Biomedical subjects

Jerry Y Niederkorn

Publications and source records attributed to Jerry Y Niederkorn.

At least 19 recordsLinked to original sources

PubMed2006

Gammadelta T cells promote anterior chamber-associated immune deviation and immune privilege through their production of IL-10.

Anterior chamber-associated immune deviation (ACAID) is a form of peripheral tolerance that is induced by introducing Ags into the anterior chamber (AC) of the eye, and is maintained by Ag-specific regulatory T cells (Tregs). ACAID regulates harmful immune responses that can lead to irreparable injury to innocent bystander cells that are incapable of regeneration. This form of immune privilege in the eye is mediated through Tregs and is a product of complex cellular interactions. These involve F4/80+ ocular APCs, B cells, NKT cells, CD4+CD25+ Tregs, and CD8+ Tregs. gammadelta T cells are crucial for the generation of ACAID and for corneal allograft survival. However, the functions of gammadelta T cells in ACAID are unknown. Several hypotheses were proposed for determining the functions of gammadelta T cells in ACAID. The results indicate that gammadelta T cells do not cause direct suppression of delayed-type hypersensitivity nor do they act as tolerogenic APCs. In contrast, gammadelta T cells were shown to secrete IL-10 and facilitate the generation of ACAID Tregs. Moreover, the contribution of gammadelta T cells ACAID generation could be replaced by adding exogenous recombinant mouse IL-10 to ACAID spleen cell cultures lacking gammadelta T cells.

Animals↗

PubMed2006

Ocular immune privilege is circumvented by CD4+ T cells, leading to the rejection of intraocular tumors in an IFN-{gamma}-dependent manner.

Although intraocular tumors reside in an immune-privileged site, they can circumvent immune privilege and undergo rejection, which typically follows one of two pathways. One pathway involves CD4(+) T cells, delayed-type hypersensitivity (DTH), and the culmination in ischemic necrosis of the tumor and phthisis (atrophy) of the eye. The second pathway is DTH-independent and does not inflict collateral injury to ocular tissues, and the eye is preserved. In this study, we used a well-characterized tumor, Ad5E1, to analyze the role of IFN-gamma in the nonphthisical form of intraocular tumor rejection. The results showed that IFN-gamma induced tumor cell apoptosis, inhibited tumor cell proliferation, and promoted rejection by inhibiting angiogenesis. Microarray analysis revealed that IFN-gamma induced up-regulation of five antiangiogenic genes and down-regulation of four proangiogenic genes in Ad5E1 tumor cells. Although IFN-gamma knockout (KO) mice have progressively growing intraocular tumors, IFN-gamma was not needed for the elimination of extraocular tumors, as all IFN-gamma KO mice rejected s.c. tumor inocula. This represents a heretofore unrecognized role for IFN-gamma in circumventing ocular immune privilege and eliminating intraocular tumors. The findings also reveal that some IFN-gamma-independent tumor rejection processes are excluded from the eye and may represent a new facet of ocular immune privilege.

Animals↗

PubMed2006

Peripheral tolerance via the anterior chamber of the eye: role of B cells in MHC class I and II antigen presentation.

Ags introduced into the anterior chamber (AC) of the eye induce a form of peripheral immune tolerance termed AC-associated immune deviation (ACAID). ACAID mitigates ocular autoimmune diseases and promotes corneal allograft survival. Ags injected into the AC are processed by F4/80(+) APCs, which migrate to the thymus and spleen. In the spleen, ocular APCs induce the development of Ag-specific B cells that act as ancillary APCs and are required for ACAID induction. In this study, we show that ocular-like APCs elicit the generation of Ag-specific splenic B cells that induce ACAID. However, direct cell contact between ocular-like APCs and splenic B cells is not necessary for the induction of ACAID B cells. Peripheral tolerance produced by ACAID requires the participation of ACAID B cells, which induce the generation of both CD4(+) regulatory T cells (Tregs) and CD8(+) Tregs. Using in vitro and in vivo models of ACAID, we demonstrate that ACAID B cells must express both MHC class I and II molecules for the generation of Tregs. These results suggest that peripheral tolerance induced through the eye requires Ag-presenting B cells that simultaneously present Ags on both MHC class I and II molecules.

Adoptive Transfer↗

PubMed2006

CD4+ T-cell-independent rejection of corneal allografts.

BACKGROUND: Several studies suggest that a significant number of corneal allografts undergo rejection in the absence of CD4 T cells. This study examined the role of CD4 T cell-independent mechanisms of corneal allograft rejection. METHODS: BALB/c corneal allografts were transplanted to C57BL/6 beige nude mice that received either CD8 or CD8 T cells from C57BL/6 CD4 knockout (KO) mice that had rejected BALB/c corneal allografts. Immune effector functions of CD8 or CD8 T cells from C57BL/6 CD4 KO mice were assessed using delayed-type hypersensitivity assays and Annexin V apoptosis assays respectively. RESULTS.: Both CD8 and CD8 T cells from CD4 KO corneal allograft rejector mice mediated corneal allograft rejection following adoptive transfer to nude mice. CD8 T cells, but not CD8 T cells, from CD4 KO mice adoptively transferred donor-specific DTH and induced apoptosis of BALB/c corneal endothelial cells in vitro. Apoptosis of BALB/c corneal endothelial cells was mediated by double negative (DN) T cells, as treatment of CD8 cells from CD4 KO mice with anti-Thy 1.2 plus complement abolished their effector function. CONCLUSION: The results support the proposition that CD4 T cell-independent rejection of corneal allografts can be mediated by either CD8 or CD8 T cells. The CD8 T cells represent a unique DN T cell population that might mediate rejection by either direct cytolysis or by inducing apoptosis of the donor corneal endothelium.

Adoptive Transfer↗

PubMed2006

Downregulation of survivin expression enhances sensitivity of cultured uveal melanoma cells to cisplatin treatment.

The purpose of this study is to evaluate the effect of a novel anti-apoptotic gene, survivin, on the resistance and susceptibility of human uveal melanoma cells to apoptosis induced by cisplatin. The sensitivity of human uveal melanoma cell lines to apoptosis induced by cisplatin was analyzed by caspase-3 assays. The expression of the anti-apoptotic protein, survivin, was examined by flow cytometry. Melanoma cells were transfected with either survivin cDNA or survivin anti-sense cDNA and examined for susceptibility to cisplatin-induced apoptosis. Six human uveal melanoma cell lines were incubated with or without cisplatin and cellular proliferation was determined by MTT assays. Significant growth inhibition was observed in 3 melanoma cell lines (OMM1, OCM3, and MEL 270). By contrast, 3 cell lines (OMM2.5, OMM2.3, and 92-1) were resistant to cisplatin-induced apoptosis. However, a positive association was observed between resistance to cisplatin-induced apoptosis and high expression of the anti-apoptotic protein, survivin. Up-regulation of survivin by gene transfer enhanced resistance to cisplatin-induced apoptosis, while transfection with survivin anti-sense rendered resistant melanoma cells susceptible to cisplatin. The combination of cisplatin and actinomycin D significantly decreased survivin expression and enhanced the cisplatin-induced apoptosis of uveal melanoma cells in vitro. These data indicate that resistance of some uveal melanoma cells to cisplatin-induced apoptosis is controlled by anti-apoptotic proteins, such as survivin, that are sensitive to actinomycin D treatment.

Antibiotics, Antineoplastic↗

PubMed2006

Desiccating stress induces T cell-mediated Sjögren's Syndrome-like lacrimal keratoconjunctivitis.

Chronic dry eye syndrome affects over 10 million people in the United States; it is associated with inflammation of the lacrimal gland (LG) and in some cases involves T cell infiltration of the conjunctiva. We demonstrate that environmental desiccating stress (DS) elicits T cell-mediated inflammation of the cornea, conjunctiva, and LG, but not other organs in mice. The lacrimal keratoconjunctivitis (LKC) was mediated by CD4(+) T cells, which, when adoptively transferred to T cell-deficient nude mice, produced inflammation in the LG, cornea, and conjunctiva, but not in any other organ. Adoptively transferred CD4(+) T cells produced LKC even though recipients were not exposed to DS. LKC was exacerbated in euthymic mice depleted of CD4(+)CD25(+)forkhead/winged helix transcription factor(+) regulatory T cells. The results suggest that DS exposes shared epitopes in the cornea, conjunctiva, and LG that induce pathogenic CD4(+) T cells that produce LKC, which under normal circumstances is restrained by CD4(+)CD25(+)forkhead/winged helix transcription factor(+) regulatory T cells.

Animals↗

PubMed2006

The pathophysiology of Acanthamoeba keratitis.

Acanthamoeba keratitis is a sight-threatening infection of the ocular surface that is produced by several free-living amebae of the genus Acanthamoeba. Infection is usually initiated by Acanthamoeba-contaminated contact lenses and produces exquisite pain and ulceration of the ocular surface. The pathophysiology of this infection involves an intricate series of sequential events that includes the production of several pathogenic proteases that degrade basement membranes and induce cytolysis and apoptosis of the cellular elements of the cornea, culminating in dissolution of the collagenous corneal stroma. Targeting such proteases could lead to the development of vaccines that target the disease process rather than the pathogen itself.

Acanthamoeba↗

PubMed2006

Effect of an anti-CD54 (ICAM-1) monoclonal antibody (UV3) on the growth of human uveal melanoma cells transplanted heterotopically and orthotopically in SCID mice.

We have shown that administration of a novel anti-CD54 monoclonal antibody (UV3) results in long-term survival of SCID mice bearing human myeloma xenografts. Previous studies have demonstrated a link between the expression of CD54 and the progression of uveal melanoma. Our study assessed the expression of CD54 on 7 human uveal melanoma cell lines and 3 cell lines established from uveal melanoma metastases. In vivo studies examined the efficacy of systemic and local administration of UV3 antibody on the progression of uveal melanoma cells transplanted either heterotopically or orthotopically into SCID mice. Five of the 7 primary uveal melanoma cell lines and all 3 of the metastases cell lines expressed CD54. Intraperitoneal injection of either IgG or F(ab')2 fragments of UV3 significantly inhibited the growth of subcutaneous and intraocular melanomas. Subconjunctival injection of either IgG or F(ab')2 fragments of UV3 produced a significant reduction in the growth of intraocular melanomas, even if the antibody was administered after the appearance of intraocular tumors. The results indicate that both primary and metastatic human uveal melanoma cells express CD54. The marked inhibition of intraocular and subcutaneous uveal melanoma progression suggests that UV3 antibody is a promising therapeutic agent for further evaluation in patients with uveal melanoma. This is especially noteworthy, as no existing therapeutic modality prevents metastasis of uveal melanoma or prolongs the survival of patients with uveal melanoma.

Animals↗

PubMed2006

The immunobiology of Acanthamoeba keratitis.

Acanthamoeba spp. are free-living amoebae that cause Acanthamoeba keratitis, a blinding corneal infection. The innate immune apparatus is crucial for the resolution of the disease. With the exception of mucosal antibody, elements of the adaptive immune system fail to prevent infection or contribute to its resolution in experimental animals.

Acanthamoeba↗

PubMed2006

See no evil, hear no evil, do no evil: the lessons of immune privilege.

Immune-mediated inflammation and allograft rejection are greatly reduced in certain organs, a phenomenon called 'immune privilege'. Immune privilege is well developed in three regions of the body: the eye, the brain and the pregnant uterus. Immune-mediated inflammation has devastating consequences in the eye and brain, which have limited capacity for regeneration. Likewise, loss of immune privilege at the maternal-fetal interface culminates in abortion in rodents. However, all three regions share many adaptations that restrict the induction and expression of immune-mediated inflammation. A growing body of evidence from rodent studies suggests that a breakdown in immune privilege contributes to multiple sclerosis, uveitis, corneal allograft rejection and possibly even immune abortion.

Animals↗

PubMed2006

Intracorneal instillation of latex beads induces macrophage-dependent protection against Acanthamoeba keratitis.

PURPOSE: Instillation of sterile 1.0 microM latex beads into the central corneal epithelium renders Chinese hamsters resistant to corneal infection with Acanthamoeba castellanii. By contrast, activation of the adaptive immune response by subcutaneous immunization with A. castellanii antigens fails to protect against Acanthamoeba keratitis. This study was undertaken to examine the mechanisms that mediate latex bead-induced resistance to Acanthamoeba keratitis. METHODS: In vitro experiments examined the effect of latex bead treatment on the capacity of A. castellanii trophozoites to adhere to and kill corneal epithelial cells. In vivo administration of antineutrophil antiserum was used to evaluate the role of neutrophils in latex-bead-induced protection against Acanthamoeba keratitis. Liposomes containing the macrophagicidal drug clodronate were used to deplete conjunctival macrophages and determine the role of macrophages in the latex-bead-induced resistance. RESULTS: Latex bead treatment did not affect adherence of trophozoites to the corneal epithelium or protect corneal epithelial or stromal cells from trophozoite-mediated cytolysis in vitro. Neutrophil depletion did not abrogate the latex beads' protective effect. Latex bead treatment induced a significant infiltration of macrophages into the corneas that peaked at day 4 of infection. Moreover, depletion of conjunctival macrophages with the macrophagicidal drug clodronate eliminated the latex beads' protective effect. CONCLUSIONS: The results indicate that intracorneal injection of latex beads induces a remarkable resistance to Acanthamoeba keratitis that is largely, if not entirely, mediated by macrophages. These results underscore the importance of the innate immune apparatus in the resistance to Acanthamoeba keratitis.

Acanthamoeba Keratitis↗

PubMed2005

Immune privilege of the eye and fetus: parallel universes?

The eye is an extension of the brain and thus many of its tissues are incapable of regeneration. Ocular inflammation can produce extensive damage to innocent bystander cells leading to blindness. However, the eye possesses multiple strategies to control immune-mediated inflammation-a phenomenon known as immune privilege. The fetus of outbred mammals expresses paternal histocompatibility antigens and represents an allograft. However, the success of placental animals is a testament to the immune privilege of the allogeneic fetus. Extensive evidence suggests that the eye and the fetus employ similar strategies for establishing immune privilege for preserving vision and the unborn respectively.

Animals↗

PubMed2005

Cutting edge: atopy promotes Th2 responses to alloantigens and increases the incidence and tempo of corneal allograft rejection.

A large body of evidence suggests that corneal allograft rejection is mediated by a type 1 Th cell response and that deviation toward type 2 immunity favors graft survival. However, clinical observations indicate that patients with severe ocular allergies have increased risk of corneal allograft rejection. We used a mouse model of atopic conjunctivitis to evaluate the effects of Th2 immune deviation on corneal allograft survival and possible mechanisms of graft rejection. Our results reveal the following novel findings: 1) atopic conjunctivitis promotes systemic Th2 immune responses to corneal graft donor alloantigens; 2) corneal allografts in atopic host eyes have an increased incidence and swifter tempo of rejection; 3) increased rejection is associated with alterations in systemic T cell-mediated responses to donor alloantigens; and 4) corneal allograft rejection in atopic hosts does not require the direct involvement of infiltrating eosinophils.

Ambrosia↗

PubMed2005

CD4(+) T-cell-mediated mechanisms of corneal allograft rejection: role of Fas-induced apoptosis.

BACKGROUND: The role of CD4(+) T cells as effector cells in corneal allograft rejection is poorly understood. We investigated the role of CD4(+) T cells as helper cells in the generation of allospecific effector macrophages in corneal graft rejection and the role of CD4(+) T cells as apoptosis-inducing effector cells. METHODS: Corneal allografts were transplanted to CD4 knockout, FasL-deficient, and macrophage-depleted hosts. An Annexin-V binding assay was used to evaluate the susceptibility of corneal cells to both Fas-dependent and CD4 T-cell-mediated apoptosis in vitro. RESULTS: Macrophages were essential for graft rejection, but not as effector cells. Anti-BALB/c CD4(+) T cells from immunized C57BL/6 mice induced apoptosis of BALB/c corneal epithelial and endothelial cells. However, anti-BALB/c CD4(+) T cells from FasL-deficient gld/gld mice did not induce apoptosis of BALB/c corneal endothelial cells. Moreover, gld/gld mice had a reduced capacity to reject BALB/c corneal allografts. Although the initial results suggested a role for Fas-induced apoptosis in corneal graft rejection, additional experiments indicated otherwise. The incidence and tempo of immune rejection of Fas-deficient lpr/lpr corneal allografts were no different than those for corneal grafts from Fas-bearing C57BL/6 donors. Moreover, CD4(+) T-cell-mediated apoptosis of corneal cells could not be blocked with either Fas-Fc fusion protein or anti-FasL blocking antibody. CONCLUSIONS: The results suggest that CD4(+) T cells function directly as effector cells and not as helper cells in the rejection of corneal allografts. Although the corneal endothelium is highly susceptible to Fas-induced apoptosis, this is apparently not the primary mechanism of CD4(+) T-cell-dependent rejection.

Animals↗

PubMed2005

Resistance and susceptibility of human uveal melanoma cells to TRAIL-induced apoptosis.

OBJECTIVE: To evaluate the resistance and susceptibility of human uveal melanoma cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). METHODS: The sensitivity of 11 human uveal melanoma cell lines was analyzed by flow cytometry for the expression of TRAIL receptors and the antiapoptotic protein survivin. Caspase-8 and caspase-10 expression was also examined using reverse transcriptase-polymerase chain reaction and Western blot analysis. RESULTS: Only 4 melanoma cell lines were sensitive to TRAIL-induced apoptosis. Positive correlation was observed between resistance and expression of survivin. Up-regulation of survivin by gene transfer enhanced resistance to TRAIL-induced apoptosis, whereas transfection with survivin antisense rendered resistant melanoma cells susceptible to TRAIL-induced apoptosis. Survivin expression and susceptibility to TRAIL-induced apoptosis could also be manipulated by treatment with actinomycin D, which produced a 30% to 50% decrease in the expression of survivin (P < .01) and a 5- to-7-fold increase in TRAIL-induced apoptosis (P < .001). CONCLUSIONS: Resistance of uveal melanoma cells to TRAIL-induced apoptosis is regulated by antiapoptotic proteins such as survivin. CLINICAL RELEVANCE: Manipulation of apoptosis regulatory proteins, such as survivin, may have therapeutic applications in the management of uveal melanomas.

Antineoplastic Agents↗

PubMed2005

Pathways of corneal and ocular surface inflammation: a perspective from the cullen symposium.

The goal of this symposium was to coalesce information presented by 22 investigators in the field of corneal and ocular surface inflammation into common pathways of inflammation. The perspective elucidated in this article defines the components of the normal ocular surface immune architecture and describes the consensus reached on the mechanisms/pathways involved in 1) acute inflammation; 2) late-stage (chronic) response; and 3) allergic disease. Seven diagrams didactically illustrate mechanisms. This paper is the introductory article in a supplement containing 18 articles by the symposium participants.

Journal Article↗

PubMed2005

Corneal immune privilege.

This year marks the 100th anniversary of the first successful corneal transplant on a human subject. Corneal allografts enjoy an exceptionally high acceptance, with rejection occurring in less than 10% of the patients who have not previously received a corneal transplant and who do not have underlying ocular inflammation. Corneal grafts survive even though HLA typing and systemic immunosuppressive drugs are not employed. The remarkable success of corneal transplants is due to a combination of anatomical, physiological, and immunological properties that conspire to prevent the induction and expression of potentially destructive immune responses to the foreign transplant.

Journal Article↗

PubMed2005

Evaluation of ocular surface inflammation in the presence of dry eye and allergic conjunctival disease.

The ocular inflammatory diseases dry eye and allergic conjunctivitis are mediated by CD4+ T cells. Th1 cells secrete interferon (IFN)-gamma and are implicated in mediating the disease process in dry eye. Allergic conjunctivitis has been classically defined as a Th2 disease because of the predominance of Th2 cytokines interleukin (IL)-4 and IL-13. A multi-hit antigen challenge mouse model of allergic conjunctivitis provides evidence that IFN-gamma, a Th1 cytokine, acts as an endothelium gatekeeper by regulating endothelial expression of vascular adhesion molecule-1 required for inflammatory conjunctival cell infiltration. Current research encourages an in-depth evaluation of the exact role Th1 and Th2 cells play in ocular inflammation.

Journal Article↗