Suppression of T cell function with anti-CD4 antibody leads to increased RGC survival after retinal ischemia-reperfusion injury

Abstract

Purpose: Ischemia contributes to the pathophysiology of a variety of neurodegenerative disorders, including stroke and glaucoma. Insufficient blood flow to the retina can lead to the development of ischemic retinopathy which results in the destruction of neural tissue in the eye and subsequent vision loss. CD4+ T cell-mediated immune responses have been proposed as critical elements in triggering ischemia-induced inflammation and neural damage. Therefore, we studied whether blocking CD4+ T cell function had a protective effect on retinal ganglion cell (RGC) survival in a transient retinal ischemic-reperfusion mouse model.

Methods: Transient retinal ischemia was induced in C57BL/6J mice by acute elevation of intraocular pressure to 110 mmHg for 60 min, followed by intravitreal injections of saline, isotype IgG (as an isotype control), or anti-CD4 antibody on day 3, 7, 10, and 14. To assess the retinal function, electroretinography (ERG) was performed on day 21 post injury. At 28 days after the ischemic injury, all mice were sacrificed and RGC quantification was performed by βIII-tubulin staining in retinal whole-mounts. In addition, FACS analysis of the draining cervical lymph nodes was performed to identify different T cell-mediated responses.

Results: The level of RGC loss was comparable between mice who received intravitreal injections of saline and isotype IgG after ischemic injury. In contrast, mice injected with anti-CD4 antibody showed significantly less RGC loss compared to mice treated with sterile saline. T cell responses measured in the draining lymph nodes did not differ between mice who received injections with either anti-CD4, isotype control or sterile saline. Retinal function as measured by ERG showed that anti-CD4 treated mice had better responses to the stimulations at 21 days after transient ischemia than mice who received saline injections.

Conclusions: Our data demonstrate that suppression of local CD4+ T cell-mediated responses in the eye protects against RGC loss and retinal function impairment after transient ischemic injury. This local suppression of T cell responses has no significant effect on the systemic immune response. The findings suggest possibilities for a new therapeutic approach in the treatment of ischemic neuropathy.

Keywords: 572 ischemia • 555 immunomodulation/immunoregulation • 531 ganglion cells