Reza Dana, M.D.
|Title||Claes H. Dohlman Professor of Ophthalmology|
|Institution||Massachusetts Eye and Ear Infirmary|
|Address||Massachusetts Eye & Ear Infrm|
Cornea Service, Department of Ophthalmology
243 Charles St
Boston MA 02114
||Fellowship (Ocular Immunology)|
||Named Fellow of the Society of Heed Fellows (Special Recognition Award)|
||Clinical Scientist Career Award|
||William & Mary Greve Scholar (RPB Special Scholar Award)|
||Second Decade Society (alumni honor)|
||Kronfeld Memorial Lecturer|
||Fry Memorial Lecturer|
||Listed in "Guide to America's Top Ophthalmologists"|
||Alta Lecturer and Visiting Professorship|
||Physician Scientist Merit Award|
||Service Recognition Award|
||Certificate of Appreciation|
2010||Listed, "Best Doctors of America" (selected by peers)|
2010||Listed, "Best Ophthalmologists" (selected by peers)|
||Alcon Research Institute Award|
2010||Lew R. Wasserman Merit Award|
I am an ophthalmologist and immunologist whose principal research interest is in determining the molecular and cellular regulation of corneal and ocular surface immunity. In particular, my lab focuses 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 vasculogenesis (hemangiogenesis and 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.
To address the principal objectives of our research program, we have 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 interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-a; specifically through the p55 receptor) work in concert to upregulate specific chemokines (CCR1 and CCR5 ligands) and cell adhesion molecules (ICAM-1) 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 TNF-a (via sTNFR-I), IL-1 (via IL-1 receptor antagonist), or molecular targeting of CCR1 and CCR5. We 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. 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.
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 in 2004. Very recently, our work has shed light onto one of the oldest mysteries in 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 2006).
In addition to these basic efforts, my clinical research efforts have focused on the efficacy of various treatment strategies for ocular surface inflammatory disorders, regulation of innate immunity, and development of novel rodent models that mimic clinical conditions, including the first non-pharmacologically mediated/non-knockout mouse model of dry eye that is being used to determine the molecular pathogenesis of this highly prevalent condition.
In addition to research, I have focused extensively on education, both clinical and research. This has included teaching of postdoctoral research fellows, clinical fellows and residents, and medical students and graduate students enrolled in various Harvard Medical School curricula—I have served as primary mentor to over 30 trainees in ophthalmology and eye research. In addition to my considerable efforts to contribute to the investigation-based peer-reviewed literature, I have also remained an editor of the 14-volume American Academy of Ophthalmology Basic and Clinical Science Course (the principal educational tool of US and Canadian residents for Board certification), responsible for virtually all content regarding corneal inflammation and immunity. Finally, as a strong believer in the importance of clinical scientists in bridging the wide gap between basic science and clinical applications, I direct the Harvard-Vision Clinical Scientist Development Program funded by the K12- with the express intent of recruiting, training, and retaining the brightest young minds to Harvard to contribute to our research efforts.
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