Originally published online as doi:10.1189/jlb.1102543 on May 22, 2003
Published online before print May 22, 2003
(Journal of Leukocyte Biology. 2003;74:167-171.)
© 2003
by Society for Leukocyte Biology
The immune privilege of corneal grafts
Jerry Y. Niederkorn
Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas
Correspondence: Jerry Y. Niederkorn, Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75093. E-mail: jerry.niederkorn{at}utsouthwestern.edu
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ABSTRACT
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Keratoplasty is the oldest and one of the most successful forms of solid tissue transplantation. In the United States, over 33,000 corneal transplants are performed each year. Unlike other forms of tissue transplantation, keratoplasties are routinely performed without the aid of tissue typing or systemic immunosuppressive drugs. In spite of this, 90% of the first-time corneal transplants will succeed–a condition that demonstrates the immune privilege of keratoplasties. The avascular nature of the corneal allograft bed led many to suspect that corneal grafts were sequestered from the immune apparatus. Although pleasing in its simplicity, this explanation has given way to a more comprehensive hypothesis that embodies multiple, interdependent mechanisms, which promote the long-term survival of corneal allografts. These mechanisms conspire to interrupt the transmission of immunogenic stimuli to peripheral lymphoid tissues; induce the generation of a deviated immune response; and neutralize immune effector elements at the host-graft interface. This paradigm is analogous to a three-legged stool. Disassembly of any one of the three components results in the collapse of immune privilege. Strategies to re-establish corneal immune privilege may have clinical application for high-risk hosts who have rejected previous corneal allografts.
Key Words: corneal allografts • keratoplasty
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INTRODUCTION
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Keratoplasty is the oldest and one of the most successful forms of solid tissue transplantation. In the United States, over 30,000 corneal transplants are performed each year [1
]. First-time recipients of corneal allografts can expect a 90% success rate, although keratoplasty is performed without the aid of tissue typing or the use of systemic immunosuppressive drugs [2
]. The unparalleled success rate of keratoplasty spawned the notion that the corneal allograft and its graft bed were endowed with immune privilege. However, clinicians often object to the proposition that corneal allografts enjoy immune privilege, as immune rejection remains the leading cause of corneal graft failure and is the most important barrier for successful keratoplasty. In this regard, it is useful to summarize the criteria that define the immune privilege of corneal allografts. Studies using rodent models of keratoplasty have shed light on the underlying mechanisms of immune privilege of corneal allografts. In many donor-host combinations, corneal allografts that are mismatched with the host at the entire major histocompatibility complex (MHC) plus multiple minor histocompatibility (H) loci are permanently accepted in over 50% of the hosts [3
,4
]. By contrast, skin allografts transplanted across similar barriers are invariably rejected [5
]. The difference in graft survival between corneal allografts and skin allografts is even more pronounced when the histocompatibility barriers are lowered (Table 1
). At least three criteria demonstrate the immune privilege of corneal allografts: corneal allografts enjoy a 90% acceptance rate in the absence of histocompatibility matching; systemic immunosuppressive drugs are not needed to ensure corneal graft survival in first time, uncomplicated cases; and corneal grafts enjoy a markedly higher acceptance rate than other categories of solid organ grafts when compared prospectively in animal models.
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IMMUNE PRIVILEGE OF CORNEAL ALLOGRAFTS: A THREE-LEGGED STOOL
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One of the most appealing explanations to account for the immune privilege of corneal allografts is based on the conspicuous avascular nature of the cornea and the corneal graft bed. This remarkable feature of the eye prompted early investigators to attribute the prolonged survival of corneal grafts to the sequestration of alien histocompatibility antigens from the systemic immune apparatus. Another appealing hypothesis suggested that the corneal allograft did not express the donor’s histocompatibility antigens, thereby rendering the transplant invisible to the host’s immune system. However, both of these explanations collapse under even the most superficial scrutiny. In certain donor-host combinations, corneal allografts undergo immune rejection, even if the graft and the graft bed display pristine avascularity. Moreover, immunohistochemical investigations have demonstrated the presence of MHC antigens on all three layers of the cornea [12
13
14
15
]. Minor H antigens, including the H–Y, male-specific minor H antigen [16
], are also expressed on corneal cells [6
,7
]. Clear, long-term corneal allografts undergo immune rejection if the host is subsequently immunized with an orthotopic skin allograft prepared from the same donor strain that provided the original corneal graft [8
]. Thus, orthotopic corneal allografts are immunogenic (capable of inducing alloimmune responses) and antigenic (vulnerable to antigen-specific attack by alloimmune effector elements).
A second hypothesis offered to explain the immune privilege of corneal allografts proposed that host cells rapidly replaced the cellular components of the corneal graft, thereby rendering the graft nonimmunogenic. This explanation, like the previous one, has been refuted by a large body of compelling, experimental, and anecdotal evidence. Animal studies using chromatin sex markers or radiolabels have demonstrated the persistence of donor cells in surviving corneal grafts [17
,18
]. Corneal grafts in patients can undergo immune rejection years after the initial keratoplasty, and as mentioned above, immune rejection of long-term, surviving corneal grafts in mice can be precipitated by immunizing the host with donor alloantigens in the form of orthotopic skin grafts [3
,4
,9
].
The last three decades of research have shown that the immune system expresses enormous redundancy in the array of effector mechanisms that mediate organ graft rejection. Given the multiplicity of effector mechanisms available to the immune system, it stands to reason that the immune privilege of corneal allografts does not rely on a single mechanism for evading immune destruction; rather, it is a compilation of anatomical, physiological, and immunological adaptations that pre-empt the induction and expression of alloimmune responses. For organ grafts to undergo immune rejection, three processes must occur: Donor histocompatibility antigens must be transported by an afferent lymphatic or blood vessel to a regional lymphoid tissue; once in the lymphoid tissue, the alloantigenic cells must directly stimulate T cells (direct pathway of alloimmunization) or shed their alloantigens, which are then processed by the host’s antigen presenting cells (APC; indirect pathway of alloimmunization), and are subsequently presented to host T cells; and immune effector elements must migrate to the graft and perform their allodestructive processes at the host/graft interface. This three-step process has been likened to an "immune reflex arc" based on its similarity to a sensory neuron/motor neuron reflex arc in which a stimulus (antigen) is transmitted by an afferent pathway (lymph or blood vessel) to a central processing component (organized lymphoid tissues/lymph nodes). The central processing component interprets the stimulus in a manner that leads to the generation of immune effector elements. The efferent mode of the immune reflex arc involves the migration of immune effector elements to the host/graft interface and culminates in tissue damage that is mediated by the immune effector elements. However, long-term survival of corneal allografts requires the simultaneous disruption of all three components of the immune reflex.
The immune privilege of corneal allografts might also be compared with a three-legged stool. For the "immune privilege stool" to function, all three legs must remain in place. Removal of any of the three legs results in the collapse of immune privilege. One leg of this stool is the afferent blockade of the immune response that occurs when normal corneal allografts lacking resident, MHC class II-positive Langerhans cells (LC) are placed into graft beds that lack blood vessels and afferent lymphatics. These two conditions prevent alloantigenic stimuli from reaching the regional lymphoid tissues. The second leg of the immune privilege stool is the corneal allograft’s ability to induce an immune deviation of the alloimmune response that results in the systemic down-regulation of T helper cell type 1 (Th1) alloimmune responses. This is analogous to a disruption of the central processing component of the alloimmune reflex arc. The third leg of the immune privilege stool is the corneal allograft’s capacity to escape attack by allodestructive immune-effector elements. The corneal graft and the underlying aqueous humor, which bathes the corneal endothelium, express cell membrane-bound and soluble molecules that neutralize immune effector elements at the graft/host interface. This leg of the immune privilege stool acts to block the efferent arm of the immune response. Removal of any one of the three legs of the immune privilege stool results in the collapse of immune privilege and culminates in corneal graft rejection. Each of these legs of the immune privilege stool is discussed in detail in the following sections of this review.
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AFFERENT BLOCKADE OF THE IMMUNE REFLEX ARC: KEEPING THE IMMUNE APPARATUS IN THE DARK
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The avascularity of the corneal graft bed has been viewed by many as the primary reason why corneal allografts enjoy a success rate that is unrivaled by all other categories of transplantation. It has been reasoned that the absence of lymphatic and blood vessels prevents corneal alloantigens from reaching regional lymphoid tissues. Indeed, corneal grafts placed into prevascularized graft beds are invariably rejected [3
,4
,9
,19
,20
]. However, the avascularity of the corneal graft bed alone cannot explain the immune privilege of corneal allografts, as graft rejection can occur in corneas transplanted into graft beds lacking patent blood vessels. Thus, in addition to the avascular status of the graft bed, factors contribute to the immune privilege of corneal allografts. Among these factors is the presence of passenger leukocytes, which are capable of emigrating from the graft and provoking alloimmune responses in the lymphoid tissues draining the graft bed.
Tissues such as the skin contain a contiguous network of LC, which serve as potent APC. LC in the skin induce robust, alloimmune responses by directly activating T cells. Indeed, as few as 10 allogeneic LC can induce allospecific, cytotoxic T lymphocyte responses in mice [21
]. The distribution and activation status of LC in the cornea differs significantly from the skin. Class II-positive, B7-positive LC are conspicuously absent from the central portion of the cornea that is normally used for transplantation [3
,4
,9
,20
,22
,23
]. Although class II-positive LC are absent from the central cornea, their appearance can be induced by a variety of stimuli including electrocautery, suturing, and instillation of sterile latex beads [9
,22
,24
]. It was originally suggested that such maneuvers induced the centripetal migration of peripheral LC into the central cornea [3
,23
,24
]; however, recent evidence suggests that MHC class II-negative LC may in fact be constitutively present in the central cornea, and various traumatic stimuli will induce their activation and conversion to a MHC class II-positive status [25
,26
]. In either case, it is clear that corneal grafts prepared from nontraumatized corneas are devoid of class II-positive LC and experience a much greater survival advantage over corneal grafts containing donor-derived LC. That is, corneal allografts pretreated so that they contain class II-positive, donor-derived LC experience a twofold increase in the incidence of immune rejection [10
,19
]. The immune privilege of these grafts can be restored by eliminating the passenger LC by treatment with UV irradiation or hyperbaric oxygen [19
]. It is noteworthy that the presence of donor-derived LC, whether they migrate from the peripheral limbus or become fully activated in situ, abolishes the immune privilege of the corneal allograft, even in an avascular graft bed. Thus, the absence of MHC class-II positive LC in the corneal allograft and the absence of a vascularized graft bed conspire to block the afferent arm of the immune reflex arc and prevent the induction of allodestructive immune responses.
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DISRUPTION OF THE CENTRAL PROCESSING COMPONENT OF THE IMMUNE REFLEX ARC: DIVERTING THE IMMUNE RESPONSE FROM A DESTRUCTIVE PATHWAY TO A TOLERANT PATHWAY
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Orthotopic corneal grafts are in direct contact with the anterior chamber of the eye. In fact, the corneal endothelium lines a significant portion of the anterior chamber. The juxtaposition of the corneal endothelium with the anterior chamber may have important consequences in determining the fate of the corneal allograft. The anterior chamber of the eye displays a unique form of immune privilege that has been recognized for over a century [20
,27
,28
]. It is well recognized that ocular immune privilege is the product of multiple, overlapping anatomical, physiological, and immuoregulatory features that are unique to the eye. These include: the presence of immunosuppressive cytokines and neuropeptides in the aqueous humor; the expression of Fas ligand (FasL) and complement regulatory proteins on ocular cells and in the aqueous humor; the severely limited lymphatic drainage of the interior of the eye; and the active antigen-specific down-regulation of Th1 immune responses to intraocular antigens [20
,27
,28
]. The antigen-specific down-regulation of delayed-type hypersensitivity (DTH) responses to antigens introduced into the anterior chamber has been termed anterior chamber-associated immune deviation (ACAID) and has been demonstrated with a wide array of antigens, including the major and minor H antigens expressed on corneal allografts [3
,4
,20
,28
]. Although ACAID is believed to be an adaptive mechanism for protecting ocular tissues from immune-mediated injury, orthotopic corneal allografts are beneficiaries of this immune-regulatory process. Sonoda and Streilein [11
] observed that mice harboring long-term, surviving orthotopic corneal allografts also demonstrated an antigen-specific down-regulation of DTH that was reminiscent of ACAID. Moreover, mice that develop donor-specific DTH after keratoplasty invariably reject their corneal allografts, and animals displaying suppressed DTH maintain clear allografts. These findings strongly suggest that orthotopic corneal allografts induce ACAID and thereby enhance their own survival. Indirect support of this was found in studies in which abrogation of ACAID by splenectomy resulted in a significant increase in corneal graft rejection [29
]. In addition to conventional 
ß T cells, at least two other T cell populations, 
T cells and natural killer T cells, are required for the induction of ACAID [30
31
32
]. It is interesting that mice depleted of either of these T cell populations, by genetic disruption or by in vivo depletion with monoclonal antibodies (mAb), results in the abrogation of ACAID and a sharp increase in the immune rejection of corneal allografts [30
,33
]. These findings imply that the high incidence of corneal graft rejection in certain donor-host combinations might represent the failure of some orthotopic corneal allografts to induce ACAID. This proposition is supported by results from several laboratories showing that induction of ACAID, through the intracameral injection of alloantigens before keratoplasty, produces a significant enhancement of corneal allograft survival [34
35
36
]. Collectively, these results indicate that the capacity of corneal allografts to induce ACAID contributes to their immune privilege.
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BLOCKADE OF THE EFFERENT ARM OF THE IMMUNE REFLEX ARC: THE BEST DEFENSE IS A GOOD OFFENSE
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One of the original explanations for the immune privilege of corneal allografts was based on the assumption that the absence of blood vessels in the corneal graft bed sequestered the corneal graft from circulating immune elements. Although the concept of an immunoanatomical isolation is not tenable, there is compelling evidence for the presence of a functional blockade of immune effector elements. Griffith and coworkers [37
] demonstrated that the apoptosis-inducing cell membrane molecule, FasL, is expressed on multiple ocular cells, including the corneal epithelium and endothelium. FasL induces programmed cell death (apoptosis) in cells bearing its receptor (Fas). Inflammatory cells such as neutrophils and activated T cells are especially vulnerable to apoptosis induced by FasL expressed on ocular cells [37
]. Moreover, FasL appears to play a critical role in protecting corneal allografts from alloimmune attack. Approximately 50% of the corneal grafts from donor mouse strains that express functional FasL on the corneal epithelium and endothelium experience long-term survival [38
,39
]. By contrast, rejection occurs in 89–100% of the corneal grafts prepared from gld/gld mutant mice, which fail to express functional FasL. Thus, FasL creates a functional blockade of the efferent arm of the immune response.
Although it is widely suspected that cytotoxic T lymphocytes (CTL) play a central role in the rejection of many categories of allografts, the evidence is not compelling in the case of corneal allografts. The tempo and incidence of corneal allograft rejection in hosts with defective CTL function, such as perforin knockout (KO) mice, ß2-microglobulin KO mice, and CD8 KO mice, are not significantly different from wild-type mice [40
41
42
]. Moreover, in vivo depletion of CD8+ T cells with anti-CD8 mAb does not prevent the rejection of corneal allografts in normal mice [43
]. By contrast, there is compelling evidence pointing to the CD4+ T cell as the pivotal cellular element in corneal allograft rejection [19
,40
41
42
43
]. The low-incidence rejection of corneal grafts mismatched at the MHC but sharing identical minor H antigens argues against the direct pathway of alloactivation [6
]. By contrast, the high-incidence rejection of MHC-matched, minor H-mismatched corneal allografts, compared with MHC-mismatched grafts, underscores the dominant role of the indirect pathway of alloactivation in corneal graft rejection. The central role of the indirect pathway of alloantigenic stimulation in corneal allograft rejection is further supported by findings indicating that pharmaceutical or immunological depletion of host APC, such as macrophages or LC, results in a steep reduction in the immune rejection of corneal allografts [44
,45
]. Collectively, these findings indicate that the CD8+ T lymphocyte is effectively disqualified as a meaningful participant in the rejection of normal corneal grafts. Thus, it appears that corneal allografts placed into avascular graft beds enjoy yet one more form of immune privilege—exemption from attack by CD8+ CTL. The underlying mechanisms for this privilege await elucidation.
The role of alloantibody in the corneal graft rejection remains unresolved. Although a preponderance of evidence points to cell-mediated immunity as the primary effector of corneal graft rejection, there is evidence suggesting that alloantibody may contribute to corneal allograft failure [46
47
48
49
]. Passive transfer of alloantibody to T cell-deficient mice results in the development of transient opacity and edema of orthotopic corneal allografts but not frank graft rejection [50
]. In vitro investigations demonstrated that the same anti-C57BL/6 alloantibody produced extensive complement-dependent lysis of C57BL/6 corneal endothelial cells but did not adversely affect C57BL/6 corneal epithelial cells. The capacity of corneal epithelial cells to resist lysis by complement-dependent alloantibody might be attributed to the expression of complement regulatory proteins, such as decay-accelerating factor, which are embedded in the cell membranes of the corneal epithelium [51
,52
]. By contrast, the in vitro susceptibility of corneal endothelial cells to complement-dependent lysis might be explained by the absence of complement regulatory proteins in this corneal cell population [52
]. In vivo, the corneal endothelium undoubtedly benefits from the buffering effects of the aqueous humor, which contains at least two complement regulatory proteins [51
,53
,54
]. Thus, the presence of membrane-bound and aqueous humor-borne inhibitors of cell-mediated immunity and complement-dependent lysis is an effective barrier for thwarting the efferent arm of the immune reflex arc.
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SUMMARY AND CONCLUSION
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The prudent use of animal models of keratoplasty has provided evidence that the immune privilege of corneal allografts is a composite of multiple anatomical, physiological, and immunoregulatory factors that collectively interfere with all three phases of the immune reflex arc, that is, the induction, regulation, and expression of the alloimmune response. The immune privilege of corneal allografts is analogous to a three-legged stool in which each leg inhibits a specific phase of the immune reflex arc. Like a three-legged stool, removal of any one of these legs results in the collapse of immune privilege and culminates in corneal graft rejection. Developing strategies for restoring or buttressing all three legs of the metaphorical three-legged immune privilege stool may prove useful in enhancing graft survival in the high-risk keratoplasty patient.
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ACKNOWLEDGEMENTS
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This work was supported by NIH Grant EY07641 and an unrestricted grant for Research to Prevent Blindness, Inc., New York, NY.
Received November 11, 2002;
revised December 16, 2002;
accepted December 20, 2002.
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INTRODUCTION
