Lymphoma allografts abrogate immune privilege within the anterior chamber of the eye

Immune privilege is extended to allogeneic tissues placed into the anterior chamber of the eye and results in part from the induction of anterior chamber-associated immune deviation (ACAID)--a condition in which the host is capable of making humoral antibodies and cytotoxic T cells specific for the antigens in question, but is selectively suppressed in its capacity to generate delayed-type hypersensitivity (DTH). Privilege is extended only transiently to tissue differing at the major histocompatibility complex; by contrast, privilege is complete for tissues offering multiple minor H incompatibilities, but no MHC disparity. During examination of host responses to tumor cell lines in this latter category, it was observed that privilege was extended to all histologic categories of tumors examined except T cell lymphomas. Moreover, the capacity of minor H incompatible tumors to maintain immune privilege and sustain prolonged survival within the anterior chamber could be abrogated if T cell lymphomas were placed into the anterior chamber of the contralateral eye. Thus, T cell lymphomas exert a systemic influence which robs the anterior chamber of its immune privilege. It is concluded that this systemic effect is intimately related to lymphokines produced by T cell lymphoma allografts. Since immune privilege seems to be a physiologic property of the anterior chamber, it is suspected that local features within this site conspire to insure that antigens placed therein interact with the immune system in a manner that bypasses lymphokine production, thus allowing for the induction of ACAID and selective suppression of DTH.     

Anterior chamber associated immune deviation: the privilege of immunity in the eye

Immune privilege in the anterior chamber of the eye, no longer considered a laboratory curiosity, results from an active, if deviant, systemic immune response. The specific features of this response, termed Anterior Chamber Associated Immune Deviation (ACAID) include (a) suppressed delayed hypersensitivity, (b) preserved humoral immunity, and (c) primed cytotoxic T cell responses. Induction of ACAID by intraocular antigens depends upon unique characteristics of the anterior segment of the eye and of the spleen. Evidence from animal models is presented in support of the contention that ACAID is an evolutionary adaptation of the immune response designed to provide those types of immune protection for the eye that interfere with vision as little as possible. ACAID may also have been created for the purpose of avoiding harmful immune responses (autoimmune diseases) to unique molecules of the eye (such as retinal S antigen), which the immune system never learns to regard as "Self." Because of this adaptation, the eye and the host are vulnerable to those pathogens whose elimination is dependent upon delayed hypersensitivity, such as malignant tumors and herpes simplex virus-1. As we come to understand the cellular and molecular mechanisms responsible for ACAID, a new generation of therapeutic strategies may be envisioned for certain eye diseases which are now of enigmatic cause and submit poorly to conventional therapy.     

Immunological privilege in the eye: a review

The eye enjoys a privileged immunological status, in contrast to most sites in the body. Historically, it was thought that the eye, due to its lack of lymphatics, was not subject to the same immune surveillance as other tissues. In opposition to this, recent study has revealed that presenting foreign material via the eye produces marked effects on systemic immunity, leading to a state of tolerance when the same foreign antigen is presented systemically. The immunology of the eye is now known to consist of a myriad of local and systemic effects.     

Ocular immune privilege in the year 2010: ocular immune privilege and uveitis

The phrase "immune privilege" was coined by Peter Medawar to describe the absence of an immune response to allografts placed into the anterior chamber of the eye or brain. We now understand that immune privilege is more than a passive microenvironment with a distinctive anatomical structure that holds back immunity. The ocular microenvironment actively engages the immune system with immunosuppressive biochemical mechanisms. The unique characteristics of ocular immune privilege appear designed to protect the eye from damage while preserving foveal vision, thus providing the host with a definite survival advantage. However, the protection is not always sufficient and the eye becomes susceptible to uveitis. Uveitis is an intraocular inflammatory disorder that encompasses a wide range of underlying etiologies. It may be idiopathic or associated with systemic disease or infection. Understanding the biochemistry of immune privilege has the potential to identify its weaknesses that allow for immunity to break through.     

Thrombospondin 1, thrombospondin 2 and the eye

Thrombospondin 1 and thrombospondin 2 (TSP1 and TSP2), which comprise the subgroup A thrombospondins, are matricellular proteins. As matricellular proteins, they modulate interactions between cells and the cellular environment, regulate cell adhesion and typically are expressed during tissue formative processes. In general, TSP1 and TSP2 counter angiogenesis (including tumour angiogenesis) and play important but contrasting roles during cutaneous repair. The two proteins are involved in development, including that of the eye, although evidence suggests that they have their greatest impact during tissue production in the adult. In the normal adult eye, they tend to be found at sites of ongoing matrix synthesis or cell-matrix interactions. At these sites, the two proteins possibly influence cellular differentiation and/or basement membrane deposition. TSP1 is also present in the intraocular fluids and drainage pathway, where it may function in maintaining the anti-angiogenic environment and in intraocular pressure control, respectively. TSP1 could also be involved in ocular immune privilege. Unlike in skin wounds, where TSP1 is derived from the blood and is present only in the early phases of repair, ocular tissue damage appears to lead to protacted TSP1 synthesis by local cells. This response might help suppress angiogenesis in the transparent tissues of the eye and so lessen visual axis opacification following injury. However, TSP2, which is also produced by damaged ophthalmic tissue and may be especially important in matrix organisation, seems to augment contraction in anomalous intraocular fibrosis. Elucidating the roles of TSP1 and TSP2 in ocular physiology and pathobiology may lead to improved therapies for neovascular, neoplastic, reparative and other ophthalmic diseases.     

Retinal pigment epithelial cells phagocytosis of T lymphocytes: possible implication in the immune privilege of the eye

AIM: To investigate the capability of retinal pigment epithelium (RPE) cells to phagocytose T lymphocytes and to further analyse the immunobiological consequences of this phagocytosis. METHODS: Human RPE cells pretreated or not by cytochalasin, a phagocytosis inhibitor, were co-cultured with T lymphocytes for different time points. Phagocytosis was investigated by optic microscopy, electron microscopy, and flow cytometry. T cell proliferation was measured by (3)H thymidine incorporation. RPE interleukin 1beta mRNA expression was quantified by real time PCR. RESULTS: RPE cells phagocytose apoptotic and non-apoptotic T lymphocytes, in a time dependent manner. This is an active process mediated through actin polymerisation, blocked by cytochalasin E treatment. Inhibition of RPE cell phagocytosis capabilities within RPE-T cell co-cultures led to an increase of lectin induced T cell proliferation and an upregulation of interleukin 1beta mRNA expression in RPE cells. CONCLUSIONS: It is postulated that T lymphocyte phagocytosis by RPE cells might, by decreasing the total number of T lymphocytes, removing apoptotic lymphocytes, and downregulating the expression of IL-1beta, participate in vivo in the induction and maintenance of the immune privilege of the eye, preventing the development of intraocular inflammation.     

The immune privilege of the eye: human retinal pigment epithelial cells selectively modulate T-cell activation in vitro

PURPOSE: To examine the effect of human retinal pigment epithelial (RPE) cells on phytohemagglutinin (PHA) activation of T cells. METHODS: Resting peripheral blood lymphocytes (PBLs) were stimulated with PHA with or without the presence of gamma-irradiated RPE cells. Proliferation and the cell cycle profile were thereafter investigated by 3H-thymidine incorporation and flow cytometric analysis. In addition, the PBLs expression of CD69, major histocompatibility complex (MHC) class I and II, CD3, as well as the IL-2 receptor chains were evaluated by flow cytometry, and the content of IL-2 in cell culture supernatant was measured by ELISA. RESULTS: Human RPE cells were found to suppress PHA-induced proliferation, cyclin A, IL-2R-alpha and -gamma, and CD71 expression and decrease the production of IL-2; but RPE cells do not inhibit the PHA-induced expression of early activation markers CD69, MHC class I and II, and of cyclin D of the PBLs. CONCLUSIONS: These results are the first to indicate that RPE cells impede generation of activated T cells by interfering with the induction of high-affinity IL-2R-alphabetagamma, IL-2 production, and the expression of CD71 and cyclin A.     

Ocular immune privilege in the immunosuppressive intraocular microenvironment

Immune privilege exists in the normal eye (anterior chamber, vitreous cavity, subretinal space): when foreign tissue/cellular grafts are placed in the eye, rejection is largely, if not completely, avoided. The ineffectiveness of the immune response in this circumstance results from eye-dependent alterations in (a) the induction of systemic immunity to graft antigens, and (b) the expression of cell-mediated immunity within the eye. Recent evidence indicates that eye-derived factors, present in the intraocular microenvironment, modify the afferent and efferent limbs of the immune response. Studies of aqueous humor as a prototype of the intraocular microenvironment have demonstrated that this fluid profoundly inhibits antigen-driven T cell activation such that proliferation and lymphokine production are curtailed. Moreover, aqueous humor modifies the functional properties of conventional antigen presenting cells (APC) such that exogenous antigens are processed uniquely. When antigen-pulsed APC exposed to aqueous humor are injected intravenously, they induce Anterior Chamber Associated Immune Deviation (ACAID). Several factors in aqueous humor have been implicated as immunosuppressants: transforming growth factorbeta, alpha-melanocyte stimulating hormone, vasoactive intestinal peptide, calcitonin gene related peptide, and hydrocortisone (because Cortisol binding globulin is virtually absent). In certain experimentally-induced ocular disorders, resident ocular cells fail to secrete immunosuppressive factors constitutively, and this may explain why immune privilege is also lost.     

细菌性眼内炎的免疫赦免及免疫应答机制

细菌性眼内炎是能导致视力严重受损的眼科重症,即使采取了及时和积极的药物及手术干预,仍会造成眼部组织不可逆的损伤.对细菌性眼内炎的研究热点是研究眼部组织对感染的免疫反应及病原微生物和宿主组织间分子和细胞的相互作用.目前国内外对细菌性眼内炎免疫应答机制的研究包括免疫赦免、固有免疫反应、补体系统、Fas配体、炎性细胞浸润、细胞因子及细胞间黏附因子的作用等方面.     

免疫赦免在小鼠角膜移植排斥中的作用研究

目的:阐明同种异体小鼠角膜移植术后免疫排斥反应及免疫赦免的相关性。方法:建立小鼠原位角膜移植及同种异体小鼠角膜移植实验模型。观察原位移植与同种异体移植术后角膜植片发生排斥的情况,对比两种移植术后植片的存活率,了解小鼠角膜移植术后发生排斥反应与免疫赦免反应之间的关系。结果:小鼠原位角膜移植术后植片100%存活;同种异体小鼠角膜移植术后存活率为25%。结论:小鼠角膜移植术后免疫排斥并非绝对,免疫赦免在角膜移植术中发挥重要作用。     

Immune privilege and suppression of immunogenic inflammation in the anterior chamber of the eye

Immunologic privilege of the anterior chamber has been associated with the capacity to induce a unique form of deviant systemic immunity after anterior chamber (AC) immunization. However, the capacity of privilege to suppress expression of immunity in the AC has not been examined. We studied the ability of the AC to sustain immunogenic inflammation after direct antigen challenge (delayed hypersensitivity-DH) in C57BL/6 mice primed to M tuberculosis (MT) antigens. Compared to subcutaneous and subconjunctival sites where primed mice demonstrated vigorous and significant DH, the anterior chambers of these mice failed to develop signs of inflammation unless toxic doses of antigen were injected. In an attempt to promote intraocular DH, the AC's of MT-primed mice were pre-treated with subinflammatory intracameral injections of IFN-gamma, a cytokine that antagonizes TGF-beta, recruits antigen presenting cells (APC) from the blood and activates resident APC precursors. It was observed that AC injection of IFN-gamma, followed 3 days later by AC challenge with 200 ng of MT, resulted in severe intraocular inflammation only in primed (but not naive) mice. We conclude that the normal mouse AC resists DH unless its immunosuppressive microenvironment is abolished, as in these experiments by IFN-gamma. We propose that impaired expression of cell-mediated immunity is an important component of immune privilege of the AC.     

眼免疫赦免的两面性及其临床意义

眼的免疫赦免卢因于眼自身对全身免疫反应诱导和表达的修饰。将抗原接种于眼前房可以诱导一种偏离形式的全身性免疫反应,称为前房相关免疫偏离。ＡＣＡＩＤ的主要特征是：（１）怕特异性迟发型超敏反应和补体结合性抗体反应的缺陷;（２）产生独特的调节性Ｔ细胞亚群。     

Epithelium-deficient corneal allografts display immune privilege beneath the kidney capsule

PURPOSE: To determine whether corneal tissue as an allograft displays immune privilege in a nonprivileged site and, if so, whether CD95 ligand expression contributes to the privileged status. METHODS:Syngenic and allogeneic corneal tissues deprived of epithelium were transplanted beneath the kidney capsule of normal mice. Syngeneic BALB/c, allogeneic C57BL/6, and allogeneic B6Smn.C3H-gld (CD95 ligand-deficient) mice were used as donors for BALB/c recipients, and syngeneic C3H/HeJ-gld (CD95 ligand-deficient) mice were used for normal C3H/HeJ recipients. Allogeneic conjunctival segments served as positive grafting controls. Graft fate was assessed by visual inspection at 4, 7, 14, and 21 days and was confirmed by histologic study. Viability of graft endothelium was assessed by immunocytochemical analysis. RESULTS. Syngeneic corneas and C57BL/6 corneas survived almost indefinitely beneath the kidney capsule. Both the stroma and the endothelial layers remained healthy and intact. Allogeneic conjunctiva evoked a strong inflammatory response attended by neovascularization. Similarly, B6-gld corneas deficient in CD95 ligand expression showed acute destruction beneath the kidney capsule. Circumstantial evidence implicates alloimmune rejection as the mechanism. CONCLUSIONS. Epithelium-deprived corneas from normal mice possess inherent immune privilege that protects them from alloimmune rejection even at nonprivileged sites. Constitutive expression of CD95 ligand contributes to the privileged status. It is inferred that the extraordinary success of orthotopic corneal allografts owes as much to the qualities of the graft as an immune-privileged tissue as to the qualities of the eye as an immune-privileged site.     

Latanoprost does not affect immune privilege of corneal allografts

The present study determined whether topical latanoprost, a prostaglandin (PG) F(2alpha) analog, influences the induction of anterior chamber-associated immune deviation (ACAID), corneal neovascularization (NV) or survival of corneal allografts in mice. BALB/c mice received topical latanoprost or PGE(2) once or multiple times daily starting 4 weeks prior to or the day of anterior chamber injection of C57BL/6 splenocytes. Induction of allo-specific ACAID was assessed by ear challenge with C57BL/6 splenocytes 1 week after subcutaneous immunization. In a separate experiment, orthotopic corneal transplantation was performed using C57BL/6 mice as donors and BALB/c mice as recipients. Recipients were randomized in a masked fashion to receive topical latanoprost or PGE(2). Graft fate was assessed clinically under surgical microscopy. Presence of MHC class II(+) CD11c(+) or CD11b(+) cells in normal BALB/c mouse eyes following latanoprost or PGE(2) administration was assessed immunohistochemically. Control mice received topical 20% dimethyl sulfoxide or no treatment. Allo-specific ACAID was induced after 2 or 6 weeks of once daily treatment with latanoprost, and was induced even after 6 weeks of multiple treatments with latanoprost. Conversely, mice receiving PGE(2) failed to develop ACAID. Opacity and corneal NV scores for allografts treated with latanoprost were statistically indistinguishable from those for control allografts (p>0.05), whereas all allografts treated with PGE(2) were rejected. Opacity and NV scores were significantly higher in these allografts than in controls (p<0.05). A number of MHC class II(+) CD11c(+) cells were present in the central cornea after PGE(2) treatment. Topical application of latanoprost does not influence induction of ACAID or graft outcomes including opacity and NV, whereas PGE(2) does. Immune privilege of corneal allograft is maintained after topical latanoprost application in mice.     

Postmortal "vital" staining of the external eye.

Two hundred and two eyes from 112 individuals were vital-stained from 2 to 46 h after death. Intensity and extension of staining were studied in ten regions. The staining gradually progressed after death, also within non-exposed areas. It most often started anteriorly on the tarsus and finanally included the fornix. Microscopy revealed diffuse cell staining by rose bengal or trypan blue. The cell nucleus was most often more intensely stained than the cytoplasm. Up to five h after death, neutral red had only stained vacuoles in the cytoplasm. Later diffuse staining of cells occurred. Tetrazolium differed from the above dyes in that the pronounced staining seen immediately after death gradually decreased in the course of time. Microscopy disclosed stained inclusion bodies in the cytoplasm up to 18 h after death. Then cell staining was only seen as a rare exception in relation to extracellular dye granules. However, the mucous thread in the inferior fornix showed gradually increasing postmortal tetrazolium staining. The amount of mucus was found to be the same in dead persons as in the living. The characteristic appearance of the dead eye is due, among other things, to ruptures of the corneal epithelium (fluorescein-stained) and cell death, and not to drying up or coating by mucus.     

Analysis of immune privilege in eyes with Mycobacteria tuberculosa adjuvant-induced uveitis

PURPOSE: To examine the effects of intravitreal Mycobacteria tuberculosa adjuvant (MTA) on ocular immune privilege. METHODS: MTA was injected into the vitreous cavity of BALB/c mouse eyes to induce anterior uveitis. The inflamed eyes were then examined for their capacity to afford immune privilege to injected allogeneic tumor cells and to promote anterior chamber-associated immune deviation (ACAID). Aqueous humor (AqH) was tested for IL-12 content and for its ability to inhibit T-cell activation. RESULTS: AqH removed from MTA-inflamed eyes at 6 and 12 h contained high levels of IL-12, which then fell almost to baseline at 24 h. This is relevant to the finding that the inflamed eye failed to support ACAID induction at an early time period and then regained the ACAID-induction capability at a later time. Nonetheless, AqH removed from MTA-inflamed eyes retained its capacity to suppress T-cell activation, and MTA-inflamed eyes afforded extended survival to alloantigenic tumor cells implanted into the anterior chamber. CONCLUSION: Intraocular inflammation evoked by MTA causes the local accumulation of IL-12 and simultaneously robs the eye of its capacity to promote systemic immune tolerance to eye-derived antigens. However, MTA-inflamed eyes retain immune privilege, as indicated by their support of the progressive growth of allogeneic tumor cells.     

小鼠眼内移植性黑色素瘤诱导免疫偏离的表达

目的　观察小鼠前房和玻璃体腔的移植性黑色素瘤是否具有诱导免疫偏离的能力。方法　将雄性昆明小鼠 60只随机分为实验组及其相应的对照组共 5组。分别于实验组小鼠的前房或玻璃体腔接种黑色素瘤B16F10细胞 ,然后观察测量和比较其抗原特异性迟发型超敏反应 (DTH)的程度。结果　 ( 1)小鼠前房和玻璃体腔移植性黑色素瘤均可进行性生长。 ( 2 )各组小鼠右耳DTH反应的肿胀值为前房组 ( 3 4± 3 5 ) μm ,玻璃体腔组 ( 3 6± 96) μm ,前房对照组 ( 194± 99) μm ,玻璃体腔对照组 ( 186± 5 5 ) μm以及空白对照组 ( 165± 118) μm。实验组与其相应对照组的差异具有显著性意义 (前房组t =-5 2 0 9,P =0 0 0 0 ;玻璃体腔组t =-3 871,P =0 0 0 2 )。 ( 3 )病理观察实验组“二免”后右耳未见炎性细胞浸润 ,而对照组则相反。结论　同种异体的昆明小鼠前房和玻璃体腔的移植性黑色素瘤均具有诱导其相关免疫偏离的能力。