Immune response depends on key molecule: Research

In a new study published in the April 1, 2003 issue of Genes and Development, scientists at University Health Network’s Advanced Medical Discovery Institute (AMDI)/Ontario Cancer Institute (OCI) have shown that a molecule called caspase-8 plays a key role in the immune system response, by controlling how T-cells are activated to respond to infections.

T-cells are white blood cells that recognize and fight off viruses and bacteria. When T-cells encounter these foreign invaders they build up a T-cell “army” by multiplying themselves many thousand-fold in process known as activation. Once their job is complete, T-cells are eliminated in a process known as apoptosis. While caspase-8 is largely recognized as a critical factor in this elimination process, this study produced a new finding: caspase-8 is also essential for the activation of T-cells at the start of the immune response.

“This research has helped us better understand how caspase-8 activates the immune system response by triggering T-cells to proliferate. When caspase-8 is inhibited, the immune response is significantly decreased,” explains Dr. Razqallah Hakem, principal investigator AMDI/OCI and Assistant Professor in Medical Biophysics at the University of Toronto.

The research builds on findings published last fall in Nature, which revealed that caspase-8 mutations are linked to immunodeficiency in humans. But the in vivo role of caspase-8 has remained uncertain until now, because deleting the molecule is lethal to embryos-making it impossible to fully understand what happens to cells without the molecule.

Researchers overcame this hurdle by targeting and eliminating caspase-8 from specific organ tissues in mice, enabling them to see how these tissues are affected by the absence of caspase-8.

“The research we’ve done has created a unique model that we and other scientists can use to further study the role of caspase-8 in the immune response,” reports AMDI researcher and lead author of the study, Leonardo Salmena, who is a PhD candidate in Medical Biophysics at the University of Toronto.

Understanding how caspase-8 operates in T-cell proliferation and activation is an important first step towards understanding immune system abnormalities and how these processes might be controlled to treat overactive immune systems. Researchers hope that continued research could impact therapies for autoimmune disorders such as lupus, multiple sclerosis, and Type I diabetes.

The research was supported by Amgen Incorporated, and by grants from the Canadian Institute of Health Research, and the National Cancer Institute of Canada.

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