukin 1, interleukin 2, interleukin 3, or inhibitors of these cytokines. Teleologically, it would seem important that animals have mechanisms to limit inflammation and immunologic reactivity in the eye in order to preserve the transparency of light- transmitting structures. Thus, a search for immunologic modulators produced by OC Is warranted. Elucidation of the mechanisms of immunologic privilege of the eye might have currently unforseen therapeutic implications, particularly in allotransplantation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007782-03
Application #
3264866
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1988-08-01
Project End
1991-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Knisely, T L; Hosoi, J; Nazareno, R et al. (1994) The presence of biologically significant concentrations of glucocorticoids but little or no cortisol binding globulin within aqueous humor: relevance to immune privilege in the anterior chamber of the eye. Invest Ophthalmol Vis Sci 35:3711-23
Knisely, T L; Grabbe, S; Nazareno, R et al. (1994) Production of interleukin-6 and granulocyte-macrophage colony-stimulating factor by murine iris and ciliary body explants. Invest Ophthalmol Vis Sci 35:4015-22
Grabbe, S; Gallo, R L; Lindgren, A et al. (1993) Deficient antigen presentation by Langerhans cells from athymic (nu/nu) mice. Restoration with thymic transplantation or administration of cytokines. J Immunol 151:3430-9
Hosoi, J; Grabbe, S; Knisely, T L et al. (1993) Aqueous humor inhibits epidermal cell antigen-presenting function. Reg Immunol 5:279-84
Grabbe, S; Bruvers, S; Lindgren, A M et al. (1992) Tumor antigen presentation by epidermal antigen-presenting cells in the mouse: modulation by granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and ultraviolet radiation. J Leukoc Biol 52:209-17
Grabbe, S; Bruvers, S; Granstein, R D (1992) Effects of immunomodulatory cytokines on the presentation of tumor-associated antigens by epidermal Langerhans cells. J Invest Dermatol 99:66S-68S
Gallo, R L; Grabbe, S; Choi, S S et al. (1992) Cyclosporin increases granulocyte/macrophage colony-stimulating factor (GM-CSF) activity and gene expression in murine keratinocytes. J Invest Dermatol 98:274-8
Grabbe, S; Bruvers, S; Gallo, R L et al. (1991) Tumor antigen presentation by murine epidermal cells. J Immunol 146:3656-61
Knisely, T L; Bleicher, P A; Vibbard, C A et al. (1991) Production of latent transforming growth factor-beta and other inhibitory factors by cultured murine iris and ciliary body cells. Curr Eye Res 10:761-71
Gallo, R L; Staszewski, R; Sauder, D N et al. (1991) Regulation of GM-CSF and IL-3 production from the murine keratinocyte cell line PAM 212 following exposure to ultraviolet radiation. J Invest Dermatol 97:203-9

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