Ocular Immune Privilege and Ocular Melanoma: Parallel Universes or Immunological Plagiarism?

Evidence of immune privilege in the eye was recorded almost 140 years ago, yet interest in immune privilege languished for almost a century. However, the past 35 years have witnessed a plethora of research and a rekindled interest in the mechanisms responsible for immune privilege in the anterior chamber of the eye. This research has demonstrated that multiple anatomical, structural, physiological, and immunoregulatory processes contribute to immune privilege and remind us of the enormous complexity of this phenomenon. It is widely accepted that immune privilege is an adaptation for reducing the risk of immune-mediated inflammation in organs such as the eye and brain whose tissues have a limited capacity to regenerate. Recent findings suggest that immune privilege also occurs in sites where stem cells reside and raise the possibility that immune privilege is also designed to prevent the unwitting elimination of stem cells by immune-mediated inflammation at these sites. Uveal melanoma arises within the eye and as such, benefits from ocular immune privilege. A significant body of research reveals an intriguing parallel between the mechanisms that contribute to immune privilege in the eye and those strategies used by uveal melanoma cells to evade immune elimination once they have disseminated from the eye and establish metastatic foci in the liver. Uveal melanoma metastases seem to have “plagiarized” the blueprints used for ocular immune privilege to create “ad hoc immune privileged sites” in the liver

Immunization of Rats Against Mesocestoides corti (Cestoda) by Subcutaneous Vaccination of Living Tetrathyridia and by Passive Transfer with Serum

Laboratory rats were subcutaneously vaccinated with 100 live tetrathyridia of Mesocestoides corti (Cestoda) and subsequently intraperitoneally challenged with 50 tetrathyridia. Necropsy 30 days postinfection revealed that vaccinated rats harbored 97.4% fewer worms compared to control rats. In a second experiment, passive transfer of immunity was accomplished by immune serum from subcutaneously vaccinated rats. Rats receiving immune serum harbored 33.4% lighter worm burdens compared to normal serum recipients

“Corneal Nerves, CD11c+ Dendritic Cells and Their Impact on Ocular Immune Privilege”

The eye and the brain have limited capacities for regeneration and as such, immune-mediated inflammation can produce devastating consequences in the form of neurodegenerative diseases of the central nervous system or blindness as a result of ocular inflammatory diseases such as uveitis. Accordingly, both the eye and the brain are designed to limit immune responses and inflammation – a condition known as “immune privilege”. Immune privilege is sustained by physiological, anatomical, and regulatory processes that conspire to restrict both adaptive and innate immune responses

Effect of Donor Langerhans Cells on Corneal Graft Rejection

Unlike other cutaneous surfaces, the central portion of the corneal epithelium is typically devoid of Langerhans cells. The absence of Ia+ Langerhans cells in the central cornea is of more than casual interest and may explain the immunologic privilege that is characteristic of corneal allografts. The present communication, summarizes previous studies that examined the role of corneal Langerhans cells in eliciting alloimmune responses and corneal graft rejection in rodents. Under normal circumstances, cornmeal allografts are poorly immunogenic when residing in the avascular ocular graft bed even though the graft displays large quantities of alloantigens. The afferent blockade of the immune response can be circumvented by donor-derived Langerhans cells that serve as potent immunogens for all categories of corneal allografts except grafts involving allodisparity only at class I major histocompatibility complex loci. Thus, the presence of donor-derived Langerhans cells exerts profound effects on the fate of corneal allografts

The role of cytotoxic T lymphocytes in corneal allograft rejection

PURPOSE. Immunologic rejection constitutes a major barrier to the success of allogeneic corneal transplants, but the specific mediators and mechanisms of graft rejection are poorly understood. Several studies have implicated cytotoxic T-lymphocyte (CTL) responses, typically associated with CD8 ϩ T cells, in promoting corneal graft rejection. This study sought to test the hypothesis that CTLs are essential in promoting corneal graft rejection. METHODS. BALB/c donor corneas were grafted orthotopically onto C57BL/6, perforin knockout, or CD8 ϩ T-cell knockout mice. The tempo and incidence of graft rejection were observed for each group. In separate experiments, donor-specific CTL and delayed-type hypersensitivity (DTH) responses were tested at the time of graft rejection by a standard chromium release assay and an ear swelling assay, respectively. RESULTS. Perforin knockout and CD8 ϩ T-cell knockout mice were as effective as wild-type C57BL/6 control mice in rejecting BALB/c donor corneas. Furthermore, animals in all three groups were found to develop robust donor-specific DTH, not CTL, responses at the time of graft rejection. Histopathologically, the rejected corneas from all three groups contained a predominantly mononuclear cellular infiltrate. CONCLUSIONS. This study rejects the hypothesis that CD8 ϩ CTLs are essential in promoting corneal graft rejection and instead further implicates donor-specific DTH reactions as the relevant immune response during graft failure. (Invest Ophthalmol Vis Sci. 2000;41:3341-3347

Effect of LFA-1 and ICAM-1 Antibody Treatment on Murine Corneal Allograft Survival

Purpose. To examine the effect of anti-LFA-1 and anti-ICAM-1 antibody treatment on orthotopic corneal graft survival in a mouse model. Methods. Anti-LFA-1 and anti-ICAM-1 antibodies were administered intraperitoneally before and shortly after orthotopic corneal transplantation. Grafts were observed by biomicroscopy, and survival times were determined. Cytotoxic T lymphocyte (CTL) and delayed-type hypersensitivity (DTH) responses to donor alloantigens were assessed at selected times after grafting. Results. Administration of anti-LFA-1 antibody reduced the incidence of graft rejection from 90% in untreated donors to 47% in anti-LFA-1 treated mice. By contrast, treatment with anti-ICAM-1 antibody alone did not reduce the incidence of rejection, although it prolonged graft survival time. Both CTL and DTH responses to donor alloantigens were severely depressed in hosts treated with either anti-LFA-1 or anti-ICAM-1 antibody. However, neither anti-ICAM-1 nor anti-LFA-1 antibody treatment prevented the rejection of orthotopic corneal grafts in previously immunized mice. Conclusions. Anti-ICAM-1 antibody does not promote graft survival even though it impairs CTL and DTH responses to donor alloantigens. By contrast, anti-LFA-1 antibody can significantly reduce the incidence of orthotopic corneal graft rejection and prevent the induction of normal allospecific CTL and DTH responses. Although anti-LFA-1 antibody is effective if given prophylactically, it is ineffective at preventing corneal graft rejection in previously immunized hosts. Invest Ophthalmol Vis Sci. 1994; 35:3218-3225. iVeratoplasty is one of the oldest, most common, and most successful forms of organ transplantation. 1 Approximately 40,000 corneal transplants are performed each year in the United States. 2 Despite a success rate that often approaches 90%, a significant number of corneal grafts fail because of immunologic rejection. 2 " 4 Thus, understanding the mechanisms of corneal graft rejection and developing improved immunosuppressive strategies could have a major impact on promoting corneal allograft survival and restoring vision. Studies on allogeneic organ transplantation in experimental animals have demonstrated that leukocytes From the ^Department of Ophthalmology and the f Graduate Progra

NK Cells Promote Th-17 Mediated Corneal Barrier Disruption in Dry Eye

The conjunctiva contains a specialized population of lymphocytes that reside in the epithelium, named intraepithelial lymphocytes (IEL).Here we characterized the IEL population prior to and after experimental desiccating stress (DS) for 5 or 10 days (DS5, DS10) and evaluated the effect of NK depletion on DS. The frequency of IELs in normal murine conjunctiva was CD3(+)CD103(+) (~22%), CD3(+)γδ(+) (~9.6%), CD3(+)NK(+) (2%), CD3(-)NK(+) (~4.4%), CD3(+)CD8α (~0.9%), and CD4 (~0.6%). Systemic depletion of NK cells prior and during DS led to a decrease in the frequency of total and activated DCs, a decrease in T helper-17(+) cells in the cervical lymph nodes and generation of less pathogenic CD4(+)T cells. B6.nude recipient mice of adoptively transferred CD4(+)T cells isolated from NK-depleted DS5 donor mice showed significantly less corneal barrier disruption, lower levels of IL-17A, CCL20 and MMP-3 in the cornea epithelia compared to recipients of control CD4(+)T cells.Taken together, these results show that the NK IELs are involved in the acute immune response to desiccation-induced dry eye by activating DC, which in turn coordinate generation of the pathogenic Th-17 response

Disruption of TGF-β Signaling Improves Ocular Surface Epithelial Disease in Experimental Autoimmune Keratoconjunctivitis Sicca

TGF-β is a pleiotropic cytokine that can have pro- or anti-inflammatory effects depending on the context. Elevated levels of bioactive TGF-β1 in tears and elevated TGF-β1mRNA transcripts in conjunctiva and minor salivary glands of human Sjögren's Syndrome patients has also been reported. The purpose of this study was to evaluate the response to desiccating stress (DS), an experimental model of dry eye, in dominant-negative TGF-β type II receptor (CD4-DNTGFβRII) mice. These mice have a truncated TGF-β receptor in CD4(+) T cells, rendering them unresponsive to TGF-β.DS was induced by subcutaneous injection of scopolamine and exposure to a drafty low humidity environment in CD4-DNTGFβRII and wild-type (WT) mice, aged 14 weeks, for 5 days. Nonstressed (NS) mice served as controls. Parameters of ocular surface disease included corneal smoothness, corneal barrier function and conjunctival goblet cell density. NS CD4-DNTGFβRII at 14 weeks of age mice exhibited a spontaneous dry eye phenotype; however, DS improved their corneal barrier function and corneal surface irregularity, increased their number of PAS+ GC, and lowered CD4(+) T cell infiltration in conjunctiva. In contrast to WT, CD4-DNTGFβRII mice did not generate a Th-17 and Th-1 response, and they failed to upregulate MMP-9, IL-23, IL-17A, RORγT, IFN-γ and T-bet mRNA transcripts in conjunctiva. RAG1KO recipients of adoptively transferred CD4+T cells isolated from DS5 CD4-DNTGFβRII showed milder dry eye phenotype and less conjunctival inflammation than recipients of WT control.Our results showed that disruption of TGF-β signaling in CD4(+) T cells causes paradoxical improvement of dry eye disease in mice subjected to desiccating stress