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Rat Corneal Allograft Survival Prolonged by the Superantigen Staphylococcal Enterotoxin B

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Rat Corneal Allograft Survival Prolonged by the Superantigen Staphylococcal Enterotoxin B Rat Corneal Allograft Survival Prolonged by the Superantigen Staphylococcal Enterotoxin B Zhiqiang Pan,1 Yu Chen,2 Wenhua Zhang,1 Ying Jie,1 Na Li,3 and Yuying Wu1 PURPOSE. The purpose of this study was to determine the The term superantigen (SAg) is used to describe those optimal conditions for prolonging corneal allograft survival by microbial products that activate a large portion of the T-cell inducing anergy with the superantigen staphylococcal entero- population (5%–30%), whereas conventional antigens stimu- toxin B (SEB). late only 0.01%. Superantigens differ from conventional anti- METHODS. A rat model of penetrating keratoplasty, whereby gens in that they bind to the outside of the peptide-binding Fisher344 donor corneas are implanted into Lewis recipients, groove of MHC class, thus exerting their effects as an intact was used to evaluate the effects of SEB on inhibiting immune- molecule without being processed. Furthermore, recognition mediated allograft rejection. To induce anergy, SEB was in- of SAgs by the T-cell receptor (TCR) depends only on the jected into the peribulbar space of Lewis rats. Furthermore, variable region of the TCR ␤ chain (V␤). Therefore, SAgs histopathology and immunofluorescent staining were used to stimulate both antigen-presenting cells (APCs) and T lympho- examine the levels of infiltrating CD4ϩ and CD8ϩ T lympho- cytes, which leads to the massive production of cytokines, cytes and NK1.1ϩ lymphocytes. enhanced expression and/or activation of cell adhesion mole- ␮ cules, T-cell proliferation, activation-induced apoptosis, and RESULTS. By administering SEB, at doses of 90 or 120 g/kg 7 4 days before and after keratoplasty, we suppressed the episode T-cell anergy. A study has shown that injecting the SAg staph- of corneal graft rejection for a median of 12 and 30 days, ylococcal enterotoxin B (SEB) into mice produces transient, rapid hyperactivation and proliferation of T cells, which are respectively. In contrast, rejection was observed when 30 or 5 60 ␮g/kg of SEB was administered. After SEB injections, lym- eliminated by activation-induced cell death within 48 hours. phocyte infiltration into the corneal grafts was reduced, and In addition, the remaining SAg-reactive cells fail to proliferate the expression of NK1.1ϩ lymphocytes was enhanced, suggest- in response to a secondary SAg challenge. The proliferative ing that anergy may be occurring. Also, there were no differ- unresponsiveness of the secondary SAg responder T cells has ences in the number of infiltrating CD4ϩ and CD8ϩ T lympho- been termed anergy. However, on subsequent analysis, second- ary SAg responder T cells may not be truly anergic because cytes cells between the control group and groups injected with 6 30 and 120 ␮g/kg SEB on postoperative days 10 and 30. they could be reacting to the second SAg exposure. Wang et al.7 showed that CD8ϩ regulatory suppressive T cells could CONCLUSIONS. Inducing anergy with the superantigen SEB pro- enforce anergy by inhibiting cell division of preactivated T longed corneal graft survival in a rat model of penetrating cells, not by the SAg response of naı¨ve T cells. keratoplasty. Therefore, these results support the possibility of Damage to healthy, transplanted tissue can be curtailed by prolonging corneal allograft survival in a clinical setting by reducing the inflammatory response of the immune system. preventing immune-mediated rejection through the administra- Our studies have shown that the bacterial superantigen SEB tion of the superantigen SEB. (Invest Ophthalmol Vis Sci. 2003; can inhibit the rejection of transplanted mouse bone marrow 44:3346–3351) DOI:10.1167/iovs.02-0845 cells and peripheral lymphocytes, suggesting that injections of SEB may induce peripheral anergy to allogeneic organ grafts. In orneal transplantation is the most common and successful ϩ addition, CD4 T cells appear responsible for maintaining this Cform of solid tissue transplantation. Although the rejection ϩ 8 rate for routine keratoplasty is only 10% in the first year, there anergy rather than the CD8 T cells. Our studies confirmed are a significant number of corneal graft failures in high-risk that the induction of transplantation anergy by SEB injections cases of keratoplasty due to immune-mediated rejection.1,2 contribute to hematopoietic chimerism, defined as the coex- Corticosteroids and cyclosporin A greatly reduce the rejection istence of host and donor cells, and that mixed lymphocyte rate of corneal allografts, but high doses and/or long-term reactions (MLRs) are significantly low. This in vivo SEB-induced administration of these drugs can produce deleterious side anergy may be associated with the clone deletion of T-helper effects, such as glaucoma, cataract formation, nephrotoxicity, (Th)1 cells. The specific dosage of SEB is critical because, if the hypertension, and hepatotoxicity.3 dosage is too high or too low, then anergy may not develop in the injected mice.8,9 Several mechanisms that can induce CD4ϩ T-cell death or unresponsiveness have been identified. These mechanisms in- 1 3 From the Beijing Institute of Ophthalmology and the Depart- clude T-cell anergy, which is due to the absence of costimula- ment of Ophthalmology, Beijing TongRen Eye Center, Capital Univer- 2 tion at the time of activation, and Fas-mediated activation- sity of Medical Sciences, Beijing, China; and the Department of Im- ␥ ␣ munology, General Hospital of PLA, Beijing, China. induced cell death (AICD). Cytokines, such as IFN- , TNF- , Supported by the National Natural Foundation of China. and IL-10, can also mediate T-cell suppression; however, the Submitted for publication August 20, 2002; revised February 25 detailed mechanisms involved in the induction of these cyto- and March 18, 2003; accepted March 27, 2003. kine-regulated T-cell death pathways have not been fully char- Disclosure: Z. Pan, None; Y. Chen, None; W. Zhang, None; Y. acterized.10 Jie, None; N. Li, None; Y. Wu, None Bacterial SAgs are a large group of polypeptides that are The publication costs of this article were defrayed in part by page produced by bacterial strains, such as Staphylococcus aureus charge payment. This article must therefore be marked “advertise- and S. pyrogenes. SAgs have been implicated in the pathogen- ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Corresponding author: Zhiqiang Pan, Beijing Institute of Ophthal- esis of toxic-shock–like syndromes in both animal models and mology, Beijing TongRen Eye Center, Capital University of Medical in humans. In particular, the in vivo immune response to the S. Sciences, 17# Hou Gou Lane, ChongNei Street, Beijing 100730, China; aureus SAg SEB represents a useful model for studying in vivo [email protected]. cytokine regulation and the phenomenon of peripheral T-cell Investigative Ophthalmology & Visual Science, August 2003, Vol. 44, No. 8 3346 Copyright © Association for Research in Vision and Ophthalmology Downloaded from iovs.arvojournals.org on 10/02/2021 IOVS, August 2003, Vol. 44, No. 8 Enhancement of Corneal Allograft Survival by SEB 3347 unresponsiveness. After their initial clonal expansion and cy- TABLE 1. Clinical Scoring Scheme for the Severity of Corneal tokine production, SEB-reactive T cells are thought to become Graft Rejection unresponsive to further TCR stimulation.11 T-cell deletion and unresponsiveness could be induced by oral administration or Type/Score Clinical Finding intrathymic injection of low doses of SEB, which could result in Graft opacity not only gut-associated lymphoid tissue (GALT) and thymic 12,13 0 No opacity alterations but also peripheral pivotal immune alterations. 1 Slight opacity, details of iris clearly visible The SEB used in this study was produced from S-6 cocci 2 Some details of iris no longer visible ferment, which has a molecular mass of 2.84 to 2.9 kDa and an 3 Pronounced opacity, pupil still isoelectric point of 8.6, and purified by affinity chromatogra- recognizable phy. In our previous experiments, SEB selectively decreased 4 Total opacity the percent of CD4ϩ T cells and CD4ϩ T/H2Kb cells, but had Graft edema no effect on the number of CD8ϩ cells after allogenic mouse 0 No edema cell transplantation. Accordingly, the proliferative response 1 Mild edema 2 Pronounced edema with raised transplant caused by MLRs in the recipient mouse decreased signifi- 8 3 Pronounced edema with small bleb cantly. Herein, we report that treating an inbred rat model of 4 Pronounced edema with large bleb allograft keratoplasty rejection with SEB injections into the Graft neovascularization peribulbar space at preoperative and postoperative day 7 led to 0 No vessels rat immune unresponsiveness (anergy), which persisted for 15 1 Vessels appearing in the corneal bed to 20 days after only one injection. Because SEB entered the 2 Vessels appearing in the graft periphery blood and induced CD4ϩ and CD8ϩ T lymphocyte unrespon- 3 Vessels extending deeper siveness, it appears that the effect was systemic.8 In all, we 4 Vessels extending to the center used the superantigen SEB to induce anergy for the purpose of prolonging corneal allograft survival and to observe any subse- quent immune reactions. bined score of all three factors were equal to or exceeded 6. Also, the mean survival time for each group was calculated. MATERIALS AND METHODS Histopathological and Animals Immunofluorescence Evaluation Adult inbred female F344 and Lew rats were purchased from the At postoperative days 10 and 30, two graft-recipient animals were Animal Institute of Chinese Medical Academy (Beijing, China) and used killed by carbon dioxide inhalation. Afterward, the eyes were enucle- as experimental subjects between 2 and 2.5 months of age. All animals ated and fixed in a buffered formalin solution (4%). For histologic were treated according to the ARVO Statement for the Use of Animals assessment, the formalin-fixed eyes were cut into 4-␮m-thick sections in Ophthalmic and Vision Research.
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