CH Dohlman Professor and Senior Scientist
20 Staniford Street
Boston, MA 02114
Visit my lab page here.
Assistant: April Dobbs, Email: firstname.lastname@example.org
The focus of the Dana Lab is on 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 (APC), and the interface of lymphangiogenesis and corneal inflammation in transplantation and chronic ocular surface inflammatory conditions, such as dry eye disease.
To address the principal objectives of our research program, we use preclinical mouse models to determine specific mechanisms involved in: (i) antigen-presenting cell (APC) mobilization in the ocular surface, (ii) APC-blood and –lymph vessel interactions, (iii) APC mobilization from the eye to lymphoid organs including regional draining lymph nodes, and (iv) APC sensitization of T cells in transplantation and autoimmunity.
1. APC mobilization in the cornea and ocular surface: Our lab was the first to discover several distinct populations of uniformly MHC class II— highly immature APCs 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 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. Blockade of this pathway can suppress the trafficking of APC from the eye to regional lymph nodes and suppress the induction of antigen-specific immunity.
2. Why the cornea is devoid of blood and lymphatic vessels: Recently, we have 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.
3. Immunobiology of dry eye disease: Dry eye disease is a chronic autoimmune disease whose precise pathogenesis was barely understood even a few years earlier although it is the most prevalent ophthalmic condition in the developed world. Our lab developed a preclinical model for dry eye disease that has permitted us 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 autoimmunity, (iii) development of Th17 cell resistance to Treg suppression, and (iv) the expression of autoreactive T cell homing chemokines on the ocular surface.
Select Bibliography (from 300+ total publications)
1. Liu Y, Hamrah P, Zhang Q, Taylor AW, Dana R. Draining lymph nodes of corneal transplant hosts exhibit evidence for donor MHC class II-positive dendritic cells derived from MHC class II-negative grafts. J Exp Medicine 2002; 195: 259-68.
2. Huq S, Liu Y, Benichou G, Dana R. Relevance of the direct pathway of sensitization in corneal transplantation is dictated by the graft bed microenvironment. J Immunol 2004: 173:4464-9.
3. Chen L, Hamrah L, Cursiefen C, Zhang Q, Pytowski B, Streilein JW, Dana R. Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) mediates induction of immunity to corneal transplants. Nature Med 2004; 10: 813-815.
4. Cursiefen C, Chen L, Saint-Geniez M, Hamrah P, Jin Y, Rashid S, Pytowski B, Persaud K, Wu Y, Streilein JW, Dana R. Nonvascular VEGFR-3 expression by corneal epithelium maintains avascularity and vision. Proc Nat Acad Sci USA 2006: 103:11405-10.
5. Shen L, Jin Y, Freeman GJ, Sharpe AH, Dana R. The function of donor versus recipient PD-L1 in corneal allograft survival. J Immunology 2007; 179: 3672-9.
6. Chauhan SK, El Annan J, Ecoiffier T, Goyal S, Zhang Q, Saban DR, Dana R. Autoimmunity in dry eye is due to resistance of Th17 to Treg suppression. J Immunology 2009; 182: 1247-52.
7. Chauhan SK, Jin Y, Goyal S, Lee HS, Fuchslugar T, Lee HK, and Dana R. A novel pro-lymphangiogenic function for Th17/IL17. Blood. 2011; 118:4630-4.
Last Update: 1/6/2014