Andrew W. Taylor, PhD, FARVO

Taylor

 

PROFESSOR OF OPHTHALMOLOGY

Telephone: 617–638-4525
Fax: 617-638-5337

Education:

B.S., University of Wisconsin, Madison, WI
M.S., Ph.D., Ohio State University, Columbus, OH

Research Interests:

Ocular System of Immune Regulation and Immune Suppression (OSIRIS)

My research program is focused on characterizing the molecular mechanisms of ocular immunosuppression and immunoregulation. The hypothesis of this research program is that ocular immune privilege suppresses immunogenic inflammation and manipulates immunity to regulate itself to the benefit of maintaining vision; and that immune privilege is the result of integrated activities of the nervous, immune, and ocular cells to maintain immune homeostasis within the ocular microenvironment. With this focus, I have developed several independent and complementary projects. The first two projects are the core of my research program. The next two are complementary projects that have the potential of their own funding support and development. The collaborative projects are pilot studies on age related macular degeneration (AMD), and on the potential for the hypoxia-adenosinergic pathway to be a mechanism in regulating ocular immunity. It is my objective to continue and expand these lines of research through collaborations, and new funding sources.

1. Role of neuropeptides in regulating adaptive and innate immunity in the eye.

My central research project has been characterizing the immunomodulating factors within the eye. Through immunochemical and biological analysis of aqueous humor, the fluid filling the anterior chamber of the eye, we have identified cytokines, growth factors, and neuropeptides that 1) suppress the activation of effector Th1 cells, 2) suppress the activation and the inflammatory activity of macrophages, and 3) mediate the induction of antigen-specific CD25+ CD4+ regulatory T cells. A major focus of our research has been on the constitutively present neuropeptides, alpha-melanocyte stimulating hormone (a-MSH), vasoactive intestinal peptide, calcitonin gene related peptide, and somatostatin. Collectively, the factors in aqueous humor suppress activation of delayed type hypersensitivity of adaptive immunity, and endotoxin activation of macrophages in innate immunity. Individually, the neuropeptides target different cells and stages in the induction of an immune response. The project has now expanded to characterize the immunosuppressive and immunomodulating activity of vitreous, neural retina, retinal pigment epithelial cells, and the contribution of the nervous system itself. The retina and neurotransmitters have been described for years to have immunosuppressive properties; however, little has been done to identify the mechanisms of this immunosuppression in the eye. The aim of this research program is to identify and to characterize the immunosuppressive activity in the ocular microenvironment, so that we can expand our understanding of the mechanisms of ocular immune privilege and use this knowledge to regulate immunity within inflamed eyes and other tissues.

2. Characterize the mechanism by which the ocular microenvironment promotes alternative activation of retinal microglia/macrophages.

Over the past couple of years, it is becoming clearer that the manner by which a macrophage is stimulated can lead to either inflammatory, anti-inflammatory, or wound repairing activity. We have recently found that the retinal pigment epithelial cells (RPE) induce the simultaneous expression of Arginase 1 and Nitric Oxide Synthase 2 (NOS2, iNOS) in macrophages. Recent publications have shown that such alternatively activated macrophages use the chemical oxidation byproducts of expressing both Arginase 1 and NOS2 to impair T cell receptor signaling, and induce apoptosis in the lymphocytes; therefore, promoting an immunosuppressive microenvironment. Our objective is to characterize the mechanisms used by RPE to induce alternative activation in macrophages, and to examine the changes in RPE activity to regulate macrophage functionality following trauma and autoimmune disease. This has implications on what is the functionality of resident microglia/macrophages and possible dendritic cells within the ocular microenvironment. This matches our hypothesis that the ocular microenvironment not only suppresses the induction immunogenic inflammation, but also manipulates the immune response to suppress itself, and in addition control wound repairing activity to prevent unregulated fibrosis and angiogenesis.

3. Using the mechanisms of ocular immunoregulation and immunosuppression to suppress autoimmune disease.

Based on our current understanding of the mechanisms of ocular immune privilege, it can be hypothesized that the reintroduction of deficient immunosuppressive factors into uveitic eyes will quench inflammation and return the eye to its normal, immune privileged status. This is a gene therapy project to correct the deficiency in the expression of immunosuppressive factors. The focus so far has been to use plasmids encoding the immunosuppressive factor a-MSH or transforming growth factor-beta2 (TGF-b2). These plasmids are injected into mouse eyes expected to expresses experimental autoimmune uveitis (EAU). The inflammation, retinal damage, and the recovery of immune privilege are being evaluated. In addition, there is a project of applying the mechanisms of ocular immunosuppression on other autoimmune disease models such as experimental autoimmune encephalomyelitis.

4. Modulation of immunity by alpha-Melanocyte Stimulating Hormone and Melanocortin Receptors.

 A central ocular immunoregulating and immunosuppressive neuropeptide is alpha-melanocyte stimulating hormone (a-MSH). The importance of a-MSH is seen its induction of regulatory T cells, and suppression of inflammatory activity of macrophages. The induction of antigen specific CD25+ CD4+ regulatory T cells by a-MSH requires that the T cells express the melanocortin 5 receptor (MC5r). The stimulation of MC1r and MC3r on macrophages by a-MSH suppresses macrophage innate inflammatory activity, and their drive to activate T cells that mediate autoimmune disease and inflammation. Moreover, a-MSH induces anti-inflammatory activity by macrophages and T cells. Little is known how a-MSH through its melanocortin receptors mediates its anti-inflammatory activity. Immune cells express three receptors of the melanocortin receptor family. In addition, the effect of a-MSH on immune cells appears to pass through different intracellular pathways, although the melanocortin receptors are all linked to cAMP accumulation. Therefore, the goal of this project is to use functional siRNA duplexes and specific agonists for MCr1, MCr3, and MCr5, and evaluate the effects of a-MSH through its individual melanocortin receptors on immune cells. In addition, we will demonstrate that a-MSH mediates a pattern of cytokines and factors associated with immunosuppression. This project will contribute to understanding whether a-MSH is only an endogenous anti-inflammatory neuropeptide, or it is an endogenous regulator necessary for the resolution of inflammation, and the maintenance of immune homeostasis. Also, the project has the potential for us to understand the immunological consequences of the functional melanocortin receptor polymorphisms found in humans, and the role of individual melanocortin receptors in regulating immunity within the eye and other tissues.

5. Collaborative Projects:

A. The biophysical studies of mutant Factor H and Age-related Macular Degeneration (AMD). A collaborative project with Dr. George Benedek, Ph.D., Professor, Department of Physics, Massachusetts Institute of Technology, and with Margaret M. DeAngelis, PhD, Assistant Professor Ophthalmology, MEEI to test the hypothesis that the condensation of proteins facilitated by mutant FH is the key to drusen formation, and the associated pathologic sequelae of AMD. This collaborative project is to act on the challenge to utilize the genetic discovery that as much as 50% of all age-related macular degeneration (AMD) patients express a single nucleotide substitution in complement Factor H, and to establish the specific molecular mechanism which explains the pathophysiology of this disease. The examination of the aggregative properties of mutant FH is a fundamentally novel theme in AMD research. We believe that AMD disease may be the result of protein condensation just as in the case of a number of other diseases such as cataracts, various amyloidoses including Alzheimer’s disease, and sickle cell disease. If so, slowing down the kinetics of such aggregation can be a promising strategy for delaying AMD beyond the normal life span.

B. The hypoxia-adenosinergic prevention and therapy of chronic uveitis. This is a newly formed collaborative project with Michail Sitkovsky, Ph.D., Professor, and Akio Ohta, Ph.D., Research Associate, Department of Pharmaceutical Sciences Northeastern University on hypoxia-adenosinergic mechanism in trauma-induced and inflammatory ocular diseases. We hypothesize that a sustained treatment with a suitable modulator of the hypoxia-adenosinergic immunosuppressive pathway will counter abnormal tissue remodeling and inflammation in the traumatized eye.

Primary teaching affiliate
of BU School of Medicine