Evaluation of Immunomodulators as Therapeutic Treatments for Sulfur Mustard-Induced Ocular Injury

Abstract

<b>Abstract ID 54458</b> <b>Poster Board 261</b> This work was conducted in an effort to develop medical countermeasures to treat exposure to toxicants that can be utilized in mass casualty scenarios. The cornea and other ocular surface tissues are particularly susceptible to chemical exposures such as sulfur mustard (SM), and long-term prognosis can be poor due to delayed complications, including persistent corneal epithelial defects, dry eye, corneal opacification, and corneal neovascularization. Such long-term complications can lead to permanent discomfort and vision deficits or blindness despite the best current treatment regimens. SM modifies basement membranes as an alkylating agent. The structures, once alkylated, may potentially be recognized as foreign by the immune cells. For example, laser debridement of a skin SM burn in a pig model resulted in superior healing, presumably because it cleared the alkylated basement membrane. Studies showed persistent inflammation affecting the cornea and anterior segment and elevated levels of inflammatory cytokines such as IL-1ss, IL-6, TNF-α, and IL-8 after SM ocular exposure in animal models. The current study is to evaluate therapeutic efficacies of immunosuppressants and other immunomodulators in a mouse model of SM vapor-induced ocular injury. We have tested FDA-approved immunosuppressants mycophenolate mofetil (MMF) and tacrolimus, which have been extensively used in organ transplantation and some inflammatory, autoimmune diseases, including uveitis. MMF especially showed its effectiveness in a mouse model of corneal graft. Other immunomodulators in our analysis included IL-1 receptor antagonist (IL-1 Ra) and granulocyte colony-stimulating factor (G-CSF). Others have showed that IL-1 Ra significantly inhibited the development of autoimmune uveitis and improved ocular surface integrity of autoimmune-mediated aqueous-deficient dry eye in mouse models, and that G-CSF greatly improved ocular injuries in a rat corneal alkali burn model. To our surprise the treatment with MMF significantly exacerbated injury progression, including corneal neovascularization, suggesting that some immune responses after ocular exposure are required for regulation of SM-induced corneal injury. In addition, SM-induced ocular injury may need agent-specific treatments based on findings that immune modulators with doses effective in other corneal injury models did not produce desirable outcomes. Findings of our study would help better understand the pathology of SM-induced ocular injury and dissect therapeutic targets.