I am an ophthalmologist and immunologist whose principal research interest is determining the molecular and cellular regulation of corneal and ocular surface immunity. In particular, we focus on the role of cytokines and chemokines in induction of antigen-specific corneal immunology, recruitment and activation of ocular antigen-presenting cells, and the interface of lymphangiogenesis and corneal inflammation. The principal venue of my research activities is in my laboratory at the Schepens Eye Research Institute, but is complemented with extensive ‘clinic-to-lab’ and translational ‘lab-to-clinic’ research activities that are performed in conjunction with my academic clinical subspecialty practice at the Massachusetts Eye and Ear Infirmary (see further below for details).
To address the principal objectives of our research program, we optimized the orthotopic model of corneal transplantation in the mouse to determine specific mechanisms involved in: (i) antigen-presenting cell (APC) mobilization in the cornea, (ii) APC-blood and –lymph vessel interactions, (iii) APC mobilization from eye to lymphoid organs including regional draining lymph nodes, and (iv) APC sensitization of T cells in transplantation and autoimmunity. Our work has been instrumental in delineating the precise mechanisms by which pro-inflammatory cytokines work in concert to upregulate specific chemokines and cell adhesion molecules that mediate trans-endothelial migration of APCs from the intravascular compartment into the corneo-limbal matrix. We 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 relevant cytokines and chemokines. We subsequently showed that once mobilized, these antigen-laden APCs can migrate from the graft to regional lymph nodes to induce T helper-1 type immunity through an interleukin-12-dependent mechanism. This pathway which becomes activated in states of high inflammation is distinct from the normal (default) migration of “tolerogenic” ocular APC to the spleen where they can promote a specific form of immune unresponsiveness termed anterior chamber-associated immune deviation, explaining how the eye, an immune privileged organ, can also be susceptible to destructive immunity. We have also shown the T cell response generated differs considerably between transplants and in chronic autoimmunity (the latter as seen in dry eye disease).
Our work led to important novel and unexpected discoveries. My lab was the first to discover several distinct populations of uniformly MHC class II— 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. We 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. We have 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. We have determined that this receptor is expressed by mature MHC class IIhi dendritic cells in the cornea, and mediates their chemotactic mobilization into lymphatics, thereby allowing their egress from the eye. Importantly, we showed that 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 we published in Nature Medicine. We have also successfully demonstrated that disruption of the ‘eye-lymphatic axis’ pharmacologically can suppress generation of autoimmune dry eye disease.
Our work has also 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. We have shown high constitutive and ectopic expression of VEGFR-3 by the corneal epithelium serves as a “sink” mechanism for VEGF-C/D, preventing their ligation of vascular endothelial VEGFR-2, and thereby functioning as a critical mechanism for maintaining corneal avascularity (PNAS). More recently, we have shown that IL-17 can promote lymphatic development through upregulation of VGEF-D (Blood).
Our work in corneal transplantation immunology permitted us since 2006 to launch a broad and productive program determining the immunopathogenesis of dry eye disease, a chronic autoimmune disease whose precise pathogenesis was barely understood even a few years earlier. We 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 (i) selective growth of neolymphatics into dry eye corneas, (ii) induction of T helper-1 (Th1) and Th17 autoimmun