Yihe Chen

Chronic non-infectious uveitis (NIU) is a vision-threatening inflammatory disease in which relapses often occur despite corticosteroids, conventional immunosuppression, and biologic therapy. A growing body of experimental and human evidence indicates that disease persistence is not explained solely by transient effector inflammation. Instead, autoreactive memory CD4 ⁺ T cells can survive after the initiating trigger and retain retinal antigen responsiveness, sustaining persistent inflammation and reinitiating acute flares and exacerbations. In experimental chronic autoimmune uveitis, a specific subset of CD44 ^hi IL-7R ⁺ IL-15R ⁺ memory CD4 ⁺ T cells is maintained in the retina and peripheral secondary lymphoid organs (SLO), while additional autoreactive memory cells can persist in bone marrow niches through signal transducer and activator of transcription 3 (STAT3)-dependent mechanisms. Human studies further show expansion of memory and T helper 17 (Th17)-associated CD4 ⁺ T cell populations in NIU; however, the dominant immune cell subsets, clonotypes, and cytokine programs vary among heterogeneous clinical entities of NIU. This review summarizes how memory CD4 ⁺ T cells are generated, maintained, and linked to ocular tissue injury, with emphasis on their effector functions, IL-7 and IL-15-dependent survival signaling, STAT3-linked persistence, trafficking, and failed control by ocular immune regulation. We further discuss memory-directed therapeutic concepts grouped as disruption of survival/signaling, restraint of trafficking, and immune tolerization or restoration of ocular immune privilege. We propose the hypothesis that, in NIU subsets demonstrably sustained by pathogenic memory CD4 ⁺ T cells, durable remission may require elimination, restraint, or reprogramming of this reservoir rather than suppression of downstream cytokines alone.

Fibrosis drives progressive organ dysfunction, yet targeted therapies remain limited. In the eye, proliferative vitreoretinopathy (PVR) is a blinding fibrotic disease without approved medical treatment. Here, single-cell RNA sequencing of human PVR membranes revealed convergent activation of hypoxia-responsive programs across major cell populations. Using a molecular probe, we directly validated spatial and temporal hypoxia in an open-globe injury model that recapitulates traumatic PVR. Intravitreal delivery of a supersaturated oxygen emulsion (SSOE) preserved retinal function while reducing fibrocellular membrane formation and inflammation. Mechanistically, human PVR cells exhibited metabolic shifts toward glycolysis alongside epithelial-mesenchymal transition (EMT). SSOE corrected cellular hypoxia, preserved mitochondrial integrity, suppressed glycolytic shift, and inhibited EMT in human retinal pigment epithelial cells, while reducing spontaneous contractility in primary human PVR cell cultures. Together, these findings identify hypoxia as a critical driver of retinal fibrosis and support localized intraocular oxygenation as a viable therapeutic strategy for preventing fibrotic vision loss.

Purpose: To compare graft survival and alloimmune responses in murine endothelial keratoplasty (EK) versus penetrating keratoplasty (PK) and to elucidate the immunological mechanisms that underlie the differential graft outcomes. Methods: Allogeneic EK and PK were performed in BALB/c recipient mice using fully disparate C57BL/6 donors; syngeneic EK recipients served as controls. Graft clarity was monitored over 16 weeks by slitlamp biomicroscopy and scored using standardized opacity grading. Anterior segment optical coherence tomography (AS-OCT) was used to measure central corneal thickness. Graft survival was assessed using Kaplan–Meier analysis. Immunohistochemistry and confocal microscopy were performed to evaluate corneal endothelial cell (CEnC) integrity through ZO-1 staining. T-cell–mediated alloimmunity was assessed using intracellular IFN-γ staining (flow cytometry) and ELISPOT assays targeting both direct and indirect antigen presentation pathways. Results: PK allografts exhibited significantly higher corneal opacity and lower survival (50%) than allogeneic EK grafts (71.4%, P < 0.0001). AS-OCT showed that corneal edema was highest in rejected PK grafts at 4 weeks and in rejected EK grafts at 16 weeks, with EK displaying a more gradual increase in thickness. Flow cytometry revealed significantly greater frequencies of IFN-γ ⁺ CD4 ⁺ T cells in PK recipients compared with EK recipients ( P < 0.001). ELISPOT assays demonstrated a more robust Th1 response in PK through both the direct and indirect sensitization pathways. Corneal endothelial cell (CEnC) density was significantly reduced in rejected EK and PK grafts compared with their respective accepted counterparts ( P < 0.01), whereas CEnC density was comparable between accepted EK and PK grafts. Conclusions: EK grafts exhibit higher graft survival rates and significantly reduced activation of host T-cell responses compared with PK grafts, which may be attributed to lower frequencies of graft-borne antigen presenting cells, thus resulting in a milder Th1-mediated immune response.

We have previously demonstrated the pathogenic function of memory CD4+ T cells, which express IL-7 receptor (IL-7R) and IL-15R, in experimental chronic autoimmune uveitis (CAU). Here, we aimed to compare the therapeutic efficacy of blocking IL-7 or IL-15 in CAU. C57BL/6J mice were induced for CAU, then intraperitoneally injected with an anti-IL-7 antibody (Ab), an anti-IL-15 Ab, or an IgG control for 2 weeks. Disease was evaluated by weekly fundoscopy, optical coherence tomography (OCT), and full-field electroretinography for four weeks from the initiation of treatment. At week 4, retina and cervical lymph nodes (CLN) were collected for flow cytometry analysis of T-cell response. The anti-IL-7 Ab led to progressively reduced retinal infiltration and structural damage, with rapid recovery of retinal function. The anti-IL-15 Ab resulted in moderately reduced retinal infiltration and structural damage, along with a delayed, partial functional improvement. Compared to the control group, the anti-IL-7 Ab group exhibited significantly reduced disease scores from baseline on fundoscopy and OCT at week 4, and substantially improved dark-adapted (DA) a-wave and light-adapted b-wave responses at week 2; although the anti-IL-15 Ab group showed significantly improved disease from baseline only on OCT and increased DA b-waves at week 4. Both treatments effectively depleted the retinal infiltrating T cells and reduced memory Th17 cells in the CLN. Our proof-of-concept study demonstrates that blocking IL-7 or IL-15 leads to specific depletion of the uveitogenic memory CD4+ T cells and disruption of disease chronicity in uveitis.

Introduction: Ocular pain is a common complaint to eye care providers, associated with a variety of ocular conditions, among which dry eye disease (DED) is affecting millions of people worldwide. Despite being highly prevalent, ocular pain is not managed adequately in the clinic. Objectives: The aim of this study was to investigate the analgesic potential of neurokinin-1 receptor (NK1R) antagonism in DED. Methods: Dry eye disease was induced in mice, and an NK1R antagonist L-733,060 was topically administered twice daily throughout the study for 14 days. Hyperalgesia and allodynia were assessed using the eye-wiping test and palpebral ratio measurements. Corneas were collected for measuring substance P (SP) levels by enzyme-linked immunosorbent assay (ELISA) and imaging nerves by immunostaining. Trigeminal ganglions (TG) were collected to determine SP levels by ELISA and transient receptor potential cation channel subfamily V member 1 (TRPV1), transient receptor potential cation channel subfamily M (melastatin) member 8, c-Fos, and activating transcription factor 3 (ATF3) mRNA levels by real-time polymerase chain reaction. Results: Treating DED mice with L-733,060 resulted in a significant reduction in eye wipe behavior, a significant increase in palpebral ratio, and significant decreases in SP levels in both the cornea and TG compared with the vehicle-treated group. In addition, NK1R antagonist treatment significantly suppressed the upregulation of TRPV1, ATF3, and c-Fos and prevented corneal nerve loss. Conclusion: Neurokinin-1 receptor antagonism effectively reduced ocular nociception, decreased neuronal activation, and preserved corneal nerves in mice with DED. These findings suggest that blockade of SP signaling pathway is a promising therapeutic strategy for managing DED pain.

Purpose: To evaluate the therapeutic efficacy of topical application of a neurokinin-1 receptor (NK1R) antagonist in a rabbit model of nonallergic ocular redness. Methods: Nonallergic ocular redness was induced in rabbits by a single, topical application of dapiparzole hydrochloride eye drops (0.5%, 1%, 2%, or 5%). The NK1R antagonist L-703,606 was topically applied to the eye at the same time of induction or 20 min after induction, and phosphate buffered saline (PBS) treatment served as the control. Superior bulbar conjunctival images were taken every 30 s for the first 2 min, followed by every 4 min for 8 min, and then every 10 min until 1 h. The severity of ocular redness was evaluated on the images using ImageJ-based ocular redness index (ORI) calculations. Results: The ORI scores were significantly increased after the application of 0.5%, 1%, 2%, or 5% dapiparzole at each time point evaluated, with the most severe redness induced by the 5% dapiprazole that led to a maximal mean increase in ORI score of 14 at 20 min post-induction and thus used for subsequent evaluation of therapeutic efficacy of NK1R antagonism. Topical L-703,606, when applied at the same time as dapiprazole induction, significantly suppressed the increase of ORI scores at all time points (∼40% decrease). Furthermore, when applied at 20 min after dapiprazole induction, L-703,606 rapidly and effectively suppressed the increase of ORI scores at 30, 40, 50, and 60 min (∼30% decrease). Conclusions: Topical blockade of NK1R effectively prevents and alleviates nonallergic ocular redness in a novel animal model.

Substance P (SP) is a neuropeptide expressed by nerves and an array of cells that serves as a critical mediator of neuroinflammation. Our recent work has demonstrated that blocking the preferred receptor for SP, neurokinin-1 receptor (NK1R), effectively suppresses the induction of acute dry eye disease (DED) by preserving regulatory T cell (Treg) function, while inhibiting antigen-presenting cell (APC) maturation and subsequent generation of effector Th17 cells (eTh17). Clinically, DED is a chronic disorder characterized by sustained ocular surface inflammation which is mediated by long-lived memory Th17 cells (mTh17) demonstrated in our well-established chronic DED model. The present study aimed to further understand the function of SP in the chronic phase of DED and its role in regulating the underlying pathogenic mTh17. In vitro culture of effector T cells isolated from acute DED with SP led to an enhanced conversion of eTh17 to mTh17, while culturing memory T cells isolated from chronic DED with SP effectively preserved the mTh17 cells. In contrast, the addition of an NK1R antagonist in the cultures abolished the SP-mediated effects. Furthermore, in vivo treatment with the NK1R antagonist during the resolution phase of acute DED significantly suppressed mTh17 generation, and treatment in the chronic phase of DED disrupted the maintenance of mTh17. Taken together, our results demonstrate that increased expression of SP promotes mTh17 generation and maintenance in chronic DED, and thus blockade of SP represents a novel promising mTh17-targeting strategy in treating chronic ocular surface inflammation.