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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Developing Strategies to Induce Tolerance in Autoimmune Diseases

Principal Investigator: Cheng-Hong Wei, MD, PhD
Office / Division / Lab: OCTGT / DCGT / GTIB


General Overview

Autoimmune diseases are disorders in which the immune system attacks the body's own cells. They are among the most prevalent classes of public health problems.

For example, the cause of autoimmune type 1 diabetes (T1D) is the destruction of the insulin-producing cells of the pancreas by the immune system.

The loss of insulin results in high glucose levels in blood that cause the long-term complications of this disease. When T lymphocytes destroy nerve tissues, the resulting damage causes multiple sclerosis.

The basis of autoimmune disease is the immune system's loss of "tolerance" to the body's own tissues. That is, the immune system fails to recognize that the person's own tissues are not foreign and should not be attacked. Cells called T lymphocytes normally help fight against infection and other material foreign to the body ("non-self"). However, certain rogue cells called "autoreactive T lymphocytes" respond to the body's own tissues and organs as if they were foreign; that is, they lose "tolerance" to the body's own cells and tissues. Usually the body destroys such cells soon after the immune system makes them, but when such autoreactive T lymphocytes evade elimination and mature, they can cause serious diseases.

Physicians usually treat autoimmune diseases with an immunosuppressive drug that decreases the activity of the immune system so it does not attack the person's own tissues or transplanted organs or tissues (e.g. islet transplants as treatment of T1D). The disadvantage of immunosuppressive drugs is that they not only suppress the attack on the patient's own cells (or transplanted cells) but also hinder the ability of the immune system to fight infectious diseases. In contrast, immune tolerance therapies are treatments that directly prevent the immune system from attacking the person's own tissues. Immune tolerance therapies are designed to work by targeting only those T cells that are already causing disease, such as T1D. In this way, they represent a better alternative to immunosuppressive therapies and their toxic side effects.

Although several promising tolerance therapies are now nearing clinical trials, there are still no approved immunotherapies for T1D, despite extensive efforts to develop them.

The aim of our research is to find methods to prevent autoreactive T lymphocytes from reacting to the insulin-producing cells as if they were "foreign" to the body. Using mouse models of T1D, we are trying to develop a strategy for efficiently inducing long-term tolerance to the insulin-producing cells by targeting the self-reactive T cells causing this disease. We are also trying to develop animal models that reliably predict the safety and efficacy of immune tolerance therapies for autoimmune diseases in humans.

Our work is aimed at understanding how autoreactive T cells survive in mouse models of T1D, how to promote their deletion, and how to generate tolerance of insulin-producing cells by manipulating the immune system response to them.

If successful, these new approaches of tolerance induction could prevent the occurrence of diabetes and also be used to promote tolerance to islet cell transplants without relying on immunosuppressive drugs. We believe that our studies of the tolerance of autoreactive T cells and protective regulatory T cells will provide important information for the design of successful new approaches to prevent T1D and other autoimmune diseases.


Scientific Overview

Type 1 diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing pancreatic beta cells by T cells. It represents a failure of the immune system to maintain tolerance to self-antigens. In individuals with T1D, persistent autoimmunity to islet antigens acts as a barrier to successful islet graft tolerance.

One effective mechanism of peripheral tolerance involves deletion of autoreactive T cells mediated by DCs in cross-tolerance. The second major way in which autoreactive T cells are controlled in the periphery is by regulatory T cells.

Studies have shown that it is possible to obtain T cell tolerance by manipulating cross-presentation in vivo. Antigens can be introduced into the cross-presentation pathway artificially, and presented to the cognate T cells by dendritic cells (DCs), resulting in tolerance and deletion of antigen-specific T cells. We have developed a method that allows us to use a short synthetic peptide modified at the N-terminus for loading lymphocytes in vitro with a class I epitope. When injected, the cells are taken up by quiescent DCs that efficiently cross-present the nominal class I epitope to CD8 T cells. One goal in our study is to determine whether this tolerance protocol will be successful in promoting deletion and tolerance of CD8 T cells specific for islet antigens involved in T1D. Similarly, intact proteins can be introduced into cross-presentation pathways in vivo to induce deletion, anergy of CD4 T cells or induction of protective regulatory T cells. We will use this strategy to induce tolerance of autoreactive CD4 and CD8 T cells.

The goal of our study is to characterize the conditions that lead to long-term tolerance of islet antigen-specific T cells in a murine model of T1D, and apply this new knowledge to targeted immune modulation and prevention of T1D. Another of our major goals is to develop animal models that reliably predict the safety and efficacy of immune tolerance therapies for autoimmune diseases in humans.

Specifically, we will focus on the following three aims:

1. Prevent the development of T1D in NOD mice with cross-presentation of islet antigens and co-stimulatory pathway manipulation.

2. Investigate the role of regulatory T cells in the tolerance of auto-reactive CD8 T cells during recurrent autoimmunity.

3. Induce protective regulatory T cells in vivo using cytokine/ immune complexes as well as immunoregulatory compounds combined with co-stimulatory blockade followed by use of induced regulatory T cells to prevent and treat T1D.

Knowledge obtained in this study will help us better understand the mechanism of tolerance induction, as well as develop novel therapies for T1D. If successful, these new methods of tolerance induction could prevent the occurrence of diabetes and also be used to promote tolerance to islet cell transplants without relying on immunosuppressive drugs.

We believe that this study will provide important information for the successful design of new approaches to prevent not only T1D but also autoimmunity in general.


Publications

Stem Cell Res Ther 2013;4(5):128
Assessment of Immunosuppressive Activity of Human Mesenchymal Stem Cells Using Murine Antigen Specific CD4 and CD8 T Cells in vitro
Nazarov C, Lo Surdo J, Bauer SR, Wei CH

Clin Dev Immunol 2011;2011:630187
NOD dendritic cells stimulated with Lactobacilli preferentially produce IL-10 versus IL-12 and decrease diabetes incidence.
Manirarora JN, Parnell SA, Hu YH, Kosiewicz MM, Alard P

Xenotransplantation 2010 Sep;17(5):329-37
Regulation of xenogeneic porcine pancreatic islets.
Arcidiacono JA, Evdokimov E, Lee MH, Jones J, Rudenko L, Schneider B, Snoy PJ, Wei CH, Wensky AK, Wonnacott K

 

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