About My Research
Center/Research Area Affiliations
- AMD Center of Excellence
- Cornea Center of Excellence
- Glaucoma Center of Excellence
- Ocular Oncology Center of Excellence
- Ocular Regenerative Medicine Institute
Biography
At Schepens Eye Research Institute of Mass. Eye and Ear, Dr. Ksander conducts research on the regulation of ocular innate, immune-mediated inflammation in glaucoma and age-related macular degeneration, as well as the regeneration of the corneal epithelium by limbal stem cells.One important challenge in regenerative medicine is replacing stem cells when they are eliminated after an injury or disease. With his laboratory, Dr. Ksander determined that the ABCB5 gene—a new member of the ATP-binding cassette (ABC) superfamily of active transporters—is expressed on adult limbal stem cells that are capable of regenerating corneal epithelium. Importantly, ABCB5 is a cell surface protein that can be used to purify ABCB5 cells from the limbus. This provides him with a unique opportunity to study the regenerative mechanisms of adult limbal stem cells and develop new methods to restore this specialized epithelium in eyes with a limbal stem cell deficiency. Dr. Ksander's current research project aims to determine the efficacy of using soluble Fas Ligand (sFasL) to prevent and/or treat sight-threatening corneal inflammation and scarring induced by trauma.
Postgraduate Training
1985: PhD, University of Illinois
- Loss of epigenetic information as a cause of mammalian aging. Cell. 2024 Feb 29; 187(5):1312-1313.
- Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma. Cell Reprogram. 2023 12; 25(6):288-299.
- Correction: Microglia preserve visual function in the aging retina by supporting retinal pigment epithelial health. Immun Ageing. 2023 Nov 11; 20(1):60.
- The Role of Epigenetics in Accelerated Aging: A Reconsideration of Later-Life Visual Loss After Early Optic Neuropathy. J Neuroophthalmol. 2024 Mar 01; 44(1):16-21.
- Microglia preserve visual function loss in the aging retina by supporting retinal pigment epithelial health. Immun Ageing. 2023 Oct 14; 20(1):53.
- Opposing Roles of Blood-Borne Monocytes and Tissue-Resident Macrophages in Limbal Stem Cell Damage after Ocular Injury. Cells. 2023 08 18; 12(16).
- ABCB5+ Limbal Epithelial Stem Cells Inhibit Developmental but Promote Inflammatory (Lymph) Angiogenesis While Preventing Corneal Inflammation. Cells. 2023 06 27; 12(13).
- Epigenetic Regulation of Corneal Epithelial Differentiation by TET2. Int J Mol Sci. 2023 Feb 02; 24(3).
- Loss of epigenetic information as a cause of mammalian aging. Cell. 2023 01 19; 186(2):305-326.e27.
- Limbal BCAM expression identifies a proliferative progenitor population capable of holoclone formation and corneal differentiation. Cell Rep. 2022 08 09; 40(6):111166.
- Midkine Promotes Metastasis and Therapeutic Resistance via mTOR/RPS6 in Uveal Melanoma. Mol Cancer Res. 2022 08 05; 20(8):1320-1336.
- High expression of SARS-CoV2 viral entry-related proteins in human limbal stem cells. Ocul Surf. 2022 01; 23:197-200.
- Human iPS cells engender corneal epithelial stem cells with holoclone-forming capabilities. iScience. 2021 Jun 25; 24(6):102688.
- Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency. Stem Cell Res Ther. 2021 03 19; 12(1):194.
- Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 12; 588(7836):124-129.
- Investigation of factors associated with ABCB5-positive limbal stem cell isolation yields from human donors. Ocul Surf. 2020 01; 18(1):114-120.
- Retinal microglia initiate neuroinflammation in ocular autoimmunity. Proc Natl Acad Sci U S A. 2019 05 14; 116(20):9989-9998.
- Soluble Fas ligand blocks destructive corneal inflammation in mouse models of corneal epithelial debridement and LPS induced keratitis. Exp Eye Res. 2019 02; 179:47-54.
- Microglia inhibit photoreceptor cell death and regulate immune cell infiltration in response to retinal detachment. Proc Natl Acad Sci U S A. 2018 07 03; 115(27):E6264-E6273.
- Repairing the corneal epithelium using limbal stem cells or alternative cell-based therapies. Expert Opin Biol Ther. 2018 05; 18(5):505-513.
- HLA Class I Antigen Expression in Conjunctival Melanoma Is Not Associated With PD-L1/PD-1 Status. Invest Ophthalmol Vis Sci. 2018 02 01; 59(2):1005-1015.
- Proceedings of the Association for Research in Vision and Ophthalmology and Champalimaud Foundation Ocular Oncogenesis and Oncology Conference. Transl Vis Sci Technol. 2019 Jan; 8(1):9.
- Limbal stem cells: identity, developmental origin, and therapeutic potential. Wiley Interdiscip Rev Dev Biol. 2018 03; 7(2).
- Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma. J Immunol. 2016 12 15; 197(12):4626-4638.
- Uveal Melanoma Cell Lines: Where do they come from? (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc. 2016 Aug; 114:T5.
- Endomucin prevents leukocyte-endothelial cell adhesion and has a critical role under resting and inflammatory conditions. Nat Commun. 2016 Feb 02; 7:10363.
- Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium. Cell Death Dis. 2015 Nov 19; 6:e1986.
- A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice. Invest Ophthalmol Vis Sci. 2015 Sep; 56(10):5965-73.
- A Murine Model for Metastatic Conjunctival Melanoma. Invest Ophthalmol Vis Sci. 2015 Apr; 56(4):2325-33.
- Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma. Ocul Oncol Pathol. 2015 Apr; 1(3):182-189.
- Integrin-linked kinase regulates senescence in an Rb-dependent manner in cancer cell lines. Cell Cycle. 2015; 14(18):2924-37.
- Modeling of human uveal melanoma in zebrafish xenograft embryos. Invest Ophthalmol Vis Sci. 2014 Sep 23; 55(10):6612-22.
- ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature. 2014 Jul 17; 511(7509):353-7.
- Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell. 2014 Jun 16; 25(6):831-45.
- Regulation of intraocular pressure by soluble and membrane guanylate cyclases and their role in glaucoma. Front Mol Neurosci. 2014; 7:38.
- Uveal melanoma cell growth is inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase. Invest Ophthalmol Vis Sci. 2014 Apr 29; 55(7):4175-85.
- Increased resistance to Staphylococcus aureus endophthalmitis in BALB/c mice: Fas ligand is required for resolution of inflammation but not for bacterial clearance. Infect Immun. 2013 Jun; 81(6):2217-25.
- Soluble Guanylate Cyclase a1-Deficient Mice: a novel murine model for Primary Open Angle Glaucoma. Ann Neurosci. 2013 Apr; 20(2):65-6.
- Soluble guanylate cyclase a1-deficient mice: a novel murine model for primary open angle glaucoma. PLoS One. 2013; 8(3):e60156.
- NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013 Jan 07; 54(1):110-20.
- RB116: an RB1+ retinoblastoma cell line expressing primitive markers. Mol Vis. 2012; 18:2805-13.
- A genome-wide RNAi screen reveals a Trio-regulated Rho GTPase circuitry transducing mitogenic signals initiated by G protein-coupled receptors. Mol Cell. 2013 Jan 10; 49(1):94-108.
- Tumor cell programmed death ligand 1-mediated T cell suppression is overcome by coexpression of CD80. J Immunol. 2011 Jun 15; 186(12):6822-9.
- Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death. PLoS One. 2011 Mar 29; 6(3):e17659.
- Spontaneous bacterial keratitis in CD36 knockout mice. Invest Ophthalmol Vis Sci. 2011 Jan; 52(1):256-63.
- Retinoblastoma cells are inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase. FASEB J. 2010 Aug; 24(8):2620-30.
- Local treatment with alpha-melanocyte stimulating hormone reduces corneal allorejection. Transplantation. 2009 Jul 27; 88(2):180-7.
- Uveal melanoma cell-based vaccines express MHC II molecules that traffic via the endocytic and secretory pathways and activate CD8+ cytotoxic, tumor-specific T cells. Cancer Immunol Immunother. 2010 Jan; 59(1):103-12.
- Lung cancer patients' CD4(+) T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells. Cancer Immunol Immunother. 2008 Oct; 57(10):1493-504.
- alphaB-crystallin protects retinal tissue during Staphylococcus aureus-induced endophthalmitis. Infect Immun. 2008 Apr; 76(4):1781-90.
- Control of ocular tumor growth and metastatic spread by soluble and membrane Fas ligand. Cancer Res. 2007 Dec 15; 67(24):11951-8.
- The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor-reactive type 1 CD4+ T lymphocytes. Cancer Immunol Immunother. 2008 Mar; 57(3):389-98.
- Recovery of activated cytotoxic T cells from minor H incompatible tumor graft rejection sites. 1989. Ocul Immunol Inflamm. 2007 May-Jun; 15(3):205-13.
- MHC class II-transduced tumor cells originating in the immune-privileged eye prime and boost CD4(+) T lymphocytes that cross-react with primary and metastatic uveal melanoma cells. Cancer Res. 2007 May 01; 67(9):4499-506.
- Influence of immune surveillance and immune privilege on formation of intraocular tumors. Chem Immunol Allergy. 2007; 92:276-289.
- Tumor escape mutants develop within an immune-privileged environment in the absence of T cell selection. J Immunol. 2006 Jul 01; 177(1):162-8.
- Requirement of CD80+ costimulation for rejection of ocular tumors and termination of immune privilege. Exp Eye Res. 2006 Sep; 83(3):574-83.
- Tumor cells transduced with the MHC class II Transactivator and CD80 activate tumor-specific CD4+ T cells whether or not they are silenced for invariant chain. Cancer Res. 2006 Jan 15; 66(2):1147-54.
- Termination of systemic immunity in the presence of intraocular tumors: influence of ocular immune privilege on tumor vaccines. Curr Eye Res. 2006 Jan; 31(1):43-55.
- A novel treatment for ocular tumors using membrane FasL vesicles to activate innate immunity and terminate immune privilege. Invest Ophthalmol Vis Sci. 2005 Jul; 46(7):2495-502.
- Epigenetic silencing of the CIITA gene and posttranscriptional regulation of class II MHC genes in ocular melanoma cells. Invest Ophthalmol Vis Sci. 2004 Sep; 45(9):3185-95.
- In vivo gene delivery and visualization of corneal stromal cells using an adenoviral vector and keratocyte-specific promoter. Invest Ophthalmol Vis Sci. 2004 Jul; 45(7):2194-200.
- Activation of tumor-specific CD4(+) T lymphocytes by major histocompatibility complex class II tumor cell vaccines: a novel cell-based immunotherapy. Cancer Res. 2004 Mar 01; 64(5):1867-74.
- Expression profiling reveals that methylation of TIMP3 is involved in uveal melanoma development. Int J Cancer. 2003 Sep 10; 106(4):472-479.
- By altering ocular immune privilege, bone marrow-derived cells pathogenically contribute to DBA/2J pigmentary glaucoma. J Exp Med. 2003 May 19; 197(10):1335-44.
- Expression of angiogenic factors Cyr61 and tissue factor in uveal melanoma. Arch Ophthalmol. 2002 Dec; 120(12):1719-25.
- Membrane Fas ligand activates innate immunity and terminates ocular immune privilege. J Immunol. 2002 Sep 01; 169(5):2727-35.
- Characterization of complex chromosomal abnormalities in uveal melanoma by fluorescence in situ hybridization, spectral karyotyping, and comparative genomic hybridization. Genes Chromosomes Cancer. 2001 Mar; 30(3):267-73.
- Cytotoxic T cells play no essential role in acute rejection of orthotopic corneal allografts in mice. Invest Ophthalmol Vis Sci. 2001 Feb; 42(2):386-92.
- Analysis of primed donor-specific T cells in recipient mice bearing orthotopic corneal allografts. Transplantation. 2000 Nov 15; 70(9):1302-10.
- Mutation analysis of the PTEN gene in uveal melanoma cell lines. Int J Cancer. 2000 Jul 01; 87(1):151-3.
- Langerhans cells, orthotopic corneal allografts, and direct and indirect pathways of T-cell allorecognition. Invest Ophthalmol Vis Sci. 2000 May; 41(6):1422-31.
- Immune privilege is extended, then withdrawn, from allogeneic tumor cell grafts placed in the subretinal space. Invest Ophthalmol Vis Sci. 1999 Dec; 40(13):3202-8.
- Anterior chamber-associated immune deviation-inducing cells activate T cells, and rescue them from antigen-induced apoptosis. Immunology. 1999 Dec; 98(4):576-83.
- Immunology of ocular tumours. Immunol Today. 1999 Nov; 20(11):482-5.
- Detection of minor alloantigen-specific cytotoxic T cells after rejection of murine orthotopic corneal allografts: evidence that graft antigens are recognized exclusively via the indirect pathway. Transplantation. 1999 Oct 15; 68(7):963-70.
- Anterior chamber-associated immune deviation, ocular immune privilege, and orthotopic corneal allografts. Transplant Proc. 1999 May; 31(3):1472-5.
- Immune privilege, tumors, and the eye. Chem Immunol. 1999; 73:137-58.
- Immunotherapy of uveal melanoma. Dev Ophthalmol. 1999; 30:220-30.
- Normal cerebrospinal fluid suppresses the in vitro development of cytotoxic T cells: role of the brain microenvironment in CNS immune regulation. J Neuroimmunol. 1998 Aug 01; 88(1-2):77-84.
- Uveal melanomas contain antigenically specific and non-specific infiltrating lymphocytes. Curr Eye Res. 1998 Feb; 17(2):165-73.
- Melanomas that develop within the eye inhibit lymphocyte proliferation. Int J Cancer. 1997 Nov 14; 73(4):470-8.
- Gene transfer of the CD80 costimulatory molecule into ocular melanoma cells using a novel episomal vector. Invest Ophthalmol Vis Sci. 1997 Nov; 38(12):2531-9.
- In vitro efficacy of carboplatin and hyperthermia in a murine retinoblastoma cell line. Invest Ophthalmol Vis Sci. 1997 Nov; 38(12):2516-22.
- Blood-borne signals that induce anterior chamber-associated immune deviation after intracameral injection of antigen. Invest Ophthalmol Vis Sci. 1997 Oct; 38(11):2245-54.
- Expression of MAGE genes in ocular melanoma during progression from primary to metastatic disease. Clin Exp Metastasis. 1997 Sep; 15(5):509-18.
- Immunity causing blindness: five different paths to herpes stromal keratitis. Immunol Today. 1997 Sep; 18(9):443-9.
- Expression of MAGE genes in ocular melanoma cell lines. J Immunother. 1997 Jul; 20(4):265-75.
- Murine orthotopic corneal transplantation in high-risk eyes. Rejection is dictated primarily by weak rather than strong alloantigens. Invest Ophthalmol Vis Sci. 1997 May; 38(6):1130-8.
- Immune deviation in relation to ocular immune privilege. J Immunol. 1997 Apr 15; 158(8):3557-60.
- Tumor cells transfected with B7-1 and interleukin-12 cDNA induce protective immunity. Ann N Y Acad Sci. 1996 Oct 31; 795:325-7.
- The effect of IL-12 on immune privilege of the eye. Ann N Y Acad Sci. 1996 Oct 31; 795:426-8.
- Role of donor-specific cytotoxic T cells in rejection of corneal allografts in normal and high-risk eyes. Transpl Immunol. 1996 Mar; 4(1):49-52.
- Minor H, rather than MHC, alloantigens offer the greater barrier to successful orthotopic corneal transplantation in mice. Transpl Immunol. 1996 Mar; 4(1):53-6.
- Fate of orthotopic corneal allografts in eyes that cannot support anterior chamber-associated immune deviation induction. Invest Ophthalmol Vis Sci. 1995 Oct; 36(11):2176-85.
- Characterization of cell-mediated immune responses elicited by orthotopic corneal allografts in mice. Invest Ophthalmol Vis Sci. 1995 Feb; 36(2):427-34.
- Imposing deviant immunity on the presensitized state. J Immunol. 1994 Oct 01; 153(7):2962-73.
- Regulation of the immune response within privileged sites. Chem Immunol. 1994; 58:117-45.
- Complete elimination ('cure') of progressively growing intraocular tumors by local injection of tumor-specific CD8+ T lymphocytes. Invest Ophthalmol Vis Sci. 1993 Dec; 34(13):3622-34.
- Evidence that active suppression contributes to the success of H-2-incompatible orthotopic corneal allografts in mice. Transplant Proc. 1993 Feb; 25(1 Pt 2):1374-6.
- Incomplete activation of lymphokine-producing T cells by alloantigenic intraocular tumours in anterior chamber-associated immune deviation. Immunology. 1993 Feb; 78(2):266-72.
- Studies on the minimum requirements for in vitro cure of tumor cells by cytotoxic T lymphocytes. Reg Immunol. 1992 Nov-Dec; 4(6):352-62.
- Local T helper cell signals by lymphocytes infiltrating intraocular tumors. J Immunol. 1992 Mar 15; 148(6):1955-63.
- Studies of tumor-infiltrating lymphocytes from a human choroidal melanoma. Invest Ophthalmol Vis Sci. 1991 Dec; 32(13):3198-208.
- Characterization of specific T helper cell activity in mice bearing alloantigenic tumors in the anterior chamber of the eye. Eur J Immunol. 1991 Aug; 21(8):1923-31.
- Termination of immune privilege in the anterior chamber of the eye when tumor-infiltrating lymphocytes acquire cytolytic function. Transplantation. 1991 Jul; 52(1):128-33.
- Infiltration and accumulation of precursor cytotoxic T-cells increase with time in progressively growing ocular tumors. Cancer Res. 1991 Jun 15; 51(12):3153-8.
- Failure of infiltrating precursor cytotoxic T cells to acquire direct cytotoxic function in immunologically privileged sites. J Immunol. 1990 Oct 01; 145(7):2057-63.
- Recovery of activated cytotoxic T cells from minor H incompatible tumor graft rejection sites. J Immunol. 1989 Jul 15; 143(2):426-31.
- Immune privilege to MHC-disparate tumor grafts in the anterior chamber of the eye. I. Quantitative analysis of intraocular tumor growth and the corresponding delayed hypersensitivity response. Transplantation. 1989 Apr; 47(4):661-7.
- Analysis of cytotoxic T cell responses to intracameral allogeneic tumors. Invest Ophthalmol Vis Sci. 1989 Feb; 30(2):323-9.
- Inhibition of lymphocyte proliferation by aqueous humor. Reg Immunol. 1989 Jan-Feb; 2(1):42-9.
- Cell-mediated immune tolerance to HSV-1 antigens associated with reduced susceptibility to HSV-1 corneal lesions. Invest Ophthalmol Vis Sci. 1987 Dec; 28(12):1986-93.
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Glaucoma
Glaucoma is a neurodegenerative disease that destroys only the retinal ganglion cells. However, the exact mechanisms by which these neurons are destroyed are still unclear. We demonstrated that a protein called Fas Ligand is expressed in the retina during the development of glaucoma. Fas Ligand exists in two forms that have opposite functions: the membrane form triggers inflammation and death of retinal neurons (neurotoxic function); while the soluble form prevents inflammation and neuronal death (neuroprotective function).
Therefore, regulating the ratio of the different forms of Fas Ligand can determine the extent of damage and vision loss during glaucoma. This discovery provides many new opportunities for therapeutic intervention for treating glaucoma.
Age-Related Macular Degeneration (AMD)
AMD is also a neurodegenerative disease that destroys photoreceptor cells within the macula, a specific area of the retina. The loss of photoreceptor cells is preceded by the development of deposits (called drusen) beneath the retina.
We discovered that at the site of drusen deposition in AMD patients the surrounding cells (called RPE cells) express a gene called NALP3 that is an important regulator of inflammation. NALP3 is important in the activation of a protein complex called the “inflammasome” that is a critical first step in the amplification of local inflammation. This data suggest that inflammation is an important early trigger in the development of AMD and also suggest a variety of new therapeutic targets that could be used to stop disease progression.
We are also studying the function of microglia and infiltrating macrophages in the laser-induced mouse model of CNV (choroidal neovascularization). We observed a significant loss of microglia during CNV that coincided with a dramatic increase in the number of infiltrating macrophages. Nanostring gene expression analysis indicate that microglia are neuroprotective, and infiltrating macrophages are neurotoxic.
Restoration of the Corneal Epithelium
Many mammalian organs (skin, stomach, intestines, colon, and eye) possess a source of adult stem cells that continually replenishes their rapidly self-renewing epithelial surfaces. One important challenge in regenerative medicine is replacing these stem cells when they are eliminated after an injury or disease. Patients with a limbal stem cell deficiency are unable to regenerate the corneal epithelium, resulting ultimately in blindness due to an irreversibly opaque cornea.
Several approaches have been used to replace limbal stem cells by transplanting tissue or cells harvested from the limbus. However, success of these procedures is severely limited by the inability to purify stem cells from the limbus.
We discovered that the ABCB5 gene—a new member of the ATP-binding cassette (ABC) superfamily of active transporters—is expressed on adult limbal stem cells that are capable of regenerating corneal epithelium. Importantly, ABCB5 is a cell surface protein that can be used to purify ABCB5+ cells from the limbus. This provides us with a unique opportunity to study the regenerative mechanisms of adult limbal stem cells and develop new methods to restore the specialized epithelium of the cornea in eyes with a limbal stem cell deficiency.