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International Immunology Advance Access originally published online on November 21, 2006
International Immunology 2007 19(1):93-98; doi:10.1093/intimm/dxl125
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

WSX-1 plays a significant role for the initiation of experimental autoimmune uveitis

Koh-Hei Sonoda1, Takeru Yoshimura1,2, Atsunobu Takeda1, Tatsuro Ishibashi1, Shinjiro Hamano3 and Hiroki Yoshida4,5

1 Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
2 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
3 Department of Parasitology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
4 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan
5 Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan

Correspondence to: K.-H. Sonoda; E-mail: sonodak{at}med.kyushu-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
WSX-1 is a subunit of the IL-27R, which plays a critical role in the initiation of Th1 responses. Murine experimental autoimmune uveitis (EAU) is a model of human autoimmune uveitis, in which a Th1 response predominates in the pathogenetic process. To explore the role of WSX-1 in this model, WSX-1–/– mice were immunized with interphotoreceptor retinoid-binding protein peptide 1–20 to induce EAU. We found that the EAU clinical and histological scores were lower in the WSX-1–/– mice up to day 21, whereas after day 21, the EAU scores were the same between the wild-type (WT) and WSX-1–/– mice with both declining at the same rate. In contrast to T lymphocytes from WT mice, WSX-1–/– T lymphocytes on day 9 after immunization failed to produce IFN-{gamma}. Similarly, expression of Th1-related chemokines, such as regulated on activation, normal T cell expressed and secreted and IP-10, in the eye was reduced in WSX-1–/– mice compared with WT mice on day 13 after immunization. In addition, sub-retinal transfer of lymphocytes from WSX-1–/– mice on day 9 after immunization did not induce EAU in the recipient mice. Importantly, IFN-{gamma} production, chemokine expression and the transferability of disease by lymphocytes became comparable for WSX-1–/– and WT mice at later stages. Thus, IL-27/WSX-1 affects the early development of EAU, and might be a target for therapy during the onset of autoimmune uveitis in humans.

Keywords: autoimmunity, cytokine, eye, IL-27, Th1


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
WSX-1 is a novel class I cytokine receptor, with homology to the IL-12Rs, which is expressed in lymphoid tissues (1). In an analysis of WSX-1-deficient mice, we demonstrated that WSX-1 was required for the normal production of IFN-{gamma} by naive CD4+ T cells (2). We also reported that signal transducer and activator of transcription (STAT) 1 was activated downstream of WSX-1, leading to T-bet induction and IL-12Rß2 expression in naive CD4+ T cells (3). These results demonstrated that WSX-1 was critical for initial Th1 commitment. IL-27, which is a newly identified IL-12-related cytokine, has been reported to be a ligand for WSX-1 and to induce Th1-polarized differentiation of CD4+ T cells (4). Although these studies have helped clarify the role of IL-27/WSX-1 signaling in the differentiation of naive CD4+ T cells into a Th1 population, the role played by WSX-1 in cytokine-mediated autoimmune diseases has yet to be elucidated.

Experimental autoimmune uveitis (EAU) is an organ-specific T cell-mediated autoimmune disease that can be induced in several animal species by immunization with retinal antigens, including interphotoreceptor retinoid-binding protein (IRBP) and superantigens (5, 6). The resulting disease resembles human uveitis in conditions such as Vogt–Koyanagi–Harada disease and Behcet's disease (7, 8). During EAU, the integrity of the blood–retina barrier is compromised, monocytes/macrophages and antigen-specific T lymphocytes move into the retina and tissue damage results. Like experimental autoimmune encephalomyelitis (EAE), several lines of evidence have shown that autoreactive Th1 cells mediate EAU, that its induction is correlated with the production of IFN-{gamma} by T cells (9, 10) and that inhibition of Th1 responses by anti-IL-12 treatment suppresses the disease (11).

To define the in vivo role of WSX-1 in the induction of Th1-mediated autoimmune diseases, we analyzed IRBP-induced EAU in WSX-1–/– mice. We also examined the cytokine production from autoreactive T cells and ability of disease transfer into the naive host.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Mice
WSX-1–/– on a C57BL/6 background (maintained for >10 continual crosses) (9) and wild-type (WT) C57BL/6 mice (SLC Japan, Shizuoka, Japan) were maintained in specific pathogen-free conditions at Kyushu University, Japan. Female mice (8–10 weeks old) were used in all experiments. All animals were treated humanely, and all experiments conformed to the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research.

EAU induction and evaluation
Knockout (KO) or WT mice were immunized with human IRBP peptide 1–20 (sequence, GPTHLFQPSLVLDMAKVLLD), which has been shown to induce EAU (12). The mice were first immunized subcutaneously in one footpad and the base of tail with the peptide in 0.2-ml emulsion of CFA (5 mg ml–1 IRBP1–20 in PBS:CFA supplemented with Mycobacterium tuberculosis strain H37RA to 2.5 mg ml–1 = 1:1, v/v), and then inoculated intra-peritoneally with 1.5 µg of pertussus toxin. Ophthalmic examinations were carried out following immunization. Tropicamide (0.5%) was applied to the eyes to induce mydriasis, and the fundus of the eye was examined using a Bonnoscope and Super Field NC Lens (Volk Optical, Mentor, OH, USA). Clinical assessments were carried out blind by two ophthalmologists, who examined the presence of dilatation, white focal lesions and white linear lesions affecting blood vessels, retinal hemorrhaging and retinal detachment. Clinical scores between 0 and 4 were assigned according to severity, as described by Thurau et al. (13) with some modifications. The mice were scored as an average of both eye scores. When the two ophthalmologists assigned different scores, the mean values were used. The severity of EAU was also assessed histopathologically at 16 days after immunization. Freshly enucleated eyes were fixed in 4% PFA and embedded in paraffin. Sections (4 µm) were cut and stained with hematoxylin and eosin. The severity of the disease was scored on a scale of 0 and 4 with half-point increments, using a semi-quantitative system (14).

Cytokine ELISAs
The inguinal lymph nodes (LNs) were removed from four or five mice on days 9, 16 and 25 after immunization. Single-cell suspensions were prepared and enriched for T cells using IMMULANTM columns (Biotecx Laboratory, Inc., Houston, TX, USA). CD4–-enriched cells were prepared using anti-CD4 Microbeads (130-1-049-201, Miltenyi Biotec, Gladbach, Germany) and an multiple sclerosis positive-selection column with a MiniMACSTM Separator (Miltenyi Biotec). CD4+ T cells (purified to ~95% by adherence to the column) or flow-through CD4– T cells were incubated with or without IRBP1–20 peptide (10 µg ml–1) at a concentration of 2 x 105 to 5 x 105 cells per 200 µl per well for 48 h at 37°C. Irradiated (20 Gy) spleen cells from B6 mice were used as antigen-presenting cells (APCs) in the cultures at a concentration of 1 x 106 cells per 200 µl per well. Supernatants were collected, and IFN-{gamma} and IL-4 concentrations were measured using mouse ELISA development kits (R&D Systems, Minneapolis, MN, USA) according to the manufacturer's instructions.

Proliferation assay
CD4+ T cell suspensions were prepared from mice on day 9 after immunization (as described above), and cultured at a concentration of 5 x 105 cells per 200 µl per well with IRBP1–20 peptide (10 µg ml–1) for 72 h. Irradiated (20 Gy) spleen cells from B6 mice were used as APCs in the culture at a concentration of 1 x 106 cells per 200 µl per well. Cell proliferation was measured using [3H]thymidine during the last 12 h of culture.

Reverse transcription–PCR analysis
Eyes were removed from mice (n = 3) on day 13 after immunization under deep anesthesia. The corneas and lenses were removed initially and then the irises, retinas and choroids were isolated. Total RNAs were extracted from the mixture of irises, retinas and choroids, and then reverse transcription (RT)–PCR analysis was performed. The primers used for the IFN-{gamma}, chemokines and ß-actin were as described previously (15). The expression of ß-actin mRNA was measured by real-time PCR (ABI PRISM 7000, Applied Biosystems, Tokyo, Japan) as an internal control for RNA input and RT. Equal amounts of cDNAs were amplified to measure the expression of IFN-{gamma}, chemokines and their receptors.

Sub-retinal transfer of immunized lymphocytes
The inguinal LNs were removed from KO or WT mice on days 9 and 16 after immunization. T cells were enriched using IMMULANTM columns (Biotecx Laboratory, Inc.) (the purity was >90%). Before all surgical procedures, recipient mice were anesthetized with an intra-peritoneal injection of a mixture of 3 mg ketamine and 0.0075 mg xylazine. Enriched T cells (2 x 106) were inoculated into the sub-retinal space using fine 32-ga needles (cat. no. 0160832, Hamilton, Reno, NV, USA) and a 10-µl syringe (cat. no. 80330, Hamilton). The tip of the needles penetrated the sclera and choroid but not retina. And then a volume of 2 µl per injection was introduced into the sub-retinal space. We are confident that we are injecting the cells into the sub-retinal space, because the tip of the needle was carefully guided under the microscope through flattened cornea covered by a glass microscope slide. After inoculation of 2-µl solution, elevated intraocular pressure completely sealed the scleral and choroidal incision without bleeding and leaking of solution. Clinical scores for EAU were evaluated 6 days after cell transfer (as described above).

Statistics
The Mann–Whitney non-parametric analysis was used to analyze differences between groups of mice. P < 0.05 was considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
WSX-1–/– mice expressed low score of EAU in the early phase
To examine the role of WSX-1 in EAU, we immunized WSX-1–/– (KO) and C57BL6 (B6, WT) mice with IRBP1–20, and evaluated the extent of disease development by ophthalmoscopy (Fig. 1A). In WT mice, pathological changes in the eye appeared on day 13 after induction, and reached maximal severity by about day 19, with clinical scores of 3 on a scale from 0 to 4. In KO mice, however, EAU scores were significantly lower than those in WT mice by day 19. In the eyes of WT mice, the fundus presented with an obscured margin around the optic disc, retinal exudates and linear vasculitis with vitreous opacity by day 16 (Fig. 1B-ii and -iii). However, in the eyes of KO mice on day 16, the margins of the optic discs were clear, and only minimal pathological changes, such as retinal vessel dilatation associated with focal vasculitis, were observed (Fig. 1B-iv). Histological examination of the eyes on day 16 (Fig. 1C) showed massive infiltrates of lymphocytes, macrophages and neutrophils in the retina and vitreous cavity in WT mice (histological score = 2.37 ± 0.82; n = 12), and only small perivascular infiltrates of lymphocytes in the retinas of KO mice (histological score = 0.63 ± 0.25; n = 15). The histological scores in the two groups were significantly different (P = 0.014). Although uveitis was reduced in the KO mice in the early phase of disease, the clinical scores were equivalent to those of the WT mice by day 21. Thereafter, the symptoms of uveitis regressed in both groups in a similar manner. These data demonstrated that WSX-1 affects the early development of IRBP-induced EAU.


Figure 1
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  		Fig. 1 EAU symptoms are reduced in WSX-1–/– mice. (A) Comparison of the ophthalmoscopic symptoms of EAU in B6 (open circle; n = 19) and KO (closed circle; n = 30) mice, from day 7 after immunization with IRBP1–20. The values represent the means ± SEMs of clinical scores, graded on a scale of 0–4 (*P < 0.01). (B) Photographs of the fundus: (i) Naive WT mice (grade 0) and (ii) WT mice on day 16 (grade 3), showing a completely obscured margin of the optic disc, severe retinal exudates and linear vasculitis (arrow); (iii) WT mice on day 16 (grade 3), showing the retinal exudates (arrow) extending to the peripheral retina and associated with vitreous opacity and (iv) KO mice on day 16 (grade 1), showing the margin of the optic disc and mildly dilated retinal vessels associated with focal vasculitis (arrow). (C) Histological examination of the eye. Massive infiltrates of lymphocytes, macrophages and neutrophils were seen in the retina and vitreous cavity in WT mice on day 16, but only mild retinal perivascular infiltration of lymphocytes was seen in KO mice. Scale bars = 50 µm. The data represent the combined results of three independent experiments. Ch, choroids; Re, retina and VC, vitreous cavity.

 
Although the KO mice were backcrossed to C57/BL6 mice >10 times, we initially included WSX-1+/– mice as a control. There were no differences in the clinical scores for EAU between WT (B6, n = 19) and WSX-1+/– (n = 15) mice at any time point up to day 21. When we compared WSX-1+/– and WSX-1–/– mice, we observed significantly lower clinical scores in the WSX-1–/– mice (0.91 ± 0.98; n = 15) than in the WSX-1+/– mice (2.42 ± 0.89; n = 15; P = 0.0025) on day 16. However, no significant difference was seen on day 21 [3.22 ± 0.71 (n = 15) and 2.63 ± 0.65 (n = 15) for WSX-1+/– and WSX-1–/–, respectively; P = 0.387]. Thus, the genetic fragment derived from strain 129 in the KO mice might not affect our system.

Lower Th1 responses in WSX-1–/– mice in the early phase of EAU
Given that EAU is mediated by Th1 responses (9, 10), we next examined IFN-{gamma} production by T cells from draining LNs after IRBP1–20 immunization. We first enriched the LN lymphocytes for CD4+ T cells from IRBP-immunized WT mice (day 9) using magnetic beads, and confirmed that IFN-{gamma} was selectively produced by CD4+ T cells rather than non-adherent CD4– T cells (Fig. 2A). We therefore decided to use CD4+ T cells, which were derived from either WT or KO mice, with irradiated splenic APCs derived from WT mice in the following experiments.


Figure 2
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  		Fig. 2 Impaired IFN-{gamma} production by WSX-1–/– lymphocytes. (A) CD4+ T cells enriched by adhesion to magnetic beads or flow-through CD4– T cells (5 x 105 cells per well) were stimulated using WT-irradiated splenic APCs (1 x 106 cells per well) and IRBP1–20. (B) CD4+ T cells were prepared from WT or KO mice on days 9, 16 and 25 after immunization. Cells (2 x 105 cells per well) were stimulated using WT-irradiated splenic APCs (1 x 106 cells per well) with or without IRBP1–20 peptide for 48 h. IFN-{gamma} levels in the culture supernatants were measured by an ELISA. (C) Lymphocytes were prepared as in (B) from WT or KO mice on day 9 after immunization, stimulated with IRBP1–20 peptide in culture and cell proliferation was measured after 72 h. Data shown are means ± SDs of triplicate samples, and are representative of three independent experiments. *P ≤ 0.05. NS, not significant.

 
On day 9 after immunization, when changes in the ocular pathology were barely detectable (Fig. 1A), CD4+ T cells from WT mice produced substantial amounts of IFN-{gamma} in response to antigen stimulation. CD4+ T cells from KO mice could produce IFN-{gamma}, however, significantly lower amount (Fig. 2B). On day 16, T cells from KO mice still produced substantially lower amounts of IFN-{gamma} than those from WT. However, there was no significant difference in IFN-{gamma} production by T cells from KO and WT mice on day 25. The ability of IFN-{gamma} production from KO mice was significantly lower than that from WT mice especially in the early phase of EAU.

To exclude the possibility that the KO mice had not been successfully immunized with IRBP1–20, we checked the response of the draining LN cells to antigen on day 9. CD4+ T cells from immunized KO mice proliferated well in response to IRBP1–20 (Fig. 2C), which showed that the KO lymphocytes had been successfully primed to respond to antigen; however, they failed to mount enough Th1 responses in the early phase of EAU. We measured not only IFN-{gamma} but also the IL-4 in the same samples. IL-4 could not be detected in any of the samples.

Expression of IFN-{gamma} and Th1-related chemokines in the eyes of WSX-1–/– mice
We next examined the expression of IFN-{gamma} and Th1-related chemokines in the eye by RT–PCR. Previous evidence has demonstrated the involvement of chemokines, such as IP-10, monocyte chemoattractant protein (MCP)-1 and regulated on activation, normal T cell expressed and secreted (RANTES), in the early phase of EAU (16). Expression of these chemokines has been correlated with the local infiltration of macrophages in other models of autoimmune inflammation, such as EAE (17). The expression of IFN-{gamma}, RANTES, IP-10 and MCP-1 was reduced in the eyes of KO mice compared with WT mice on day 13 after immunization (Fig. 3, left panel). In contrast, on day 25 after immunization, the expression of IFN-{gamma} and chemokines in the eyes of KO and WT mice was comparable (Fig. 3, right panel). We thus concluded that early expression of cytokines and chemokines to promote Th1 cell activation is dependent on the expression of WSX-1.


Figure 3
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  		Fig. 3 Reduced expression of IFN-{gamma} and Th1-related chemokines in the eyes of KO mice. Total RNAs were extracted from the eyes of WT and KO mice on day 13 (left panel) and day 25 (right panel) after immunization. Equal amounts of cDNAs, adjusted to ß-actin-expression levels, were amplified using primers for IFN-{gamma} and Th1-related chemokines. Experiments were performed three times with similar results.

 
Sub-retinal transplantation of immunized WSX-1–/– CD4+ T cells (day 9) fails to transfer EAU
Th1 responses play an important role in the pathogenesis of EAU, not only because they result in IFN-{gamma} production and subsequently macrophage activation but also because they stimulate Th1 cells to migrate to, and accumulate at, the site of inflammation, mediated by specific chemokines (as described above). It is possible that the failure to initiate EAU in KO mice was due to the impairment of early cell migration into the eye. To address this issue, we evaluated the ability of immunized lymphocytes to transfer EAU when transplanted into the sub-retinal space of unimmunized mice.

Column-enriched T cells from immunized WT (B6) mice on days 9 and 16 after immunization induced EAU when transferred into the eye of naive WT mice after 6 days (Fig. 4A). T cells from KO mice on day 16 after immunization also induce comparable EAU in naive WT mice. However, T cells from KO mice on day 9 after immunization induce low-scored EAU in naive WT mice (Fig. 4A). Histological examination revealed minimum infiltration of lymphocytes in the retinas of the recipient mice (Fig. 4B). Histological scores in the WT mice, which received lymphocytes from mice 9 days after immunization, were 2.17 ± 0.31 for lymphocytes from WT donors (n = 6) and 0.67 ± 0.11 for lymphocytes from KO donors (n = 6); the difference between the two groups was significant (P = 0.005). Histological scores in the WT mice, which received lymphocytes from mice 16 days after immunization, were 2.33 ± 0.21 for lymphocytes from WT donors (n = 6) and 2.00 ± 0.26 for lymphocytes from KO donors (n = 6); the difference between the two groups was not significant (P = 0.354).


Figure 4
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  		Fig. 4 Induction of EAU by the sub-retinal transfer of immunized lymphocytes. Column-enriched T cells were prepared from inguinal LNs from WT or KO mice on days 9 and 16 after immunization with IRBP1–20. T cells (2 x 106) from WT or KO mice were transferred into the sub-retinal space of naive WT (B6) mice (n = 5). (A) EAU symptoms in the eye were evaluated 6 days after transfer, using a 0–4 clinical score. The values represent means ± SEMs. *P < 0.05. Data are representative of three independent experiments. (B) Eyes were examined histologically on day 9 after cell transfer. Inflammatory infiltrates were detected in the retina and vitreous cavity in the naive mice receiving WT lymphocytes (WT to B6, score 2), and no apparent infiltrates were detected in the mice receiving WSX-1–/– lymphocytes (KO to B6, score 0.5). Scale bars = 50 mm. Re, retina and VC, vitreous cavity.

 
These data suggested the attenuation of early phase EAU in KO mice might not only be merely due to the failure of accumulation into the eye but also due to some functional changes of autoreactive T cells (including lower IFN-{gamma} production, as shown in Fig. 2). Importantly, T cells from KO mice could induce autoaggressive immune response on day 16 after immunization. Taken together, we concluded that IL-27/WSX-1 affected the function of autoreactive T cells during the early development of EAU.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Ocular inflammation leads to vision loss as a result of the destruction and scarring of delicate tissue along the visual axis. Thus, understanding the pathophysiology of uveitis, especially that of autoimmune origin, is important for therapy. Recent evidence has shown that human autoimmune uveitis, as seen in Behcet's disease, is associated with Th1 responses (18); this was also the case with the murine model of uveitis used in this study (9, 10). As IL-12 is a potent inducer of Th1 responses, this cytokine is likely to be critically involved in the induction of EAU (5–7, 19). Here we report that WSX-1 plays a significant role in the onset of EAU, as the EAU during its early phase was significantly reduced and IRBP-specific Th1 responses were interfered in KO mice. In addition, the expression of Th1-related chemokines was reduced in the eyes of KO mice. A similar impairment in the induction of EAU has been observed in IL-12 p40–/– mice (19), and in mice treated with an anti-IL-12 mAb (11). However, unlike IL-12 p40–/– mice, clinical and histological scores for EAU in the WSX-1–/– mice eventually reached comparable levels to those in WT mice (Fig. 1A). This confirms our earlier finding that WSX-1 has an important role in the initiation of Th1 responses, whereas its role at later stages is replaced by the up-regulation of IL-12R (2).

Recently, new members of the IL-12/IL-12R family have been identified (20). IL-12 and related cytokines mediate Th1 responses in distinct cell populations: IL-27/WSX-1 targets cells involved in the initial induction of Th1 responses, IL-12/IL-12R targets effector Th1 cells and IL-23/IL-23R targets memory Th1 cells. Thus, our observation that Th1-mediated EAU, especially during its initial phase, was suppressed in the absence of WSX-1 is consistent with existing evidence. WSX-1 deficiency impaired not only IFN-{gamma} production but also the expression of Th1-related chemokines in the eye, which should additionally contribute to the suppression of uveitis by preventing the migration and accumulation of inflammatory lymphocytes in the region.

The role of WSX-1 in the initiation of Th1 responses was first demonstrated in our previous study (2); subsequently, we showed that STAT1-mediated T-bet induction provided the molecular basis for the Th1 induction by IL-27/WSX-1 (3). Recently, however, a distinct and apparently contradictory role for IL-27/WSX-1 as an attenuator of inflammation has been reported (21, 22). We also demonstrated two-sided roles of IL-27; induction of Th1 differentiation on naive CD4+ T cells versus suppression of pro-inflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells through STAT3 (23). Although it is also unclear how and in what situations IL-27/WSX-1 fulfills these two distinct roles, the immune response elicited by immunization with the antigen that induces EAU is assumed to be qualitatively distinct from that elicited by the systemic protozoan infections, in which IL-27 functions as an attenuator of robust inflammatory responses.

Although Th1 lymphocytes are the major effector cells in EAU (9–11, 19), it is important to note that EAU is not only mediated by a Th1 response. Jones et al. (24) demonstrated that IFN-{gamma}-deficient mice developed EAU of equivalent severity to that seen in WT mice, suggesting a role for a deviant effector response involving Th2 cells. This might provide an alternative explanation for the onset, but not the final stages, of EAU being affected in WSX-1 KO mice: WSX-1 might contribute to the early development of a conventional Th1 response, but not to other effector pathways, in EAU.

The importance of WSX-1 in protecting against pathogens, especially intracellular protozoa, has been emphasized previously (2, 21, 22). However, this report is the first to demonstrate the important role of WSX-1 in the initiation of Th1-mediated autoimmunity. Further understanding of the role of IL-27/WSX-1 in autoimmune disease might shed light on the overlapping but distinct roles played by IL-12-related molecules, and will no doubt provide clues to novel therapeutic interventions for human diseases of autoimmune origin.


   Acknowledgements
 
The authors thank A. Yoshimura for generous help, S. Muroi for animal husbandry and members of Project W for helpful discussion. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture, Japan (H.Y. and K.-H.S.), the Japan National Society for the Prevention of Blindness (K.-H.S.), the Uehara Memorial Foundation (H.Y.) and the Sumitomo Foundation (Grant for Basic Science Research Projects, H.Y.).


   Abbreviations
 
APC, antigen-presenting cell
EAE, experimental autoimmune encephalomyelitis
EAU, experimental autoimmune uveitis
IRBP, interphotoreceptor retinoid-binding protein
KO, knockout
LN, lymph node
RANTES, regulated on activation, normal T cell expressed and secreted
RT, reverse transcription
STAT, signal transducer and activator of transcription
WT, wild type

   Notes
 
Transmitting editor: T. Watanabe

Received 26 July 2006, accepted 26 October 2006.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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