Description of Research
Dr. Reza Dana is an ophthalmologist and immunologist whose principal research interest is determining the molecular and cellular regulation of corneal and ocular surface immunity. In particular, his focus is on the role of cytokines and chemokines in induction of antigen-specific corneal immunology, recruitment and activation of ocular antigen-presenting cells, dysfunction of T regulatory cells in transplantation and autoimmunity, and the interface of lymphangiogenesis and corneal inflammation. The principal venue of his research activities is in the Dana laboratory at the Schepens Eye Research Institute, but is complemented with ‘clinic-to-lab’ and translational ‘lab-to-clinic’ research activities that are performed in conjunction with his academic clinical subspecialty practice at the Massachusetts Eye and Ear Infirmary.
To address the principal objectives of his research program, Dr. Dana and his laboratory have used the orthotopic model of corneal transplantation in the mouse to determine specific mechanisms involved in:
Antigen-presenting cell (APC) mobilization in the cornea.
T regulatory cell function in transplantation.
The function of the immune system in regulating angiogenesis.
Use of tolerogenic APC for promotion of graft survival.
The work of the Dana laboratory work has been instrumental in delineating the precise mechanisms by which pro-inflammatory cytokines, e.g. interleukin-1 (IL-1) and tumor necrosis factor-alpha, work in concert to upregulate specific chemokines and cell adhesion molecules that mediate trans-endothelial migration of APCs from the intravascular compartment into the corneolimbal matrix. They have shown that this process of APC mobilization into the corneal matrix can be effectively suppressed, with concomitant blunting in the activation of cornea-specific immunity, with topical blockade of TNF-a or specific CC and CXC chemokines. The Dana laboratory subsequently showed that once mobilized, these antigen-laden APCs can migrate from the eye to regional lymph nodes to induce T helper-1 type immunity through an interleukin-12-dependent mechanism in transplantation and a T helper-17 response in autoimmunity as in dry eye disease. This pathway, which becomes activated in states of high inflammation, is distinct from the normal (default) state of “tolerogenic” ocular APC that promote immune unresponsiveness.
The work of Dr. Dana and his laboratory has led to important novel and unexpected discoveries. The Dana lab was the first to discover several distinct populations of uniformly MHC class II-negative or – low, highly immature, APCs (including epithelial Langerhans cells and stromal CD11b+ myeloid CD11c+ dendritic cells) in the central cornea, breaking a longstanding dogma that the cornea was devoid of any antigen-presenting cell population. They also showed that these immature/precursor populations can mature to acquire high CD40, CD80, and MHC class II expression as they egress the eye through selective upregulation of specific receptors (e.g. CCR7) to prime naïve T cells under conditions of inflammation, including after corneal transplantation. The Dana lab has also determined a novel role for the tyrosine kinase receptor vascular endothelial growth factor receptor-3 (VEGFR-3), which is known to be a growth factor for lymphatic (and to some extent budding blood vessel) endothelia. They have determined that this receptor is expressed by mature MHC class II-hi dendritic cells in the cornea, and mediates their chemotactic mobilization into lymphatics, thereby allowing their egress from the eye. Importantly, Dr. Dana and his lab have shown that the blockade of this pathway can suppress the trafficking of APC from the eye to regional lymph nodes and suppress the induction of delayed hypersensitivity to corneal transplants—a finding they published in Nature Medicine. They have also successfully demonstrated that disruption of the ‘eye-lymphatic axis’ pharmacologically can suppress generation of autoimmune dry eye disease.
In addition, the work of the Dana lab has shed light onto one of the oldest mysteries in ophthalmic biology— namely, how the cornea maintains its avascular structure, and thereby allows for light to be focused on the retina with minimal interference. Their studies have shown high constitutive and ectopic expression of VEGFR-3 by the corneal epithelium serves as a “sink” mechanism for VEGFC/D, preventing their ligation of vascular endothelial VEGFR-2, and thereby functioning as a critical mechanism for maintaining corneal avascularity (PNAS).
More recently, the Dana lab's work in corneal transplantation immunology permitted them to launch a productive program determining the immunopathogenesis of dry eye disease, a chronic autoimmune disease whose precise pathogenesis was barely understood even a few years earlier. The lab developed, and validated, a novel preclinical model for dry eye disease that did not rely on gene deletion or transgenic technology and used it in our basic research program to focus on the molecular mechanisms that mediate:
Selective growth of neolymphatics into dry eye corneas
Induction of T helper-1 (Th1) and Th17 autoimmunity
Development of Th17 cell resistance to Treg suppression
Expression of autoreactive T cell homing chemokines on the ocular surface.
These studies have been complemented with a number of ‘proof of concept’ therapeutic strategies in preclinical models of dry eye, such as antagonism of cytokines (IL-1, IL-17), prolymphangiogenic factors (VEGF-C/D, VEGFR-3), T cell homing chemokines (CCR5), and leukocyte recruitment mechanisms such as integrins (VLA-4).
Dr. Dana's basic investigation efforts have been complemented with an active program in clinical and translational research, many supported by the K24 NIH mechanism. Dr. Dana created the Cornea Research department at the Mass. Eye and Ear in 2007, staffed by 7 full-time staff, where nearly 50 prospective investigator initiated studies are performed by the Cornea faculty at Mass Eye and Ear. Studies have focused on novel strategies to manage high-risk corneal and stem cell transplants, pathological corneal angiogenesis, dry eye, and in vivo corneal immuno- and neuro-imaging. These studies have been facilitated by 7 successful FDA IND approvals received by his group since 2008.