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Self-antigen immunization may help slow glaucoma progression
As a neurodegenerative disease, glaucoma may be effectively treated by controlling local immune response, according to a physicist researcher.
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Open-angle glaucoma is a neurodegenerative disease, and boosting T-cell activity in the retina may be one way of protecting retinal nerves, according to one researcher. A controlled local immune response may be a way to slow neural damage, although not to prevent its onset, said Michal Schwartz, PhD.
During Glaucoma Subspecialty Day at last year’s American Academy of Ophthalmology meeting, Dr. Schwartz shared the results of animal and in vitro research into the role of the immune system in the pathogenesis of glaucoma.
“When all is said and done, glaucoma is a disease pathophysiologically defined by retinal ganglion cell loss,” said R. Rand Allingham, MD, who moderated the session. “To date, the only proven method to reduce or prevent ganglion cell death is through reduction of IOP, an important but one of many risk factors for glaucomatous optic neuropathy. Neuroprotection, though elusive, is logical goal for glaucoma treatment.”
Dr. Allingham noted that many pathways may lead to apoptotic retinal ganglion cell death, and Dr. Schwartz’s “groundbreaking” work on the role of the immune system explores one of those potential pathways.
A neurodegenerative disease
Dr. Schwartz said healthy retinal neurons in a glaucomatous eye are “embedded in a degenerating environment,” and these neurons are the targets for neuroprotective efforts.
“We are saying that open-angle glaucoma is not an inflammatory disease, but a disease that can benefit from controlled local immune response,” Dr. Schwartz said.
In glaucoma, the healthy neurons are threatened by their environment, she said. That environment, “as in any other neurodegenerative condition, includes glutamate, nitric oxide and other self-compounds that can be toxic if the cells are overwhelmed,” she said. “Our target in neuroprotection is fighting off these enemies, or making the neuron more resistant to the threatening condition. The target is to delay progression or slow degeneration.”
Boosting neuroprotection
Dr. Schwartz and other researchers have sought a physiological defense mechanism that could help the central nervous system (CNS) fight off the adverse conditions found in glaucoma and other neurodegenerative diseases, she said.
“If we can find this, we can boost it. We know microglia are the resident defensive cells in the CNS,” she said. “These are the immune cells. Under normal conditions, the microglia can fight off adverse conditions. If the adverse conditions are too severe, the microglia can become cytotoxic. Rather than helping, they can adversely affect the condition.”
Dr. Schwartz and others have found that if microglia are well controlled and activated by the systemic immune system, they can be protective rather than destructive, she said.
“We formulated the concept of protective autoimmunity,” she said. “We suggested that autoimmune T-cells [go to the site of damage], and they can control microglia so as to make them helpful rather than adversely affect the condition.”
Proof of participation
To prove that the peripheral immune system was participating in the repair or protection of healthy neurons, Dr. Schwartz and colleagues first set out to demonstrate, using animal models, that if they increased T-cell levels, they would consequently increase the ability for neurons to survive.
“First, we discovered that following injury, if we increase the level of T-cell we increase the ability for neurons to survive,” Dr. Schwartz said.
In a model of elevated IOP, in animals with immune deficiency, the number of surviving neurons was decreased significantly compared to animals with healthy immune response. In a similar model with increased IOP, neurons were adversely affected by steroid treatment. The number of surviving also decreased with aging, she said.
“All of this led us to suggest that T-cells are needed at the site of the lesion,” Dr. Schwartz said. “We have in vitro studies that show that when T-cells go to the site of the lesion, they activate the microglia. The microglia can then [better resist glutamate]. They produce growth factor without producing cytotoxic molecules such as TNF-alpha. The T-cells are shaping microglia in a way that helps the neurons to fight off the adverse condition.”
Boosting protective T cells
Dr. Schwartz and colleagues then sought a way to boost the protective T-cell activity. They have focused on developing a vaccine using a self-antigen that does not have a risk of causing autoimmune disease, she said
“There are numerous antigens that can do the job,” she said. “One such antigen we selected is Copaxone (glatiramer acetate, Teva), a drug which was developed for multiple sclerosis.”
In a model of elevated IOP, in animals with IOP raised to 30 mm Hg, neuron loss was 30%; with a single injection of the vaccine, neuron loss was reduced to 5%.
“For long-lasting neuroprotection with the vaccine, we have to boost occasionally,” Dr. Schwartz said. “We found that when we boost weekly or monthly we sustain the neuroprotective effect.”
In addition to the neuroprotective effect, the researcher also found that the Copaxone treatment may boost neurogenesis, she said.
“We have in vitro studies suggesting that indeed microglia encountering T-cells can be both neuroprotective and support neurogenesis. So we may have not only protection but also repair and renewal,” she said.
A systemic disease
“We are further suggesting that glaucoma is not only a disease of the visual system, it is also a systemic disease,” Dr. Schwartz said.
Vaccinations such as those she has investigated in animals have also shown benefit in Parkinson’s, Alzheimer’s and other neurodegenerative diseases, she said.
“Glaucoma is not an autoimmune disease, yet excessive levels of autoimmune T-cells, rather than helping, can cause a mode of normal tension glaucoma,” she said.
Vaccination with a self-antigen will not prevent disease onset, Dr. Schwartz said, but it may alter its progression. She said Copaxone is one of a family of vaccines that may be of benefit not only in elevated IOP but also in normal-tension glaucoma.
For Your Information:
- Michal Schwartz, PhD, can be reached at Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel; 972-8-934-2467; fax: 972-8-934-6018; e-mail: michal.schwartz@weizmann.ac.il.
- R. Rand Allingham, MD, can be reached at Duke University Eye Center, P.O. Box 3802; Durham, NC 27710; 919-684-2975; fax: 919-681-8267; Web site: www.dukeeye.org.
- Teva Pharmaceuticals, maker of Copaxone, can be reached at Teva Neuroscience, 901 E. 104th St., Suite 900, Kansas City, MO 64131; e-mail: info@teva.net.
- Daniele Cruz is an OSN Staff Writer who covers all aspects of ophthalmology.