September 10, 2018

 

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The Department of Laboratory Medicine and Pathology (LMP) spotlights work being done in the Jameson lab on T cell self-tolerance to test how vaccines work in treating autoimmune disease and cancer.

 

The following article was taken from the LMP website on September 10, 2018:

Jameson homes in on T cell self-tolerance

As a pioneer in transplant surgery, the University has been at the forefront of immunology for more than half a century, exploring how the risk of transplant rejection by the human immune system can be minimized.  Steve Jameson and his colleagues in the Center for Immunology aim to keep immunological research at the forefront for making advances in enhancing vaccines and in treating autoimmune disease and cancer. 

Jameson’s lab has been testing how vaccines work in the T cell context. In experimental studies in mice, he and his colleagues have applied vaccines to the skin to see whether the epicutaneous application was sufficient to generate an effective memory CD8+ T cell response that would be protective against bacterial and viral infections.  That work has opened up a new research avenue.  Jameson was recently awarded a five-year, $2.4 million National Institute of Allergy and Infectious Diseases grant for his project “Making and breaking of CD8+ T-cell self-tolerance.” 

In cancer immunotherapy, one goal is to provoke an immune response that targets cancerous cells but leaves normal healthy cells of the body alone.  In many cases, however, cancer cells evade destruction by only expressing targets for the immune system that are shared on healthy cells. This means that, in those cases, effective cancer immunotherapy would likely lead to damage to normal cells – such as destruction of the pigmented skin cells called melanocytes as the price to pay for controlling melanoma. Autoreactive CD8+ T cells are typically thought to be eliminated (a process called “clonal deletion”) during immune system development in order to prevent an auto-immune reaction against healthy tissues.  Over the past two decades, however, immunologists have found that “self-tolerance” can render CD8+ T cells to be physically present but in a “non-responsive” state called anergy. Understanding the mechanistic basis for anergy – and ways in which this form of self-tolerance can be “broken” for tumor immunotherapy – is the focus of the new work by Jameson and his fellow investigators.

“Our data show that mouse T cell tolerance to proteins on normal melanocytes typically involves a form of anergy, not deletion,” Jameson said.  “In the proposed studies we will investigate the basis for this form of tolerance.”   He said his studies could have broad significance for understanding autoimmune diseases such as vitiligo, psoriasis, alopecia and other skin conditions that can all be caused by T cell autoimmune responses to melanocytes.   They also may be clinically relevant by revealing potential mechanisms of CD8+ T cell self-tolerance disruption.  Immunotherapy with immune checkpoint inhibitors, which has revolutionized the treatment of melanoma, is a case in point. 

Jameson will employ a threefold approach in his investigations of CD8+ T cell self-tolerance:

  • Explore the basis of CD8+ T cell anergy.
  • Test the reversibility of anergy.
  • Examine how the lack of physiological exposure to normal skin infections and inflammation may compromise the value of current mouse models.

Jameson and his research team will use acute skin inflammation and infection models in their studies.  Team members will also use inbred mice that have been naturally infected with normal mouse microbes, so-called “dirty” mice.  Jameson helped to develop the model, which more closely mimics the human immune system experience than do standard laboratory mice models.