From the Journals

Genetics dictate interferon-alfa diarrhea risk

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Toward personalized medicine

Many studies have implicated cytokines in various human GI-tract disorders, but there is still limited information in the literature about their exact role in the maintenance and disturbance of tissue homeostasis and the molecular mechanisms involved.

Dr. Jason C. Mills

Dr. Jason C. Mills

In this study, the authors used human colonic mucosa explant culture, a 3-D system that preserves the architecture of the tissue and various mucosal resident cells that can interact to trigger immune responses. By using tissue fragments from different patients, they were able to dissect the sequence of cellular and molecular events triggered by interferon-alfa (IFN-alfa), which involves the crosstalk between the colonic epithelium and immune cells in the lamina propria with induction of a Th1 T-cell response, culminating in epithelial cell apoptosis and subsequent intestinal barrier disruption.
Dr. Luciana H. Osaki

Dr. Luciana H. Osaki

Interestingly, IFN-alfa did not induce apoptosis in all human colonic fragments analyzed, showing that their culture model accounts for variability among individuals, recapitulating the heterogeneous response of cancer patients to IFN-alfa-based treatment who present with intestinal dysfunction as a side effect. The use of such models of human primary cell culture helps us develop a better understanding of how cytokines affect the GI mucosa, potentially leading to alternative targets for treatments. They also could be used to determine the individual patient differences underlying diverse responses to cytokines and drugs, which is particularly important to the advance of precision/personalized medicine.

Jason C. Mills, MD, PhD, and Luciana H. Osaki, PhD, are with the division of gastroenterology, departments of medicine, pathology and immunology, and developmental biology, Washington University, St. Louis. They have no conflicts of interest.



Genetics are probably to blame for why some patients have significant intestinal side effects from Roferon-A (interferon alfa-2a, recombinant – Roche) while others do not, according to a new French investigation reported in issue of Cellular and Molecular Gastroenterology and Hepatology.

They cultured intestinal wall samples taken from 20 colon cancer patients when they had surgery; none of them had been exposed to chemotherapy, radiation, or immunosuppressives. The team bathed the cells in IFN-alfa 2a and other biochemicals to see how they reacted. It was bench work, but the findings could eventually be useful if the team identifies the genetic risk factors for Roferon intestinal side effects and finds better options for patients at risk. Roferon is widely used for blood cancer, melanoma, viral hepatitis, and renal and hepatocellular carcinomas.

“IFN-alfa 2a elicited a rapid (24 hours) disruption of surface and crypt colonic epithelial cells via apoptosis that was variable in intensity among the 20 individuals studied. This apoptotic effect was dependent on the initiation of an IFN-gamma response … expressed in T cell–positive lamina propria cells,” the investigators said.

“IFN-alfa impairs human intestinal mucosa homeostasis by eliciting epithelial barrier disruption via apoptosis … The IFN-alfa–elicited impairment of intestinal mucosa homeostasis is heterogeneous among individuals,” Dr. Jarry and her associates wrote.

“This ex vivo finding parallels clinical observations of the interpatient variability of Roferon therapy side effects. … It has been reported that approximately 60% of patients with chronic hepatitis or cancer treated with Roferon have intestinal disorders, especially diarrhea,” they said.

The authors had no conflicts of interest. The work was funded by the University of Nantes.

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