Identification of an immunodominant and highly immunopathogenic determinant in the retinal interphotoreceptor retinoid-binding protein (IRBP).

The Fas-Fas ligand (FasL) interaction is important for maintaining lymphocyte homeostasis by signaling for activation-induced cell death. Mice homozygous for the lpr or gld mutations do not express functional Fas or FasL, respectively, and spontaneously develop progressive autoimmune symptoms. Recent studies implicated expression of FasL on immunologically privileged tissues in protection from immune-mediated damage. Conversely, tissue expression of Fas may facilitate damage. We evaluated the susceptibility of lpr and gld mice to induction of experimental autoimmune uveitis (EAU), a T cell-mediated autoimmune disease induced with retinal Ags, which targets the neural retina. gld as well as lpr mice immunized with a retinal Ag developed disease of lower incidence and severity than wild-type controls. Delayed hypersensitivity responses were not significantly different among immunized gld, lpr, or wild-type mice, although in vitro Ag-specific lymphocyte responses of the mutant mice were lower. To evaluate whether the diminished ability of gld and lpr mice to develop EAU was due to a defect at the level of the tissue or the immune system, radiation bone marrow chimeras constructed between wild-type and mutant mice were immunized to induce EAU. Mutant recipients of wild-type bone marrow, but not wild-type recipients of mutant bone marrow, developed normal disease scores. These results indicate that normal expression of Fas and of FasL on cells of the immune system is important for EAU expression. Unexpectedly, neither lack of Fas nor lack of FasL on the ocular tissues affected expression of EAU.

Section: E Xperimental Autoimmune Uveitis (Uveoretinitis) (Eau)mentioning

confidence: 99%

Fas and Fas Ligand Expressed on Cells of the Immune System, not on the Target Tissue, Control Induction of Experimental Autoimmune Uveitis

Wahlsten¹,

Gitchell²,

Chan³

et al. 2000

“…The induction of uveitis in Lewis rats using peptide R16 has been previously described (13,14). Briefly, the rats were immunized s.c. with 200 l of an emulsion containing 30 g of R16 and 500 g of Mycobacterium tuberculosis H37Ra (Difco, Detroit, MI) in CFA (Sigma-Aldrich, St. Louis, MO), distributed over six spots on the tail base and flank.…”

Section: Animal Model Of Eaumentioning

confidence: 99%

Conversion of Monophasic to Recurrent Autoimmune Disease by Autoreactive T Cell Subsets

Shao

Song

Sun

et al. 2003

Autoimmune uveitis has been elicited in susceptible rodents by several ocular-specific Ags. In most of these animal models the induced uveitis is acute and monophasic. Because recurrent uveitis poses the highest risk for blinding ocular complications in human disease, a spontaneous relapsing animal model would be most helpful in understanding the disease pathogenesis. In our current study we have observed that the adoptive transfer of interphotoreceptor retinoid-binding protein residues 1177–1191-specific T cells to naive Lewis rats induced a chronic relapsing disease, in contrast to the monophasic disease induced by immunization with interphotoreceptor retinoid-binding protein residues 1177–1191 emulsified in CFA. The chronic relapsing uveitis induced by autoreactive T cell subsets is dependent on the number of autoreactive T cells generated as well as their activation status. Our study documented a spontaneous model of recurrent uveitis in the rat, which should assist us in the study of disease pathogenesis and the design of specific therapy.

“…In the mouse model EAU can be elicited by immunization with one of several retinal Ags or by the adoptive transfer of retinal Ag-specific CD4 ϩ T cells (1)(2)(3)(4). Ag-specific Th1 cells then target the neural retina where the endogenous Ag is located and incite an inflammatory cascade resulting in progressive and irreversible destruction of the retinal photoreceptor cell layer that can lead to blindness (2).…”

Section: S Tudies Of Experimental Autoimmune Uveoretinitis (Eau)mentioning

confidence: 99%

Blockade of Costimulation Through B7/CD28 Inhibits Experimental Autoimmune Uveoretinitis, But Does Not Induce Long-Term Tolerance

Silver¹,

Hathcock

Chan³

et al. 2000

It has been reported that costimulation blockade can result in T cell anergy. We investigated the effects of blocking costimulatory molecules in vivo on the development of experimental autoimmune uveoretinitis (EAU), a model for autoimmune uveitis in humans that is induced in mice by immunization with the retinal Ag interphotoreceptor retinoid binding protein. B10.A mice immunized with a uveitogenic regimen of interphotoreceptor retinoid-binding protein were treated with Abs to B7.1 and B7.2 for 2 wk. Evaluation of EAU and immunological responses 1 wk later showed that disease had been abrogated, and cellular responses were suppressed. To determine whether the costimulation blockade resulted in tolerance, adult-thymectomized mice immunized for uveitis and treated with anti-B7 or anti-CD28 were rechallenged for uveitis induction 5 wk after the initial immunization. Although confirmed to be disease free after the initial immunization, both anti-B7- and anti-CD28-treated mice developed severe EAU and elevated cellular responses after the rechallenge, equivalent to those of control mice. We conclude that in this model costimulatory blockade in vivo prevents the development of autoimmune disease, but does not result in long-term tolerance. The data are compatible with the interpretation that B7/CD28 blockade prevents generation of effector, but not of memory, T cells.