Although many have said that the eyes are the window to the brain, few have considered the possibility that this window could admit novel therapeutic interventions. Among those few are Yale researchers who have been studying the immunological nexus between the posterior eye and the other parts of the central nervous system (CNS).

These researchers, led by associate research scientist Eric Song, MD, PhD, recently reported that intravitreal immunization protects mice against intracranial viral challenge. Moreover, the researchers indicated that intravitreal immunization could protect against bacteria and even tumors, allowing therapeutic immune responses against glioblastoma.

Details appeared in Nature, in an article titled, “Compartmentalized ocular lymphatic system mediates eye–brain immunity.”

The article presents the researchers’ discovery that in the eyes of mice, there are two distinct lymphatic systems. One regulates immune responses in the front of the eye; the other, the rear of the eye. The researchers also found that the latter drains to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath.

“These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases,” the article’s authors noted. “This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signaling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses.”

Harnessing this new biology, Song’s team is currently testing newly created drugs from his lab delivered through eye injections that may help combat macular edema, or leaky blood vessels of the retina common in people with diabetes, and glaucoma.

“There is a shared immune response between the brain and the eye,” Song observed. “And the eyes provide easier access for drug therapies than the brain does.”

To acquire an organ-level view of lymphatic-like vasculature gene signatures in the eye and the optic nerve, Song and colleagues employed a spatial transcriptomics technique—specifically, transcriptomics in combination with immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO). “[We] mapped the larger lymphatic vasculature network in the optic nerve sheath and described its functionality in draining the vitreous to the deep cervical lymph nodes,” the researchers noted. “These results are in accordance with the known nexus between the eye and CNS1 and further extend this concept by demonstrating a shared immune surveillance mechanism between the two sites.”

“Previously, both the eye and brain, which are devoid of traditional lymphatic vessels, were considered immune-privileged tissues because foreign tissue grafts can survive after implantation,” the researchers continued. “Furthermore, antigens delivered to both the anterior and posterior chamber of the eye have been reported to induce peripheral immune tolerance. However, our study revealed that pathogenic antigens delivered to the posterior eye through intravitreal vaccination can drain to deep cervical lymph nodes and initiate a local protective immune response in the brain that is dependent on CD4+ T cells, B cells, and local antibodies in the CNS compartment.”

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