Meredith S. Gregory-Ksander, Ph.D.

Harvard Medical School

Assistant Professor of Ophthalmology

Schepens Eye Research Institute of Massachusetts Eye and Ear

Associate Scientist

Research Summary

Center/Research Area Affiliations

Biography

Dr. Gregory-Ksander's research focuses on two areas. First, she aims to lucidate the mechanisms of immune privilege by which the retina defends against pathogens, while simultaneously protecting retinal tissue during infection. Second, she aims to determine how age-related changes in immune privilege and subsequent inflammation contributes to the development of glaucoma and age-related macular degeneration. Dr. Gregory-Ksander has identified two critical mediators of ocular inflammation—Fas ligand and the NLRP3 inflammasome. Current studies in her laboratory focus on how these molecules mediate protective immunity and defense against pathogens and how age-related changes in these molecules may contribute to the development of inflammation associated with glaucoma and age-related macular degeneration.

Education

Ph.D., Loyola University, Chicago, Illinois (1999)

Her Story

In the eye, inflammation is tightly regulated to provide the eye with protection against pathogens, while at the same time, protecting the visual axis from sight-destroying inflammation. These mechanisms are collectively called immune privilege.

Dr. Gregory-Ksander’s research focuses on two areas. First, she aims to elucidate the mechanisms of immune privilege by which the retina defends against pathogens, while simultaneoulsy protecting retinal tissue during infection. Second, she aims to understanding how age-related changes in immune privilege and subsequent inflammation contribute to the development of glaucoma and age-related macular degeneration (AMD). In particular the Gregory-Ksander laboratory is interested in how different forms of Fas ligand—a critical mediator of immune privilege—contribute to the disruption of immune privilege and development of inflammation associated with glaucoma and AMD. She hopes her work ultimately will help researchers identify new targets to protect the retina and preserve vision in patients with glaucoma and/or AMD.

Host Response to Endophthalmitis

Endophthalmitis is an infection of the posterior segment of the eye that can destroy the eye within 72 hours. The overall goal of this collaborative project is to combine the immunology expertise of the Gregory-Ksander laboratory, with the microbiology expertise of Dr. Michael Gilmore’s laboratory to identify:

  • Key innate effector mechanisms central to host resistance to endophthalmitis
  • Key bacterial virulence traits that promote pathogenesis

The identification of these factors will reveal novel targets to be used in the development of new therapeutic approaches and preventive strategies to help prevent infection and preserve vision for many patients undergoing cataract extraction or other ocular surgery. The laboratories have separated the pathway that leads to protective immunity and defense against pathogens from the pathway that leads to destructive inflammation and non-specific ocular tissue damage. As a result, they have identified novel targets that may be used to enhance host defense, while at the same time limiting non-specific tissue destruction.

Glaucoma

Glaucoma is one of the most common causes of blindness worldwide and, while there are many different forms of glaucoma that differ significantly in clinical presentation and disease progression, they all share a common endpoint, which is the loss of retinal ganglion cells (RGCs). New treatments are needed, since current therapies can delay, but not stop disease progression. One of the major barriers to the development of novel treatments is the incomplete understanding of the disease pathogenesis.

In collaboration with Dr. Bruce Ksander, Dr. Gregory-Ksander is using multiple mouse models of glaucoma (inducible and spontaneous) to study the mechanism by which retinal ganglion cells die. They hypothesize that in response to injury caused by elevated intraocular pressure (IOP), there is increased expression of Fas and FasL within the retina. However, the extent of retinal apoptosis is determined by the ratio of membrane/soluble FasL expressed by microglia and/or infiltrating macrophages. In a 2011 publication, they reported the protective effects of sFasL in an inducible mouse model of glaucoma.

The ultimate goals of this research are to:

  • Demonstrate that soluble Fas ligand can be used to prevent the death of retinal ganglion cells associated with glaucoma
  • Identify additional targets for the early treatment of glaucoma in an effort to prevent RGC death, preserve vision, and prevent blindness

Age-Related Macular Degeneration (AMD)

AMD is a leading cause of blindness worldwide. Loss of vision is due to the degeneration of photoreceptors which can occur in two forms of AMD:

  • Wet AMD develops with choroidal neovascularization (CNV), vascular leakage, hemorrhaging, and retinal detachment
  • Dry AMD develops with a geographic loss of RPE cells and loss of the overlaying photoreceptors

Only patients with wet AMD develop CNV, which is associated with more severe vision loss. In wet AMD, the loss of vision is caused primarily by the leakage of fluid and blood from the choroidal neovascularization. Anti-VEGF therapy has emerged as the treatment of choice for patients with wet AMD and has been shown to preserve vision in many patients by preventing leakage from the existing choroidal neovascularization and inhibiting the growth of new vessels. However, some patients never respond to anti-VEGF therapy, while still others stop responding after initial success, highlighting the need for new therapies.

The Gregory-Ksander laboratory’s preliminary data demonstrate that membrane FasL plays a critical function in preventing vascular leakage in a murine model of laser induced CNV. The ultimate goals of their research are to:

  • Elucidate the mechanism(s) by which soluble and membrane-bound FasL regulate vascular leakage
  • Determine whether the membrane form of FasL can be used as a new treatment for wet AMD

Projects

Research Interests

  • Mechanisms of immune privilege in the retina
  • How age-related changes in immune-privilege and inflammation contribute to diseases like glaucoma and AMD

Host Immune Response to Endophthalmitis

In collaboration with Dr. Michael Gilmore, Dr. Gregory-Ksander’s laboratory has set up a murine model of S. aureus-induced endophthalmitis to examine the host immune response to endophthalmitis. Her research on ocular infections aims to enhance the host’s inflammatory response to efficiently eliminate the pathogen, while preventing destruction of normal eye tissue. Using a mouse model of endophthalmitis, she has identified several proteins—Fas ligand, alphaB-crystallin, and TLR2—that play a central role in regulating inflammation and protecting the host tissue from destruction.

Immunology of Glaucoma

Glaucoma is one of the leading causes of blindness worldwide, affecting nearly 70 million people. While there are many forms of glaucoma, the death of retinal ganglion cells and the associated loss of vision remains the common endpoint. Unfortunately, the molecular mechanisms that cause retinal ganglion cell death are largely unknown. Dr. Gregory-Ksander hypothesizes that the form of Fas ligand expressed on the microglia and/or astrocytes determines whether these cells are neurotoxic (membrane FasL) or neuroprotective (soluble FasL) during glaucoma. The ultimate goal of this research is to use soluble Fas ligand to prevent the death of retinal ganglion cells associated with glaucoma, resulting in the preservation of vision and the prevention of blindness.

Fas Ligand and Vascular Leakage in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the primary cause of blindness in patients 60 years of age and older. The growth of abnormal blood vessels into the retina is the main cause of severe vision loss, in part due to vessel leakage of blood and fluid that causes damage to the surrounding retinal tissue.

In collaboration with Dr. Ann Marshak-Rothstein at University Massachusetts School of Medicine in Worcester, Dr. Gregory-Ksander has identified a novel function for membrane Fas ligand in preventing vascular leakage. The goal of this study is to:

  1. Determine whether the administration of this protein can be used to prevent vascular leakage in a mouse model of laser-induced choroidal neovascularization
  2. Elucidate the mechanism by which this protein functions

Publications

Selected Publications

Dr. Gregory-Ksander has published more than 35 peer-reviewed articles. Below is a list of selected publications. View her publications on PubMed.

  1. Sugi, N, E Whiston, BR Ksander, M Gregory. Increased resistance to staphylococcus aureus endophthalmitis in BALB/c mice: Fas ligand is required for resolution of inflammation but not bacterial clearance. Infection and Immunity. 2013 Jun;81(6):2217-25
  2. 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;54(1):110-120.
  3. Callegan M, M Gregory-Ksander, Wilcox, S Lightman. Ocular Inflammation and Infection. Int J Inflam. 2012;2012:403520.
  4. 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;6(3):e17659.