It has been over 60 years since the phrase immune privilege was used by Sir Peter Medawar to describe the lack of an immune response against allografts placed into the ocular microenvironment. Since then, we have come to understand that the mechanisms of ocular immune privilege include unique anatomical features of a blood barrier and a lack of direct lymphatic drainage. Also, we know that the ocular microenvironment is rich with immunosuppressive molecules that influence the activity of immune cells. Moreover, the placement of foreign antigen into the ocular microenvironment can induce a systemic form of tolerance to the foreign antigen called anterior chamber-associated immune deviation (ACAID). Many soluble immunomodulators are found in aqueous humour, and are a mixture of growth factors, cytokines, neuropeptides, and soluble receptors. This is a continuously growing list. The mechanisms of ocular immune privilege induce apoptosis, promote the production of anti-inflammatory cytokines, and mediate the activation of antigen-specific regulatory immunity. These mechanisms of immune privilege also attempt to impose themselves upon immunity within the uveitic eye. The adaptation of several anatomical and biochemical mechanisms to establish an immune privileged microenvironment within the eye makes the eye immunologically unique. It is a tissue site where we may learn how immunity is regulated in inflammation and at rest. Success in translating the lessons of ocular immune privilege to other tissues has the potential to drastically change the therapy and clinical outcomes of autoimmune diseases and allograft survival.

To examine the widely accepted dogmas that corneal grafts lack passenger leukocytes or cells capable of migrating directly to lymph nodes (LNs), we tracked the migration of corneal graft-derived transgenic green fluorescent protein (GFP; Ia^b) cells into the draining LNs of allogeneic (Ia^d) recipients. GFP⁺ cells were identified in cervical LNs several hours after transplantation, and this traffic was significantly enhanced when grafts were placed in inflamed recipient beds. Draining cells were Ia^b+, CD45⁺, and CD11c⁺, and examination of ungrafted corneas revealed numerous similarly CD45⁺CD11c⁺CD3⁻CD8α⁻ cells that uniformly lacked major histocompatibility complex (MHC) class II expression; transmission electron microscopy confirmed the presence of morphologically similar cells. After transplantation, or placement in culture, these CD11c⁺ cells became class II⁺ in a time-dependent manner and were capable of allostimulatory function. However, the stimulatory capacity of these cornea-derived dendritic cells (DCs) was suppressed compared with splenic controls. These results demonstrate for the first time that the cornea is endowed with resident DCs that are universally MHC class II⁻ but that are capable of expressing class II antigen after surgery and migrating to draining LNs of allografted hosts. These data refute the tenet that the cornea is immune privileged due to lack of resident lymphoreticular cells or due to antigenic sequestration from systemic immunity.

The aqueous humor of the eye contains factors that regulate immunological responses within the immunosuppressive ocular microenvironment. Besides TGF-β, the proteins in the low molecular weight (< 3500 Da) fraction of normal aqueous humor are also immunosuppressive. The low molecular weight fraction of aqueous humor inhibits IFN-γ production and proliferation of antigen-stimulated lymph node cells. Neuropeptides are one possible family of low molecular weight factors in aqueous humor. Through the utilization of an antigen capturing enzyme-assay, the immunosuppressive neuropeptide alpha-melanocyte stimulating hormone (α-MSH) was detected in normal aqueous humor of humans, rabbits, and mice. The mean concentration of α-MSH in normal aqueous humor of humans was 20±3 pM, of rabbits 11±1 pM, of BALB/c mice 16±3 pM, and of C57BL/6 mice 14±3 pM. These physiological concentrations of α-MSH inhibited the production of IFN-γ by antigen-stimulated lymph node cells. In contrast to the low molecular weight fraction, α-MSH did not inhibit proliferation. There was a 26% recovery of IFN-γ production when α-MSH was absorbed from the low molecular weight fraction. The results demonstrate neuropeptides to be constitutive components of normal aqueous humor and that factors with the capability of differential regulation of effector T-cell activity may be present within the immunosuppressive ocular microenvironment.

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 that contribute to allograft survival in the immune privileged tissue. This review presents the current understanding of how the mechanism of ocular immune privilege promote tolerogenic activity by antigen presenting cells, 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 a graft destroying immune responses within the eye. As more is understood about the molecular mechanisms of ocular immune privilege greater is the potential in using these molecular mechanisms in therapies to prevent allograft rejection.

Suppression of immune-mediated inflammation within the normal anterior chamber (AC) of the eye is in part the result of active suppression of effector T cell activities by immunosuppressive cytokines found in aqueous humor (AqH), the fluid filling the AC. There are immunosuppressive factors found in the low m.w. fraction (< 5 kDa) of AqH, including the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH). In seeking other factors, we now report that the neuropeptide vasoactive intestinal peptide (VIP) is also present in normal AqH. VIP immunoreactivity was found in normal rabbit eyes at a concentration of 12 +/- 1 nM. At this intraocular concentration, VIP suppressed Ag-stimulated lymph node cell (LNC) proliferation and IFN-gamma production in vitro. Although suppression of LNC proliferation was not neutralized by absorption of VIP from the low m.w. fraction of AqH, removal of VIP did neutralize suppression of IFN-gamma production by this fraction of AqH. Absorption of both VIP and alpha-MSH from this fraction of AqH permitted production of IFN-gamma by Ag-stimulated LNC that was no different than absorbing VIP alone. The low m.w. fraction of AqH absorbed of either alpha-MSH and VIP lost its ability to suppress local adoptive transfer of delayed-type hypersensitivity. The results suggest that VIP is an important immunosuppressive neuropeptide in AqH. Neuropeptides play an important role in ocular immune privilege and creation of an intraocular immunosuppressive microenvironment.

The evolutionarily conserved TGF-β proteins are distributed ubiquitously throughout the body and have a role in almost every biological process. In immunity, TGF-β has an important role in modulating immunity. Much is understood about the process of TGF-β production as a latent molecule and of the consequences and the intercellular signaling of active TGF-β binding to its receptors; however, there is little discussed between the production and activation of TGF-β. This review focuses on what is understood about the biochemical and physiological processes of TGF-β activation and identifies the gaps in understanding immune cell activation of TGF-β. A mechanistic understanding of the process activating TGF-β can lead to regulating multiple biological systems by enhancing or inhibiting TGF-β activation.