Bruce Ksander, Ph.D.
- Bruce Ksander, Ph.D.
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.
Ph.D 1986, University of Illinois
Ksander BR, US Patent pending “Animal models of Adnexal tumors.” (Massachusetts Eye & Ear Infirmary)
- Bruce Ksander, Ph.D.
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.
- Bruce Ksander, Ph.D.
Molecular Solutions to Low Vision Resulting from Battlefield Injuries
This research project will determine the efficacy of using soluble Fas Ligand (sFasL) to prevent and/or treat sight-threatening corneal inflammation and scarring induced by trauma. It does not include any research on corneal transplants. The major goals of this grant are: (i) Determine the capacity of corneas treated with adenoviral vectors containing the cDNA for sFasL to suppress corneal inflammation and scarring following burns (chemical or thermal); (ii) Determine if sFasL treatment prevents the infiltration and/or activation of innate inflammatory cells within corneas following burns; (iii) Determine if sFasL treatment prevents the infiltration and/or activation of innate inflammatory cells within corneas following burns; (iv) Develop a purified recombinant sFasL protein that is easily delivered via “eye-drops” to the cornea. Determine the effectiveness of these eye-drops in preventing corneal inflammation and scarring following burns.
The Immunobiology of Corneal Transplants
The long-term goals of this project are to understand: (a) why primary orthotopic corneal allografts are so well tolerated (display immune privilege), and (b) why grafts in “high-risk” eyes fare so poorly. Two hypotheses are tested: Hypothesis 1. Atypical expression of alloantigens and expression of immunomodulatory molecules on corneal cells contribute to the cornea’s immune privileged status. Hypothesis 2. MHC class II and/or minor H alloantigen expression rob the corneal epithelium of its graft-acceptance promoting capacity. Our experiments will enable us to discover novel cellular and molecular mechanisms with which to create protocols with greater power to promote graft acceptance in clinical situations where graft failure is common.
- Bruce Ksander, Ph.D.
Click here for a PubMed list of abstracts formatted by BioMed Central
Thompson JA, Srivastava MK, Bosch JJ, Ksander BR, and Ostrand-Rosenberg S. The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor reactive CD4+ T lymphocytes. Cancer Immunol Immunother. 57(3): 389-398, 2008.
E Whiston, N Sugi, MC Kamradt, C Sack, S Heimer, M Engelbert, MS Gilmore, BR Ksander, M Gregory. aB-crystallin protects retinal tissue during S. aureus-induced endophthalmitis. Infection and Immunity, 76 (4):1781-90, 2008.
Srivastava MK, Bosch JJ, Thompson JA, Ksander BR, Edelman MJ, Ostrand-Rosenberg S. 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. 57 (10):1493-1504, 2008.
Hamrah P, Haskova Z, Shang Q, Taylor AW, Ksander BR, Dana MR. Local treatment with alpha-melanocyte stimulating hormone reduces corneal allorejection. Transplantation 88 (2): 180-187, (2009).
Bosch JJ, Iheagwara UK, Reid S, Srivastava MK, Wolf J, Lotem M, Ksander BR, Ostrand-Rosenberg S. Uveal melanoma cell-based vaccines express MHC II molecules that raffic via the endocytic and secretory pathways and activate CD8+ cytotoxic, tumor-specific T cells. Cancer Immunol Immunother. 59 (1): 103-112, 2009.
Theodoropoulou S, Kolovou R, Morizane Y, Kayama M, Nicolaou F, Miller JW, Gragoudas E, Ksander BR, Vavvas D. Retinoblastoma cells are inhibitied by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent Kinase. FASEB J 2010 Aug, 24:2620-30
Mensink HW, Chen PW, Lindenhovius CL, Jager MJ, Ksander BR. Tumors generated in the immune privileged ocular microenvironment escape elimination by down regulating tumor antigens. Invest. Ophthalmol. Vis. Sci. (under review April 2010; under revision June 2010).
Klocke J, Barcia R, Heimer S, Cario E, Zieske J, Gilmore MS, Ksander BR, Gregory MS. Spontaneous Bacterial Corneal Keratitis in CD36 Knockout Mice. Invest Ophthalmol Vis Sci 2011 Jan, 52:256-63
Gregory MS, Hackett CG, Abernathy EF, Lee KS, Saff RR, Hohlbaum AH, Moody KL, Hobson MW, John SW, Chen DF, Marshak-Rothstein A, Ksander BR. Membrane-bound Fas-Ligand induces retinal ganglion cell death in glaucoma. Immunity (under review June 2010)