A Model System for T-Cell Targeting of the Vascular Endothelium

Ann Marshak-Rothstein, PhD
Boston University

Project Summary:

Systemic sclerosis (SSc) can be a debilitating chronic inflammatory disorder associated with severe alterations of vascular tissue and excessive fibrosis of the skin and other internal organs. A number of factors implicate an immunological imbalance in at least the initial stages of this disorder, but the target tissue and type of immune response that promotes the unique features of this disease remain poorly defined. Dr. Marshak-Rothstein and her colleagues believe that the nature of immune response is determined by the local microenvironment in which an immune response takes place. Since vascular dysfunction is one of the earliest manifestations of SSc and is commonly associated with infiltration of activated T cells around blood vessels, it is possible that the distinct pathology of SSc and the unique set of autoantigens targeted in SSc reflect initial damage to the vasculature mediated by an effector T cell population. To test this premise, they intend to establish an experimental mouse model that will allow them to specifically target effector T cell populations to the vascular endothelium. They will then use this model to examine other fundamental aspects of the immune stimulus and response.

Research Update:

Dr. Marshak-Rothstein is proceeding with the development of a transgenic model which, when complete, will enable expression of a foreign protein in certain blood vessel cells (and only there). Subsequent transfusion of immune cells that are known to recognize that foreign protein will then initiate an autoimmune response. They hypothesize that this initial injury will turn into a self-sustaining fibrotic process that causes additional vascular damage and perhaps major organ damage such as lung damage.

This year, the double transgenic mouse should become available and enable the key experiment to be done—site specific injury of the epithelial by the immune system. If Dr. Rothstein’s model successfully recapitulates the disease it would, among other things, give researchers an opportunity to try to understand how to therapeutically turn off the disease before it fully develops.

What this project means for people with scleroderma:

These studies should establish a highly reproducible mammalian model of SSc that will allow investigators to identify and modulate the immunological parameters that lead to chronic vascular diseases such as systemic sclerosis

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