Researchers Unlock Mystery of Cellular/Molecular Defect That Can Lead to Human Autoimmune Disease

Newswise — Researchers at Columbia University Medical Center have identified a defect in the T cell regulatory pathway which normally controls autoreactive T cells that attack the body’s own tissues and organs. A majority of people with Type 1 diabetes who were tested in the study were found to have the newly-identified cellular/molecular defect, and the researchers were able to successfully correct the defect in-vitro.

The study will be published on September 27, 2010 in The Journal of Clinical Investigation.

“For decades, autoimmune diseases have been treated by reducing overall immune response. That’s been effective in extending life spans, but has been hard on the quality of life for many of those patients,” said Hong Jiang, M.D. Ph.D., a faculty member of the Division of Rheumatology, in the Department of Medicine at Columbia University Medical Center, and the leading scientist of the study and corresponding author of the paper. “Now that we understand the specific mechanism of how regulatory T cells discriminate between ‘self’ and ‘non-self,’ and the cellular/molecular defect that makes that process go awry, we hope to develop new type of therapies that specifically target the defect in patients without damaging their normal immune functions.”

A key feature of the immune system is its ability to discriminate between self and non-self. When any of the mechanisms that prevent the immune system from attacking itself break down, it can result in autoimmune disorders. Previous studies by this group have shown, in mice, that a particular type of immune T cells, known as CD8+ T cells, are essential to discriminate self from non-self.

“Until now, it wasn’t known if this mechanism exists in humans,” said Leonard Chess, M.D., also from the Division of Rheumatology at Columbia University Medical Center and a collaborating author of the study. “But our research has confirmed these CD8+ T cells do, in fact, exist in humans, and that they play an important role in stopping the immune system from attacking itself. And that understanding could lead to develop novel therapies for a wide range of autoimmune diseases.”

The findings from Jiang and Chess are based on their original scientific theory known as the “avidity model” of peripheral T cell regulation. This theory provides the conceptual basis for how novel therapies can be designed to selectively target only the T cells that are harbingers of autoimmunity.

The Columbia researchers tested a number of patients with Type 1 diabetes, and found that the majority of them had a defect in CD8+ T cells that impacted their recognition of a common target structure known as HLA-E/Hsp60sp, previously identified by the researchers. That defect resulted in a failure of the CD8+ T cells to discriminate self from non-self. The high incidence of that defect in patients with Type 1 diabetes suggests these CD8+ T cells may play a major role in the development and control of the disease. The researchers were successfully able to correct the defect in the CD8+ T cells from most of the diabetic patients in-vitro.

Current therapies for treating autoimmune disease and controlling rejection of transplants result in nonspecific suppression of normal function of the immune system. In contrast to these existing approaches (which systemically suppress the immune system), therapies based on this new research are designed to selectively suppress immune responses to self-antigens without damaging the body’s normal anti-infection and anti-tumor responses.

Another major advantage of the new therapy over antigen-specific strategies is that therapies can be developed independent of the knowledge of any particular self-antigens involved.

In addition, now that scientists have a greater understanding of the defect that leads to certain autoimmune diseases, assays could be developed to detect that defect, giving doctors an opportunity for early diagnosis, early treatment and eventually prevention of autoimmune diseases. That would be particularly important, because, for example, patients with Type 1 diabetes often don’t learn they have the disease until significant damage has been done. Assays might also be used to check the status of organ transplants, to control chronic rejection.

“This scientific breakthrough could lead to a wide range of therapeutic and diagnostic possibilities,” says Sara Gusik, a representative from Columbia Technology Ventures, the technology transfer office of Columbia University, which has already filed patent applications on this work. Some of the advances could include vaccines or biotechnology agents for early diagnosis, early treatment, leading to possible cure and prevention of a variety of autoimmune diseases, including Type 1 diabetes, multiple sclerosis, thyroid disease, rheumatoid arthritis, and others. The researchers envision that the new conceptual framework of the “avidity model” may also lead to solutions that address chronic graft rejection in organ transplantation.

To view this article in Chinese, please visit: http://bit.ly/9B1KTT.

References:

Jiang H, Chess L. The specific regulation of immune responses by CD8+ T cells restricted by the MHC class Ib molecule, Qa-1. Annu Rev Immunol. 2000 Apr;18:185-216.

Jiang H, Wu Y, Liang B, Zheng Z, Tang G, Kanellopoulos J, Soloski M, Winchester R, Goldstein I, Chess L. An affinity/avidity model of peripheral T cell regulation. J Clin Invest. 2005 Feb;115(2):302-12.

Chen W, Zhang L, Liang B, Saenger Y, Li J, Chess L, Jiang H. Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20472-7.Jiang H, Chess L. Qa-1/HLA-E-restricted regulatory CD8+ T cells and self-nonself discrimination: an essay on peripheral T-cell regulation. Hum Immunol. 2008 Nov;69(11):721-7.

Wu Y, Zheng Z, Jiang Y, Chess L, Jiang H. The specificity of T cell regulation that enables self-nonself discrimination in the periphery. Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):534-9.

Jiang H, Chess L. How the immune system achieves self-nonself discrimination during adaptive immunity. Adv Immunol. 2009;102:95-133.

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