Topical immunotherapy for particulate matter-induced ocular toxicity

Toxic particulate matter (PM) is generated by the incomplete combustion of organic and inorganic material. Military toxic exposure to PM in the battlefield setting is associated with burn pits, incinerators, vehicular emissions, and industrial activities. Extensive clinical evidence links PM exposure to several systemic conditions, including ocular surface disease (OSD). However, knowledge on the pathophysiological mechanism underlying PM-induced acute ocular toxicity and chronic OSD, and therapeutics targeting this etiology are lacking. PM exposure is a major risk factor for OSD. In veterans, exposure to incinerated waste during deployment was significantly associated with a greater risk of ocular surface symptoms, more severe self-reported OSD symptoms, and increased Meibomian gland dropout. While acute ocular toxicity is reversible, prolonged exposures will inevitably increase the risk of developing chronic OSD. Together, these data highlight an etiological role for PM in ocular surface disease associated with military toxic PM exposure and reveals an urgent unmet medical need for a targeted therapy among the Veteran population, which can safely and effectively reduce ocular surface signs and symptoms associated with both the acute and chronic consequences of military toxic PM exposure. The objective of this research proposal is to determine the mechanistic role that three key biological pathways play in the ocular toxicity of PM using pre-clinical in vitro and in vivo models and to determine the feasibility of human pooled immune globulins as novel targeted therapeutic intervention. Pooled human intravenous immune globulins (IVIG) are FDA-approved plasma products currently used for the treatment of primary immunodeficiency syndrome, which we have successfully used to demonstrate efficacy and safety in preclinical experimental models and an academic Phase 1 clinical trial in patients with DED. We hypothesize that PM elicits ocular toxicity and OSD through three contributing mechanisms that include activation of neutrophils and generation of neutrophil extracellular traps (NETosis), a type I allergic response and degranulation of mast cells and eliciting pro-inflammatory responses. We further propose that topical pooled human immune globulins (Flebogamma® DIF) will attenuate PM-induced toxicity and chronic ocular surface disease in vitro and in vivo. We will test our hypothesis using three Specific Aims: (i) determine the efficacy of pooled human immune globulins against PM-induced deleterious cellular and molecular changes in vitro by evaluating NETosis, mast cell degranulation and pro-inflammatory cytokine release profiles; (ii) determine the efficacy of pooled human immune globulins in preclinical models of PM-induced toxicity, including rabbits in mice. We will further test the effect of PM on the immune cell populations by performing single cell RNA Sequencing of conjunctival and corneal tissues; and (iii) determine the efficacy of pooled human immune globulins to protect against ocular surface wash-induced NETosis and mast cell degranulation. Here, we will use ocular surface washes from veterans with a history of military toxic exposures and ocular surface disease to trigger NETosis and mast cell degranulation in vitro and evaluate the efficacy of Flebogamma® 5% DIF. This project addresses an urgent unmet need for better understanding and therapeutic management of chronic OSD in Veterans. Successful execution of this project will (i) determine the pathophysiological mechanisms underlying ocular symptoms associated with military toxic PM exposure, and (ii) critically evaluate the therapeutic potential of pooled human immune globulins for the treatment of the chronic consequences of military toxic PM exposure. The clinical and regulatory experience of the Research Team with pooled human immune globulins has the potential for rapid translation to clinical use, which will benefit the large Veteran population suffering Project Number: 1I01BX007265-01 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Simon Kaja (+1 co-PI) | Institution: EDWARD HINES JR VA HOSPITAL, HINES, IL | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NURF-H (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11179701