Impact Factor 5.511

Among the world's top 10 most-cited Immunology journals

Review ARTICLE

Front. Immunol., 08 February 2016 | https://doi.org/10.3389/fimmu.2016.00037

Ocular Immune Privilege and Transplantation

  • Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA

Allografts are afforded a level of protection from rejection within immune-privileged tissues. Immune-privileged tissues involve mechanisms that suppress inflammation and promote immune tolerance. There are anatomical features, soluble factors, membrane-associated proteins, and alternative antigen-presenting cells (APC) that contribute to allograft survival in the immune-privileged tissue. This review presents the current understanding of how the mechanism of ocular immune privilege promotes tolerogenic activity by APC, and T cells in response to the placement of foreign antigen within the ocular microenvironment. Discussed will be the unique anatomical, cellular, and molecular mechanisms that lessen the chance for graft destroying immune responses within the eye. As more is understood about the molecular mechanisms of ocular immune privilege greater is the potential for using these molecular mechanisms in therapies to prevent allograft rejection.

What is Immune Privilege

The phrase immune privilege is a transplantation term defined by Peter Medawar and colleagues in the 1940s (1). They demonstrated that skin allografts placed within the anterior chamber of the eye survive indefinitely in contrast to their rapid rejection in other more conventional tissues such as the skin. This happened even when the recipient is already immunized against the alloantigens, but only if the blood–ocular barrier was maintained. It had been observed that once there is vascular leakage into the anterior chamber the graft is rejected. Another characteristic of allograft placement into the anterior chamber is that it does not immunize the recipient (2). Since the eye has no observable direct lymphatic drainage, it had suggested that alloantigen could not reach the regional lymph nodes and initiate an immune response. Such mechanisms of sequestration of antigen and antigen-expressing tissues has erroneously led some to think that the ocular microenvironment should be devoid of all immune cells and immune responses. This is clearly not the case (3).

There are resident immune cells with the potential of being antigen-presenting cells (APC) within the cornea, iris, ciliary body, and the retina. In the retina, they are the resident macrophage-like microglial cells (48), and there is very little evidence of cellular migration from blood circulation into the healthy ocular microenvironment (9). There is some speculation that resident macrophages and microglial cells are turned over, but this has only been seen in irradiated mice (1013). It is also possible that the microglia of the retina are like microglial in the rest of the CNS are long-lived and are not initially bone marrow derived (9, 1416). When there is inflammation, such as with uveitis, it is clear that the blood–ocular barrier is leaking, and that most of the infiltrating immune cells are coming through breaches in the barrier (13, 17, 18).

The blood–ocular barrier is made from the tight junctions of the pigmented epithelial cell layer of the uveal track, of the endothelial cells of the inner-retina capillaries and the avascular cornea (19). This enclosed space allows for the eye to form its own microenvironment to regionally suppress the activation of inflammation and to control the functionality of immune cells. Locally produced soluble factors found in aqueous humor, and the soluble and membrane-bound factors of the pigmented epithelial cells described in detail later suppress the activation of inflammation (2039). These factors are a defined group of proteins, neuropeptides, and biochemicals that modify the behavior, differentiation, and survival of immune cells within the ocular microenvironment. Their combined actions make the ocular microenvironment highly anti-inflammatory; moreover, the mechanism of immune privilege makes immune cells (monocytes, macrophages, dendritic cells, microglial cells, and T cells) to contribute to the anti-inflammatory microenvironment (3, 4042). This promotes a self-perpetuating anti-inflammatory immune response, and induction of immune tolerance, which protects the eye from the irreversible collateral damage of inflammation that can lead to blindness.

It has very much been demonstrated that immune cell activity is present, but it is driven within the ocular microenvironment toward anti-inflammatory and tolerogenic immune responses. In addition, the placement of alloantigen-expressing grafts into the anterior chamber or within the retina induces alloantigen-specific systemic tolerance (1, 31, 41, 4347). This has shown that the presence of foreign antigen with the eye is not hidden.

What are the Immune Responses to the Placement of Foreign Antigen within the Eye

The prolonged survival of incompatible grafts in the eye is the definition of immune privilege (1). The mechanism of how this is achieved is through induction of systemic tolerance to the alloantigens and the regional suppression of inflammation (40). These mechanisms establish a strong blockade in activating a graft destructive immune response. Although this is not an absolute suppression of immunity, understanding the mechanisms of immune privilege has led to understand that a large part is to regulate APC activity in a manner that activates regulatory T (Treg) cells (6, 4749).

The placement of foreign antigen into the anterior chamber, vitreous, or in the sub-retinal space induces systemic tolerance to the antigen. The initial experiments demonstrating this phenomenon were done by placing MHC-mismatched tumor cells into the anterior chamber of the eye, resulted in graft survival of skin from the same MHC-mismatched mouse strain (50, 51). By contrast, mice that had the tumor cells placed into the skin rejected both the tumor cells and the subsequent skin graft. The induction of systemic tolerance was considered a deviation from the expected hypersensitivity immune response and was called anterior chamber-associated immune deviation (ACAID). Also, the same ACAID-like response is seen when any foreign antigen is placed in the vitreous, or sub-retinal space (44, 52, 53). Like the immune response to allografts, it is unclear what is the evolutionary advantage of ACAID unless it is either a byproduct of the anti-inflammatory environment of the eye or part of controlling the immune response to presented autoantigens within the eye.

The tolerance induced in ACAID is efferent suppression mediated by a tolerogenic CD8+ T cell. It is antigen specific, and it suppresses the activation of effector T cells responding to the same source of antigen. Within hours after injecting antigen into the eye, the antigen disseminates almost throughout the body. This suggested for a long time that the tolerogenic mechanism of the eye was similar to inject antigen directly into the blood circulation; however, the tolerance induced by antigen placed into the eye is dependent on the spleen, and the presentation of antigen by a F4/80+ macrophage (54, 55). The induction of the ACAIDogenic APC can be done by treating cultured macrophages with aqueous humor or with the aqueous humor factor TGF-β2 while providing antigen or a source of antigen, like cells expressing alloantigens (5659). These ACAIDogenic APC leave the eye via the blood circulation and home to the marginal zones of the spleen. They form cellular clusters with NKT cells as well as CD4+ and CD8+ T cells (60). Also, in these clusters are B cells that take up antigen directly from the ACAIDogenic APC and present the antigen (61). These clusters are mediated by the production of RANTES made by NKT cells stimulated by CD1d on the ACAIDogenic APC and this brings in CD8+ T cells (60, 62). The result is the induction and expansion of antigen-specific efferent suppressor CD8+ T cells. These cells are responsible for the antigen-specific systemic prevention of graft rejection and hypersensitivity (6365). Since the mechanism of inducing ACAIDogenic APC is a local effect of the immune-privileged ocular microenvironment, it is possible that presentation of CD1d in the eye would also locally activate tolerogenic NKT cells. It has been shown that cornea allograft survival is associated with CD1d stimulation tolerogenic NKT cells like in the ACAID response (66, 67). By contrast, failure to stimulate the NKT cells to promote Treg cell activation may be associated with corneal allograft rejection. Therefore, from understanding the mechanisms of the ACAID, it is possible to speculate that APC in the ocular microenvironment are also influenced by ocular TGF-β2 to CD1d-stimulated NKT cells that are anti-inflammatory, and mediators of Treg cell activation.

Similar tolerogenic APC induced by TGF-β2 is seen when antigen is placed into the sub-retinal space (68). The study of sub-retinal induction of ACAIDogenic APC has shown that part of the induction of immune deviation is a cascade of TGF-β2 activation from latent to active mediated by thrombospondin-1, and it receptor CD38 on the F4/80+ macrophages (68). Therefore, antigen, either soluble or shed from transplanted cells, is processed by APC under the influence of the ocular microenvironment, and that these antigen-loaded APC migrate to the spleen to initiate tolerance, or remain within the eye to mediate anti-inflammatory activity and stimulate Treg cells.

Molecular Mechanisms of Ocular Immune Privilege

One of the original observations about ocular immunobiology was that placement of foreign antigen into the eye of a recipient with an already established effector immune response does not elicit an inflammatory response (1). An additional element of immune regulation is the anti-inflammatory mechanisms of the ocular microenvironment itself that works to prevent induction of inflammation and suppress the activity of effector immune cells (69, 70). This is seen as the mechanisms of immune suppression mediated by soluble molecules of aqueous humor, and membrane expressed molecules of cells within the ocular microenvironment.

The most understood immunosuppressive mechanisms of ocular immunobiology are the effects of aqueous humor on immune cells. Since the blood barrier does not inhibit effector T cell migration into the eye (71, 72), there are several mechanisms regulating T cell activity within the immune-privileged eye. When effector T cells with APC-presenting antigen are injected into the anterior chamber, the inflammation mediated by the antigen-activated effector T cells is suppressed (69). Also, the T cell-mediated inflammation is suppressed when the APC and the T cells are first treated with aqueous humor, and adoptively transferred into tissues other than the eye. Molecular analysis of aqueous humor shows that TGF-β2 has the possibly of being the major regulatory molecule; however, it is in a latent form and rarely found active in fresh aqueous humor of healthy eyes (7376). The first reports of aqueous humor suppression of T cell activation used pooled, frozen aqueous humor samples (77). The freezing and thawing of aqueous humor activate the TGF-β2, and because of the overwhelming potency of TGF-β2 on T cell activity, the first descriptions of aqueous humor suppressive activity were more of a study on the effects of TGF-β2 on immune reactions (78). One of these is the induction of the ACAIDogenic APC (59). Careful collection of aqueous humor, and its immediate use in assays, keeping TGF-β2 in its latent form, has revealed a wealth of other soluble immunomodulating molecules dominated by neuropeptides such as alpha-melanocyte-stimulating hormone (α-MSH) (20).

Each of the molecules of aqueous humor target different cells of the immune response and different activities (41). The result is the induction of CD4+ Treg cells from an already established population of effector T cells (79). This induction of CD4+ Treg cells is mediated mostly by the activity of the neuropeptide α-MSH. This is enhanced by the suppression of effector T cell activity by the other neuropeptides vasoactive intestinal peptide, somatostatin, and also by TGF-β2 when activated (21, 24, 79). The APC are also converted from presenting antigen that promote effector T cell activity to present antigen that activates Treg cells (80, 81). This is mediated by α-MSH, neuropeptide Y, and TGF-β2 that activate suppressive APC, and antigen-activated Treg cells. This means that molecules within the eye prevent immune-mediated inflammation while promoting the immune response to regulate itself. Since the immune response is an already established effector response, the activated Treg cells are inducible Treg (iTregs) cells meaning that the healthy ocular microenvironment is a site of immune reeducation. Therefore, immune privilege maybe more than suppressing inflammation, and that its immunosuppressive mechanisms can be used as a molecular approach to therapeutically promote long-term allograft survival through the induction of tolerance.

The cells of the cornea and the retina express on their membrane surfaces molecules that interact with immune cells to promote regulatory activity or apoptosis in the T cells. Many of the cells of cornea constitutively express FasL and PD-1 family of molecules (38, 8284). The encounter between activated T cells and corneal endothelial cells leads to apoptosis of the T cells. The expression of B7-2 on pigmented epithelial cells lining the uveal track is associated with the conversation of naive T cells into Treg cells (35). This action is compounded by the fact that the pigmented epithelial cells are a source of many soluble immunomodulating molecules, such as TGF-β2, α-MSH, and neuropeptide Y (25, 28). Since naive T cells rarely migrate into peripheral tissues, the induction of apoptosis in the effector T cells is an important mechanism in preventing targeted immune attacks within the ocular tissues. Also, this could be a selective mechanism to allow for Treg cells to function within the eye, since they are more resistant to FasL-induced apoptosis (85), and that PD-1 is an activation signal for Treg cells (81, 86). This indicates that even transplanted ocular tissues, such as the cornea, carry molecules with the potential to mediate immunosuppression and tolerance.

The retina expresses not only FasL like the cornea but also molecules unique to the regulation of microglial cells or migrating macrophages. Neurons of the retina express CD200 that binds to CD200L and suppresses microglial cell-mediated inflammation (87). Mice with CD200:CD200L interaction knocked out are more susceptible to uveitis (87). Along with this regulation, soluble molecules from the retinal pigment epithelial cells (RPE) alternatively activate the microglia cells and macrophages (28, 80). This alternative activation makes these potential APC act and appear like myeloid-derived suppressor cells (MDSC) (88). The most we can understand of MSC is that they prevent effector T cell activation and suppress inflammation. Their presence in tumors has blocked many attempts at anti-cancer immunotherapy (89). Having such cells as part of the healthy retina is a potential advantage for preventing autoimmune attack and inflammation (81, 90, 91). The major molecular mediators of this are the neuropeptides α-MSH and NPY (28).

The placement of allogeneic neuroretinal cells or stem cells into the retina shows protection but is eventually rejected (92). This rejection is devoid of inflammation, and how the cells are eliminated is unknown. There is no rejection if the cells differentiate into neuronal cells and make connections with other retinal cells (93). This suggest that while immune privilege can prevent an inflammatory response non-integrated neurons must some how be targeted for removal, and an alloimmune response accelerates this clearance.

Experimental conditions that alter the ocular microenvironment to make it no different from conventional tissues, such as creating a high-risk cornea graft bed, or wounding RPE monolayers, demonstrate the importance of maintaining immune privilege to the success of ocular allografts. High-risk cornea graft beds have elevated levels of dendritic cells and vascularization with in the cornea stoma, and allograft rejection is almost assured (6, 94, 95). Experimentally designed high-risk corneas in rodents do not support ACAID, suggesting that changes in the cornea are most likely opening a barrier, probably through corneal neovascularization. Also, ACAID is lost in eyes with laser and sodium iodate wounded RPE monolayers (95, 96). The microglial cells change under these conditions from acting as suppressor cells into proinflammatory cells (28). This further demonstrates that changes in the barrier that defines the ocular microenvironment have a profound influence on APC activity. The activity changes from supporting a blockade of inflammation and effector T cell activation to one where the APC themselves may contribute to the destructive immune response. How they change and what mediates the change is unknown. It is not clear which of the molecules and mechanisms of the ocular immune privilege is no longer active in high-risk ocular tissues.

Using the Mechanism of Immune Privilege to Promote Allograft Survival

It still remains to be seen if it is possible to use the molecular mechanisms of immune privilege to promote allograft survival. Some serendipitous discoveries suggest that it maybe possible involving ACAID, anti-inflammatory activity of aqueous humor, and ocular induction of Treg cells. Although there are several proposals, it will be awhile before any can be practical and administered in the clinic, but there are a few that can be done as a process of preparing and treating the allograft.

One issue of ocular immune privilege is whether it rests with the cells of eye or solely with the molecules within the healthy ocular microenvironment. Arguing that immune privilege is with the cells is the finding that allogeneic retinal progenitor cells (RPC) exhibited limited immunogenicity and may produce immunosuppressive factors that promote their survival when implanted. One idea of delivering RPC to remodel retinas is to place them in a degradable scaffolding (97). When the RPC are seeded on poly(lactic-co-glycolic acid) polymer, and grafted under allogeneic kidney capsules they survive, and cells begin to differentiate into neurons and astrocytes. This happens even after the grafts are treated with IFN-γ to stimulate immunogenicity. When allogeneic RPC-containing polymers are seeded with syngeneic APC, the APC acted like ACAIDogenic APC and promote alloantigen-specific tolerance. This suggests that it is possible to create a localized immune-privileged site using cells of immune-privileged tissues within a defined structural microenvironment.

It is clear that soluble immunomodulating molecules of ocular immune privilege drive the induction of regulatory immunity. It is possible to use these molecules to suppress allograft rejection. The aqueous humor neuropeptide α-MSH is one of these soluble molecules of ocular immune privilege that has been used to generate retinal autoantigen-specific Treg cells in vitro (98). When these α-MSH-induced Treg cells are adoptively transferred into recipients with sub-retinal neonatal retinal allografts the grafts survive and the retinal cells begin to differentiate (99). This has demonstrated that the autoantigen-activated Treg cells within the retina provided the necessary immune protection needed for neonatal retinal cell development. Corneal allografts treated with eye drops containing α-MSH promote graft survival (100). These two studies have suggested that the use of the soluble molecules of immune privilege could be a new therapeutic approach in promoting allograft survival. Whether the survival is because of α-MSH suppression of inflammation by inhibiting proinflammatory cytokine production, or in the activation of Treg cells is not known. Use of α-MSH to treat models of autoimmune uveitis suggests that both may be its action (101).

Conclusion

There is a need to continue to understand the molecular nature of ocular immune privilege. There is a unique molecular relationship between the ocular microenvironment and immune cells to suppress inflammation and promote regulatory immunity. Although the benefits of ocular immune privilege have been seen with corneal allografts, understanding the mechanisms of this benefit means extending it to other allografts in other tissues. The potential exists that as more is understood about the molecular building blocks of ocular immune privilege that these molecules can be applied to extend the survival of all allografts. Such a possibility would result in less need for tissue typing, and systemic anti-rejection drugs, while increasing the pool of potential allogeneic donors.

Author Contributions

The author confirms being the sole contributor of this work and approved it for publication.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This work is supported in part by the Massachusetts Lions Eye Research Foundation.

References

1. Medawar P. Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol (1948) 29:58–69.

Google Scholar

2. Barker CF, Billingham RE. The role of afferent lymphatics in the rejection of skin homografts. J Exp Med (1968) 128(1):197–221. doi:10.1084/jem.128.1.197

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Stein-Streilein J. Immune regulation and the eye. Trends Immunol (2008) 29(11):548–54. doi:10.1016/j.it.2008.08.002

PubMed Abstract | CrossRef Full Text | Google Scholar

4. McMenamin PG, Holthouse I, Holt PG. Class II major histocompatibility complex (Ia) antigen-bearing dendritic cells within the iris and ciliary body of the rat eye: distribution, phenotype, and relation to retinal microglia. Immunology (1992) 77:385–93.

PubMed Abstract | Google Scholar

5. Paques M, Simonutti M, Augustin S, Goupille O, El Mathari B, Sahel JA. In vivo observation of the locomotion of microglial cells in the retina. Glia (2010) 58(14):1663–8. doi:10.1002/glia.21037

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Hamrah P, Dana MR. Corneal antigen-presenting cells. Chem Immunol Allergy (2007) 92:58–70. doi:10.1159/000099254

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Knickelbein JE, Watkins SC, McMenamin PG, Hendricks RL. Stratification of antigen-presenting cells within the normal cornea. Ophthalmol Eye Dis (2009) 1:45–54.

PubMed Abstract | Google Scholar

8. Hamrah P, Zhang Q, Liu Y, Dana MR. Novel characterization of MHC class II-negative population of resident corneal Langerhans cell-type dendritic cells. Invest Ophthalmol Vis Sci (2002) 43(3):639–46.

PubMed Abstract | Google Scholar

9. Albini TA, Wang RC, Reiser B, Zamir E, Wu GS, Rao NA. Microglial stability and repopulation in the retina. Br J Ophthalmol (2005) 89(7):901–3. doi:10.1136/bjo.2004.060293

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Dullforce PA, Garman KL, Seitz GW, Fleischmann RJ, Crespo SM, Planck SR, et al. APCs in the anterior uveal tract do not migrate to draining lymph nodes. J Immunol (2004) 172(11):6701–8. doi:10.4049/jimmunol.172.11.6701

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Chen L, Yang P, Kijlstra A. Distribution, markers, and functions of retinal microglia. Ocul Immunol Inflamm (2002) 10(1):27–39. doi:10.1076/ocii.10.1.27.10328

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Xu H, Chen M, Mayer EJ, Forrester JV, Dick AD. Turnover of resident retinal microglia in the normal adult mouse. Glia (2007) 55(11):1189–98. doi:10.1002/glia.20535

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Kaneko H, Nishiguchi KM, Nakamura M, Kachi S, Terasaki H. Characteristics of bone marrow-derived microglia in the normal and injured retina. Invest Ophthalmol Vis Sci (2008) 49(9):4162–8. doi:10.1167/iovs.08-1738

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci (2007) 10(12):1538–43. doi:10.1038/nn2014

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Ransohoff RM. Microgliosis: the questions shape the answers. Nat Neurosci (2007) 10(12):1507–9. doi:10.1038/nn1207-1507

CrossRef Full Text | Google Scholar

16. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science (2010) 330(6005):841–5. doi:10.1126/science.1194637

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Eter N, Engel DR, Meyer L, Helb HM, Roth F, Maurer J, et al. In vivo visualization of dendritic cells, macrophages, and microglial cells responding to laser-induced damage in the fundus of the eye. Invest Ophthalmol Vis Sci (2008) 49(8):3649–58. doi:10.1167/iovs.07-1322

PubMed Abstract | CrossRef Full Text | Google Scholar

18. McMenamin PG, Crewe J. Endotoxin-induced uveitis. Kinetics and phenotype of the inflammatory cell infiltrate and the response of the resident tissue macrophages and dendritic cells in the iris and ciliary body. Invest Ophthalmol Vis Sci (1995) 36(10):1949–59.

PubMed Abstract | Google Scholar

19. Campbell M, Humphries P. The blood-retina barrier: tight junctions and barrier modulation. Adv Exp Med Biol (2012) 763:70–84.

PubMed Abstract | Google Scholar

20. Taylor AW, Streilein JW, Cousins SW. Identification of alpha-melanocyte stimulating hormone as a potential immunosuppressive factor in aqueous humor. Curr Eye Res (1992) 11(12):1199–206. doi:10.3109/02713689208999545

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Taylor AW, Streilein JW, Cousins SW. Immunoreactive vasoactive intestinal peptide contributes to the immunosuppressive activity of normal aqueous humor. J Immunol (1994) 153(3):1080–6.

PubMed Abstract | Google Scholar

22. Goslings W, Prodeus A, Streilein J, Carroll M, Jager M, Taylor A. Small molecular weight factor in aqueous humor acts on C1q to prevent antibody-dependent complement activation. Invest Ophthalmol Vis Sci (1998) 39(6):989–95.

Google Scholar

23. Taylor A, Yee D, Streilein J. Suppression of nitric oxide generated by inflammatory microphages by calcitonin gene-related peptide in aqueous humor. Invest Ophthalmol Vis Sci (1998) 39(8):1372–8.

Google Scholar

24. Taylor A, Yee D. Somatostatin is an imunosuppressive factor in aqueous humor. Invest Ophthalmol Vis Sci (2003) 44(6):2644–9. doi:10.1167/iovs.02-1216

CrossRef Full Text | Google Scholar

25. Zamiri P, Masli S, Kitaichi N, Taylor A, Streilein J. Thrombospondin plays a vital role in the immune privilege of the eye. Invest Ophthalmol Vis Sci (2005) 46(3):908–19. doi:10.1167/iovs.04-0362

CrossRef Full Text | Google Scholar

26. Zamiri P, Masli S, Streilein JW, Taylor AW. Pigment epithelial growth factor suppresses inflammation by modulating macrophage activation. Invest Ophthalmol Vis Sci (2006) 47(9):3912–8. doi:10.1167/iovs.05-1267

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Zamiri P, Masli S, Kitaichi N, Taylor AW, Streilein JW. Thrombospondin plays a vital role in the immune privilege of the eye. Ocul Immunol Inflamm (2007) 15(3):279–94. doi:10.1080/09273940701382432

CrossRef Full Text | Google Scholar

28. Kawanaka N, Taylor AW. Localized retinal neuropeptide regulation of macrophage and microglial cell functionality. J Neuroimmunol (2011) 232(1–2):17–25. doi:10.1016/j.jneuroim.2010.09.025

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Apte RS, Sinha D, Mayhew E, Wistow GJ, Niederkorn JY. Cutting edge: role of macrophage migration inhibitory factor in inhibiting NK cell activity and preserving immune privilege. J Immunol (1998) 160(12):5693–6.

PubMed Abstract | Google Scholar

30. D’Orazio TJ, DeMarco BM, Mayhew ES, Niederkorn JY. Effect of aqueous humor on apoptosis of inflammatory cell types. Invest Ophthalmol Vis Sci (1999) 40(7):1418–26.

PubMed Abstract | Google Scholar

31. Wenkel H, Streilein JW. Evidence that retinal pigment epithelium functions as an immune-privileged tissue. Invest Ophthalmol Vis Sci (2000) 41(11):3467–73.

PubMed Abstract | Google Scholar

32. Ishida K, Panjwani N, Cao Z, Streilein JW. Participation of pigment epithelium in ocular immune privilege. 3. Epithelia cultured from iris, ciliary body, and retina suppress T-cell activation by partially non-overlapping mechanisms. Ocul Immunol Inflamm (2003) 11(2):91–105. doi:10.1076/ocii.11.2.91.15914

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Sugita S, Keino H, Futagami Y, Takase H, Mochizuki M, Stein-Streilein J, et al. B7+ iris pigment epithelial cells convert T cells into CTLA-4+, B7-expressing CD8+ regulatory T cells. Invest Ophthalmol Vis Sci (2006) 47(12):5376–84. doi:10.1167/iovs.05-1354

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Kawazoe Y, Sugita S, Keino H, Yamada Y, Imai A, Horie S, et al. Retinoic acid from retinal pigment epithelium induces T regulatory cells. Exp Eye Res (2012) 94(1):32–40. doi:10.1016/j.exer.2011.11.002

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Sugita S, Futagami Y, Smith SB, Naggar H, Mochizuki M. Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor beta. Exp Eye Res (2006) 83(6):1459–71. doi:10.1016/j.exer.2006.08.005

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Sugita S, Horie S, Nakamura O, Maruyama K, Takase H, Usui Y, et al. Acquisition of T regulatory function in cathepsin L-inhibited T cells by eye-derived CTLA-2alpha during inflammatory conditions. J Immunol (2009) 183(8):5013–22. doi:10.4049/jimmunol.0901623

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Sugita S, Usui Y, Horie S, Futagami Y, Aburatani H, Okazaki T, et al. T-cell suppression by programmed cell death 1 ligand 1 on retinal pigment epithelium during inflammatory conditions. Invest Ophthalmol Vis Sci (2009) 50(6):2862–70. doi:10.1167/iovs.08-2846

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Sugita S, Usui Y, Horie S, Futagami Y, Yamada Y, Ma J, et al. Human corneal endothelial cells expressing programmed death-ligand 1 (PD-L1) suppress PD-1+ T helper 1 cells by a contact-dependent mechanism. Invest Ophthalmol Vis Sci (2009) 50(1):263–72. doi:10.1167/iovs.08-2536

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Bora NS, Gobleman CL, Atkinson JP, Pepose JS, Kaplan HJ. Differential expression of the complement regulatory proteins in the human eye. Invest Ophthalmol Vis Sci (1993) 34(13):3579–84.

PubMed Abstract | Google Scholar

40. Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol (2003) 3(11):879–89. doi:10.1038/nri1224

CrossRef Full Text | Google Scholar

41. Taylor AW. Ocular immune privilege. Eye (Lond) (2009) 23(10):1885–9. doi:10.1038/eye.2008.382

CrossRef Full Text | Google Scholar

42. Niederkorn JY, Stein-Streilein J. History and physiology of immune privilege. Ocul Immunol Inflamm (2010) 18(1):19–23. doi:10.3109/09273940903564766

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Streilein JW, Niederkorn JY, Shadduck JA. Systemic immune unresponsiveness induced in adult mice by anterior chamber presentation of minor histocompatibility antigens. J Exp Med (1980) 152(4):1121–5. doi:10.1084/jem.152.4.1121

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Jiang LQ, Streilein JW. Immunologic privilege evoked by histoincompatible intracameral retinal transplants. Reg Immunol (1990) 3(3):121–30.

PubMed Abstract | Google Scholar

45. Niederkorn JY. The immune privilege of corneal grafts. J Leukoc Biol (2003) 74(2):167–71. doi:10.1189/jlb.1102543

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Liu Y, Hamrah P, Zhang Q, Taylor AW, Dana MR. Draining lymph nodes of corneal transplant hosts exhibit evidence for donor major histocompatibility complex (MHC) class II-positive dendritic cells derived from MHC class II-negative grafts. J Exp Med (2002) 195(2):259–68. doi:10.1084/jem.20010838

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Sano Y, Okamoto S, Streilein JW. Induction of donor-specific ACAID can prolong orthotopic corneal allograft survival in “high-risk” eyes. Curr Eye Res (1997) 16(11):1171–4. doi:10.1076/ceyr.16.11.1171.5109

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Ma N, Streilein JW. Contribution of microglia as passenger leukocytes to the fate of intraocular neuronal retinal grafts. Invest Ophthalmol Vis Sci (1998) 39(12):2384–93.

PubMed Abstract | Google Scholar

49. Streilein JW, Ma N, Wenkel H, Ng TF, Zamiri P. Immunobiology and privilege of neuronal retina and pigment epithelium transplants. Vision Res (2002) 42(4):487–95. doi:10.1016/S0042-6989(01)00185-7

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Kaplan HJ, Streilein JW, Stevens TR. Transplantation immunology of the anterior chamber of the eye. II. Immune response to allogeneic cells. J Immunol (1975) 115(3):805–10.

PubMed Abstract | Google Scholar

51. Kaplan HJ, Streilein JW. Immune response to immunization via the anterior chamber of the eye. I. F. Lymphocyte-induced immune deviation. J Immunol (1977) 118(3):809–14.

PubMed Abstract | Google Scholar

52. Wenkel H, Chen PW, Ksander BR, Streilein JW. Immune privilege is extended, then withdrawn, from allogeneic tumor cell grafts placed in the subretinal space. Invest Ophthalmol Vis Sci (1999) 40(13):3202–8.

PubMed Abstract | Google Scholar

53. Sonoda KH, Sakamoto T, Qiao H, Hisatomi T, Oshima T, Tsutsumi-Miyahara C, et al. The analysis of systemic tolerance elicited by antigen inoculation into the vitreous cavity: vitreous cavity-associated immune deviation. Immunology (2005) 116(3):390–9. doi:10.1111/j.1365-2567.2005.02239.x

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Lin HH, Faunce DE, Stacey M, Terajewicz A, Nakamura T, Zhang-Hoover J, et al. The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance. J Exp Med (2005) 201(10):1615–25. doi:10.1084/jem.20042307

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Streilein JW, Niederkorn JY. Induction of anterior chamber-associated immune deviation requires an intact, functional spleen. J Exp Med (1981) 153(5):1058–67. doi:10.1084/jem.153.5.1058

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Hsu SM, Mathew R, Taylor AW, Stein-Streilein J. Ex-vivo tolerogenic F4/80(+) antigen-presenting cells (APC) induce efferent CD8(+) regulatory T cell-dependent suppression of experimental autoimmune uveitis. Clin Exp Immunol (2014) 176(1):37–48. doi:10.1111/cei.12243

CrossRef Full Text | Google Scholar

57. Wilbanks GA, Streilein JW. Fluids from immune privileged sites endow macrophages with the capacity to induce antigen-specific immune deviation via a mechanism involving transforming growth factor-beta. Eur J Immunol (1992) 22(4):1031–6. doi:10.1002/eji.1830220423

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Hara Y, Okamoto S, Rouse B, Streilein JW. Evidence that peritoneal exudate cells cultured with eye-derived fluids are the proximate antigen-presenting cells in immune deviation of the ocular type. J Immunol (1993) 151(10):5162–71.

PubMed Abstract | Google Scholar

59. Wilbanks GA, Mammolenti M, Streilein JW. Studies on the induction of anterior chamber-associated immune deviation (ACAID). III. Induction of ACAID depends upon intraocular transforming growth factor-beta. Eur J Immunol (1992) 22(1):165–73. doi:10.1002/eji.1830220125

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Faunce DE, Stein-Streilein J. NKT cell-derived RANTES recruits APCs and CD8+ T cells to the spleen during the generation of regulatory T cells in tolerance. J Immunol (2002) 169(1):31–8. doi:10.4049/jimmunol.169.1.31

PubMed Abstract | CrossRef Full Text | Google Scholar

61. D’Orazio TJ, Niederkorn JY. Splenic B cells are required for tolerogenic antigen presentation in the induction of anterior chamber-associated immune deviation (ACAID). Immunology (1998) 95(1):47–55. doi:10.1046/j.1365-2567.1998.00581.x

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Sonoda KH, Stein-Streilein J. Ocular immune privilege and CD1d-reactive natural killer T cells. Cornea (2002) 21(2 Suppl 1):S33–8. doi:10.1097/00003226-200203001-00008

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Wilbanks GA, Streilein JW. Characterization of suppressor cells in anterior chamber-associated immune deviation (ACAID) induced by soluble antigen. Evidence of two functionally and phenotypically distinct T-suppressor cell populations. Immunology (1990) 71(3):383–9.

PubMed Abstract | Google Scholar

64. Jiang L, He H, Yang P, Lin X, Zhou H, Huang X, et al. Splenic CD8+ T cells secrete TGF-beta1 to exert suppression in mice with anterior chamber-associated immune deviation. Graefes Arch Clin Exp Ophthalmol (2009) 247(1):87–92. doi:10.1007/s00417-008-0947-8

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Paunicka K, Chen PW, Niederkorn JY. Role of IFN-gamma in the establishment of anterior chamber-associated immune deviation (ACAID)-induced CD8+ T regulatory cells. J Leukoc Biol (2012) 91(3):475–83. doi:10.1189/jlb.0311173

CrossRef Full Text | Google Scholar

66. Sonoda KH, Stein-Streilein J. CD1d on antigen-transporting APC and splenic marginal zone B cells promotes NKT cell-dependent tolerance. Eur J Immunol (2002) 32(3):848–57. doi:10.1002/1521-4141(200203)32:3<848::AID-IMMU848>3.0.CO;2-I

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Sonoda KH, Taniguchi M, Stein-Streilein J. Long-term survival of corneal allografts is dependent on intact CD1d-reactive NKT cells. J Immunol (2002) 168(4):2028–34. doi:10.4049/jimmunol.168.4.2028

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Masli S, Turpie B, Hecker KH, Streilein JW. Expression of thrombospondin in TGFbeta-treated APCs and its relevance to their immune deviation-promoting properties. J Immunol (2002) 168(5):2264–73. doi:10.4049/jimmunol.168.5.2264

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Cousins SW, Trattler WB, Streilein JW. Immune privilege and suppression of immunogenic inflammation in the anterior chamber of the eye. Curr Eye Res (1991) 10(4):287–97. doi:10.3109/02713689108996334

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Streilein JW, Cousins SW. Aqueous humor factors and their effect on the immune response in the anterior chamber. Curr Eye Res (1990) 9:175–82. doi:10.3109/02713689008999439

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Kim MK, Caspi RR, Nussenblatt RB, Kuwabara T, Palestine AG. Intraocular trafficking of lymphocytes in locally induced experimental autoimmune uveoretinitis (EAU). Cell Immunol (1988) 112(2):430–6. doi:10.1016/0008-8749(88)90312-7

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Chan CC, Caspi RR, Roberge FG, Nussenblatt RB. Dynamics of experimental autoimmune uveoretinitis induced by adoptive transfer of S-antigen-specific T cell line. Invest Ophthalmol Vis Sci (1988) 29(3):411–8.

PubMed Abstract | Google Scholar

73. Cousins SW, McCabe MM, Danielpour D, Streilein JW. Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor. Invest Ophthalmol Vis Sci (1991) 32(8):2201–11.

PubMed Abstract | Google Scholar

74. Connor TB Jr, Roberts AB, Sporn MB, Danielpour D, Dart LL, Michels RG, et al. Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye. J Clin Invest (1989) 83(5):1661–6. doi:10.1172/JCI114065

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Jampel HD, Roche N, Stark WJ, Roberts AB. Transforming growth factor-beta in human aqueous humor. Curr Eye Res (1990) 9(10):963–9. doi:10.3109/02713689009069932

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Knisely TL, Bleicher PA, Vibbard CA, Granstein RD. Production of latent transforming growth factor-beta and other inhibitory factors by cultured murine iris and ciliary body cells. Curr Eye Res (1991) 10(8):761–71. doi:10.3109/02713689109013870

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Kaiser CJ, Ksander BR, Streilein JW. Inhibition of lymphocyte proliferation by aqueous humor. Reg Immunol (1989) 2(1):42–9.

PubMed Abstract | Google Scholar

78. Taylor AW. Review of the activation of TGF-beta in immunity. J Leukoc Biol (2009) 85(1):29–33. doi:10.1189/jlb.0708415

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Taylor AW, Alard P, Yee DG, Streilein JW. Aqueous humor induces transforming growth factor-beta (TGF-beta)-producing regulatory T-cells. 1997. Ocul Immunol Inflamm (2007) 15(3):215–24. doi:10.1080/09273940701382234

CrossRef Full Text | Google Scholar

80. Lau CH, Taylor AW. The immune privileged retina mediates an alternative activation of J774A.1 cells. Ocul Immunol Inflamm (2009) 17(6):380–9. doi:10.3109/09273940903118642

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Lee DJ, Taylor AW. Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice. J Immunol (2013) 191(8):4103–11. doi:10.4049/jimmunol.1300182

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Stuart PM, Griffith TS, Usui N, Pepose J, Yu X, Ferguson TA. CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J Clin Invest (1997) 99(3):396–402. doi:10.1172/JCI119173

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science (1995) 270(5239):1189–92. doi:10.1126/science.270.5239.1189

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Hori J, Wang M, Miyashita M, Tanemoto K, Takahashi H, Takemori T, et al. B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. J Immunol (2006) 177(9):5928–35. doi:10.4049/jimmunol.177.9.5928

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Weiss EM, Schmidt A, Vobis D, Garbi N, Lahl K, Mayer CT, et al. Foxp3-mediated suppression of CD95L expression confers resistance to activation-induced cell death in regulatory T cells. J Immunol (2011) 187(4):1684–91. doi:10.4049/jimmunol.1002321

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev (2010) 236:219–42. doi:10.1111/j.1600-065X.2010.00923.x

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Copland DA, Calder CJ, Raveney BJ, Nicholson LB, Phillips J, Cherwinski H, et al. Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis. Am J Pathol (2007) 171(2):580–8. doi:10.2353/ajpath.2007.070272

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol (2009) 9(3):162–74. doi:10.1038/nri2506

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest (2015) 125(9):3356–64. doi:10.1172/JCI80005

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Crook KR, Jin M, Weeks MF, Rampersad RR, Baldi RM, Glekas AS, et al. Myeloid-derived suppressor cells regulate T cell and B cell responses during autoimmune disease. J Leukoc Biol (2015) 97(3):573–82. doi:10.1189/jlb.4A0314-139R

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Li H, Dai F, Peng Q, Gan H, Zheng J, Xia Y, et al. Myeloid-derived suppressor cells suppress CD4(+) and CD8(+) T cell responses in autoimmune hepatitis. Mol Med Rep (2015) 12(3):3667–73. doi:10.3892/mmr.2015.3791

CrossRef Full Text | Google Scholar

92. Jiang LQ, Streilein JW. Immune responses elicited by transplantation and tissue-restricted antigens expressed on retinal tissues implanted subconjunctivally. Transplantation (1991) 52(3):513–9. doi:10.1097/00007890-199109000-00025

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Jiang C, Klassen H, Zhang X, Young M. Laser injury promotes migration and integration of retinal progenitor cells into host retina. Mol Vis (2010) 16:983–90.

PubMed Abstract | Google Scholar

94. Ross J, He YG, Pidherney M, Mellon J, Niederkorn JY. The differential effects of donor versus host Langerhans cells in the rejection of MHC-matched corneal allografts. Transplantation (1991) 52(5):857–61. doi:10.1097/00007890-199111000-00020

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Wenkel H, Streilein JW. Analysis of immune deviation elicited by antigens injected into the subretinal space. Invest Ophthalmol Vis Sci (1998) 39(10):1823–34.

PubMed Abstract | Google Scholar

96. Qiao H, Lucas K, Stein-Streilein J. Retinal laser burn disrupts immune privilege in the eye. Am J Pathol (2009) 174(2):414–22. doi:10.2353/ajpath.2009.080766

PubMed Abstract | CrossRef Full Text | Google Scholar

97. Ng TF, Lavik E, Keino H, Taylor AW, Langer RS, Young MJ. Creating an immune-privileged site using retinal progenitor cells and biodegradable polymers. Stem Cells (2007) 25(6):1552–9. doi:10.1634/stemcells.2006-0780

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Taylor A, Namba K. In vitro induction of CD25+ CD4+ regulatory T cells by the neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH). Immunol Cell Biol (2001) 79(4):358–67. doi:10.1046/j.1440-1711.2001.01022.x

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Ng TF, Kitaichi N, Taylor AW. In vitro generated autoimmune regulatory T cells enhance intravitreous allogeneic retinal graft survival. Invest Ophthalmol Vis Sci (2007) 48(11):5112–7. doi:10.1167/iovs.07-0175

PubMed Abstract | CrossRef Full Text | Google Scholar

100. Hamrah P, Haskova Z, Taylor AW, Zhang Q, Ksander BR, Dana MR. Local treatment with alpha-melanocyte stimulating hormone reduces corneal allorejection. Transplantation (2009) 88(2):180–7. doi:10.1097/TP.0b013e3181ac11ea

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Taylor AW, Lee D. Applications of the role of alpha-MSH in ocular immune privilege. Adv Exp Med Biol (2010) 681:143–9. doi:10.1007/978-1-4419-6354-3_12

CrossRef Full Text | Google Scholar

Keywords: immune privilege, anterior chamber-associated immune deviation, immune tolerance, regulatory T cells

Citation: Taylor AW (2016) Ocular Immune Privilege and Transplantation. Front. Immunol. 7:37. doi: 10.3389/fimmu.2016.00037

Received: 14 October 2015; Accepted: 25 January 2016;
Published: 08 February 2016

Edited by:

James I. Kim, Harvard Medical School, USA

Reviewed by:

Philippe Saas, Etablissement Français du Sang BFC, France
Karen Bieback, Institute of Transfusion Medicine and Immunology, Germany

Copyright: © 2016 Taylor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Andrew W. Taylor, awtaylor@bu.edu