- Uveitis is a serious ophthalmological disorder characterized by intraocular infiltration of inflammatory cells. In most cases, uveitis is derived from the adaptive immune response. More specifically, CD4+ T lymphocytes play an important role in the pathogenesis of uveitis by recognizing uveitogenic antigen and orchestrating the immune response. While it is known that OX40 co-stimulatory molecule increases ocular inflammation via stimulation of naïve CD4+ T lymphocytes, OX40 augmentations of effector T cell re-stimulation and infiltration into the eye is not fully characterized. Our overall goal is to elucidate the function and mechanism of OX40 (a critical T cell co-stimulatory molecule) in orchestrating an abnormal immune response during uveitis.
Our lab employed an adoptive transfer mouse model as an in vivo model for controlled immunity transference. We used DO11.10 strains of BALB/c background whose transgenic T cell receptor (TCR) is modified to specifically recognize ovalbumin. The novel ovalbumin (OVA) adoptive transfer model was developed in our lab and allowed for us to study the transference of immunity from our donor T cell transgenic mice to our in vivo recipient antigen-challenged model mice which would allow us to observe the increased severity with OX40 stimulation. T cells were harvested from donor DO11.10 mice and stimulated with OVA peptide along with OX40 activating antibody in vitro, and then transferred to recipient mice without transgenic T cell. OVA peptide was administered via intraocular injections and inflammation was assessed 24 hours post-antigen challenge. CD4+ T cells of the host mice do not naturally respond to OVA, therefore response to OVA needs to be mediated by donor T cells. Furthermore, via RT-PCR methods, OX40 function was strongly correlated with enhanced chemokine and cytokine production including IL-17, IFN-γ, and CCL20. Lastly, neutralization experiments of IL-17 and IFN-γ showed decreased overall ocular inflammation.
This study not only helped to further advance our understanding of this important co-stimulatory molecule in activated T lymphocyte function, but also helped us better understand the role of OX40 in ocular inflammation. We were also able to understand functionality of important cytokines and chemokines in the pathogenesis of uveitis. This study can ultimately help in developing a clinical therapeutic approach to uveitis.