Bruce Ksander, Ph.D.

Profile

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Associate Scientist, Schepens Eye Research Institute

Associate Professor of Ophthalmology, Harvard Medical School

 

 

 

 

Dr. Ksander's current research project,  Molecular Solutions to Low Vision Resulting from Battlefield Injuries, will determine the efficacy of using soluble Fas Ligand (sFasL) to prevent and/or treat sight-threatening corneal inflammation and scarring induced by trauma. To read more about Dr. Ksanders project, please click here.

Education

Ph.D 1986, University of Illinois

Contact Information

617-912-7443
FAX: 617-912-0113
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Patent

Ksander BR, US Patent pending “Animal models of Adnexal tumors.” (Massachusetts Eye & Ear Infirmary) 

Research Story

Immune privilege

Within certain anatomical sites (eye, brain, testis, and the maternal-fetal interface) foreign tissue survives for an extended period of time and escapes from normal immune-mediated rejection. The failure of immune effector mechanisms to eliminate foreign tissue from privileged sites is due to the induction of a highly regulated immune response in which non-specific inflammation is reduced via several different mechanisms. One mechanism eliminates Fas receptor positive lymphocytes that infiltrate into the eye. Fas Ligand, which triggers the Fas receptor and activates a signaling pathway that results in apoptosis, is constitutively expressed on tissues within the eye. Our current research is directed at understanding the mechanisms by which Fas Ligand contributes to establishing and maintaining immune privilege within the eye and also determining how this mechanism fails to protect the eye during ocular disease (uveitis and cornea allograft rejection).

 

Immunity to cornea allografts

One of the best examples of immune privilege in the eye is the exceptionally high acceptance rate of corneal allografts. Unlike other types of foreign allografts that are only accepted if donor and recipient are matched at the major histocompatibility loci, corneal allografts are accepted at a high rate regardless of whether the donor and recipient are matched. One reason for this phenomenon is that the major transplantation antigens are less important than the minor transplantation antigens in corneal allograft survival. However, further research in the role of minor transplantation antigens has been hampered by a lack of information on minor antigens. Our research is directed at studying the role of minor transplantation antigens in the survival of corneal allografts. We are currently using a genetically defined group of minor transplantation antigens.

 

Immunity to ocular tumors

Melanomas that develop within the eye are treated by a variety of different methods that, in general, successfully control primary tumor growth. However, all of these treatments fail to alter the incidence of metastatic disease, which is unusually high. There is currently no successful treatment available for patients with metastatic melanomas derived from ocular tumors. Our previous studies indicate that ocular melanomas are immunogenic tumors that express tumor antigens recognized by specific T cells. In order to successfully activate specific T cells, we propose to use a form of gene therapy that increases the immunogenicity of primary ocular melanoma cells. The ultimate goal of this research is to develop a tumor cell vaccine that protects ocular melanoma patients from developing metastatic tumors.  Protection is achieved by using primary tumor cells to stimulate tumor-specific T cells that eliminate metastatic tumor cells.  We hypothesize that primary tumor cells genetically engineered to express the costimulatory molecules CD80 and Class II will stimulate tumor-specific helper and cytotoxic T cells among the patient's peripheral blood lymphocytes.  These lymphocytes will possess the ability to eliminate metastatic tumor cells.

Laboratory Staff

Formally Supervised Trainees

 

1989-1991 Yasuhara Bando, MD/Clinical Ophthalmologist, Japan
1991-1993 Satoshi Miki, MD/Clinical Ophthalmologist, Japan
1994-1997 Toshihiko Uno, MD/Clinical Ophthalmologist, Japan
1994-1998 Peter Chen, PhD/Assistant Professor, UTSW, Dallas
1995-1996 Johan Tran, PhD/Clinical Optometrist, USA
1995-1998 David Verbik, PhD/Dentist, USA
1997-1999 Kazuhisa Miyamoto, MD/Clinical Ophthalmologist, Japan
1998-2003 Zdenka Haskova, MD,PhD/Associate Medical Director at Genentech
1999-2001 Amanda Repp, PhD/ Research Scientist,Industry
2000-2002 Victor Perez, MD/Associate Professor, Bascom Palmer Eye Institute, Miami
2000-2002 Co Bosch / PhD graduate student, USA
2000-2004 Meredith Gregory, PhD/Assistant Professor, MEEI
2001-2002 Hanneke Mensink, MD/Ophthalmology Resident, Holland
2002-2003 Caroline Lindenhovis/Medical Student, Holland
2002-2003 Sean Koh, MD/Clinical Ophthalmologist, USA
2003-2004 Eric Huang, MD/Anesthesiology Resident , USA
2005-2007 Norito Sugi, MD,PhD/Assistant Professor, Dept. Ophthalmology, Japan
2005-2007 Demitrios Vavvas, MD, PhD/Assistant Professor, Dept. Ophthalmology, MEEI
2005-2008 Co Bosch, MD/Oncology Resident, Germany
2006-2007 Rita Barcia, PhD/Research Scientist/Industry, Portugal
2008-2009 Elsbeth Van Zeeburg, MD/Ophthalmology Resident, Holland
2009-2010 Tony Chiang, MD/Ophthalmology Resident, Holland
2010-2010 Julia Kittler/Medical Student Germany
2008-2013 Evi Kolovou, MD/Research Fellow, MEEI

Research Projects

Dr. Ksander's research is focused in three areas:

  1. Understanding the function of inflammation during the development of glaucoma

  2. Understanding the function of microglia and infiltrating macrophages in the development of age related macular degeneration

  3. Restoration of the corneal epithelium using limbal stem cells. The majority of my effort is directed at these research projects.

Glacuoma

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. 25

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 laserinduced 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: (i) microglia are neuroprotective, and (ii) 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 surface. One important challenge in regenerative medicine is replacing these stem cells when they are eliminated following 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.

Current Publications

Click here for a PubMed list of abstracts formatted by BioMed Central

  1. Sugi N, Whiston EA, Ksander BR, Gregory MS.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. doi: 10.1128/IAI.00405-12. Epub 2013 Apr 8. PMID:23569113

  2. Buys ES, Ko YC, Alt C, Hayton SR, Jones A, Tainsh LT, Ren R, Giani A, Clerté M, Abernathy E, Tainsh RE, Oh DJ, Malhotra R, Arora P, de Waard N, Yu B, Turcotte R, Nathan D, Scherrer-Crosbie M, Loomis SJ, Kang JH, Lin CP, Gong H, Rhee DJ, Brouckaert P, Wiggs JL, Gregory MS, Pasquale LR, Bloch KD, Ksander BR.Soluble guanylate cyclase α1-deficient mice: a novel murine model for primary open angle glaucoma. PLoS One. 2013;8(3):e60156. doi: 10.1371/journal.pone.0060156. Epub 2013 Mar 20. PMID:23527308

  3. Bejjani A, Choi MR, Cassidy L, Collins DW, O'Brien JM, Murray T, Ksander BR, Seigel GM. RB116: an RB1+ retinoblastoma cell line expressing primitive markers. Mol Vis. 2012;18:2805-13. Epub 2012 Nov 29. PMID:23233783

  4. Tseng WA, Thein T, Kinnunen K, Lashkari K, Gregory MS, D'Amore PA, Ksander BR. NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013 Jan 7;54(1):110-20. doi: 10.1167/iovs.12-10655. PMID:23221073

  5. Vaqué JP, Dorsam RT, Feng X, Iglesias-Bartolome R, Forsthoefel DJ, Chen Q, Debant A, Seeger MA, Ksander BR, Teramoto H, Gutkind JS. 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. doi: 10.1016/j.molcel.2012.10.018. Epub 2012 Nov 21. PMID:23177739

  6. Haile ST, Bosch JJ, Agu NI, Zeender AM, Somasundaram P, Srivastava MK, Britting S, Wolf JB, Ksander BR, Ostrand-Rosenberg S. 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. doi: 10.4049/jimmunol.1003682. Epub 2011 May 9. PMID:21555531

  7. Gregory MS, Hackett CG, Abernathy EF, Lee KS, Saff RR, Hohlbaum AM, Moody KS, Hobson MW, Jones A, Kolovou P, Karray S, Giani A, John SW, Chen DF, Marshak-Rothstein A, Ksander BR.Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death. PLoS One. 2011 Mar 29;6(3):e17659. doi: 10.1371/journal.pone.0017659. PMID:21479271

  8. Klocke J, Barcia RN, Heimer S, Cario E, Zieske J, Gilmore MS, Ksander BR, Gregory MS. Spontaneous bacterial keratitis in CD36 knockout mice. Invest Ophthalmol Vis Sci. 2011 Jan 5;52(1):256-63. doi: 10.1167/iovs.10-5566. Print 2011 Jan. PMID:20847111

  9. Theodoropoulou S, Kolovou PE, Morizane Y, Kayama M, Nicolaou F, Miller JW, Gragoudas E, Ksander BR, Vavvas DG. Retinoblastoma cells are inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase. FASEB J. 2010 Aug;24(8):2620-30. doi: 10.1096/fj.09-152546. Epub 2010 Apr 6. Erratum in: FASEB J. 2012 Oct;26(10):4383-4. PMID:20371623

  10. Hamrah P, Haskova Z, Taylor AW, Zhang Q, Ksander BR, Dana MR. Local treatment with alpha-melanocyte stimulating hormone reduces corneal allorejection. Transplantation. 2009 Jul 27;88(2):180-7. doi: 10.1097/TP.0b013e3181ac11ea. PMID:19623012