News & Research

    University of California, San Francisco, San Francisco, California

Immune modulation for the treatment of type 1 diabetes

General Research Subject: Type 1 Diabetes

Focus: Immunology, Islet Biology\Apoptosis, Transplantation

Type of Grant: Mentor Based Minority Postdoctoral Fellowship

Project Start Date: July 1, 2010

Project End Date: June 30, 2013

Diabetes Type: Type 1 diabetes

Research Description

The immune response is a complex interaction of T cells, B cells, and monocytes. T cells are critical in the immune response because they orchestrate antiviral and antibacterial responses as well as facilitate antibody responses. However, the ability of the immune system to distinguish self from non-self relies on multiple mechanisms that maintain immune tolerance. The breakdown of tolerance in genetically susceptible individuals results in autoimmune diseases such as diabetes, multiple sclerosis, and arthritis. Over the past 30 years, Dr. Bluestone's laboratory has been involved in efforts to modify autoimmune responses and to understand the underlying mechanisms of T-cell tolerance. He has made seminal discoveries in the fieldand has developed novel therapies to induce immune tolerance that are now being tested in man. His efforts have focused on developing a new generation of suppressives - drugs that will 'turn off' selected parts of the immune system, leaving the disease-fighting capabilities intact. These approaches include the development of an FcR non-binding anti-CD3 mAb, regulatory T cells and CTLA4Ig that selectively target activation of T cells without the requirement for long term toxic drug treatment. These drugs is currently in clinical trials in type 1 diabetes. In addition, he has studied the negative co-stimulatory factors, PD-1 and CTLA-4, that control autoimmunity. The ADA minority fellowship will provide a special opportunity for a qualified individual to join the Bluestone laboratory and embark on a project in this area of immune tolerance and diabetes.

Research Profile

Mentor: Jeffrey Bluestone             Postdoctoral Fellow: S Armando Villalta

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

The immune response is a complex interaction of T cells, B cells, and monocytes. T cells are critical in the immune response because they orchestrate antiviral and antibacterial responses as well as facilitate antibody responses. However, the ability of the immune system to distinguish self from non-self relies on multiple mechanisms that maintain immune tolerance. The breakdown of tolerance in genetically susceptible individuals results in autoimmune diseases such as diabetes, multiple sclerosis, and arthritis. Over the past 30 years, our laboratory has been involved in efforts to modify autoimmune responses and to understand the underlying mechanisms of T-cell tolerance. We have made seminal discoveries in the field and have developed novel therapies to induce immune tolerance that are now being tested in man. Our efforts have focused on developing a new generation of suppressives - drugs that will 'turn off' selected parts of the immune system, leaving the disease-fighting capabilities intact. These approaches include the development of an FcR non-binding anti-CD3 mAb, regulatory T cells and CTLA4Ig that selectively target activation of T cells without the requirement for long term toxic drug treatment. These drugs are currently in clinical trials in type 1 diabetes. In addition, we have recently shown that the cancer drug, Gleevec, a receptor tyrosine kinas inhibitor is very effective in reversing type 1 diabetes in the NOD mouse model. The ADA minority fellowship will provide a special opportunity for a qualified minority individual to join the Bluestone laboratory and embark on a project in this area of immune tolerance and diabetes. It is our hope and aspiration that the work conducted by these fellows will play a key role in the development of novel immunotherapeutics that will halt, reverse or even prevent this disease.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

The studies conducted in this effort will have a vital role in the future prevention and cure of type 1 diabetes by determine the molecular basis of the disease pathogenesis and potential drugs to reverse beta cell destructions. For those with disease, these effects, perhaps in conjunction with new sources of islet (islet transplantation or embryonic stem cell-derived islets) will be able to cure those with this condition.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?

As an immunologist, I have been working for over 30 years on understanding the basis for self-non-self discrimination, namely why our immune system, which is designed to recognize foreign agents such as viruses and bacteria, on occasion recognizes self proteins such as insulin leading to over 80 autoimmune diseases such as type 1 diabetes. My efforts in diabetes research became very personal in the early 90's when my father became increasingly insulin dependent and began to suffer the ravages of the disease leading to amputations and loss of kidney function. In fact, in 2001, I donated a kidney to my father. Thus, this research is very personal and this award will help me train the next generation of scientists who will lead the effort going forward.
In what direction do you see the future of diabetes research going?

The cure for type 1 diabetes will depend on developing combination therapies that halt the autoimmune response thus preventing ongoing islet destruction, coupled with new cell replacement therapies that will allow for renewed insulin production.