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“There’s a lot more work to be done.” – Aida Habtezion

Discovering the significance of GPR15 for treating IBD.

In the beginning of her career at Stanford, Habtezion was a fellow in the lab of Eugene Butcher, MD (professor, pathology). “Being in Dr. Eugene Butcher’s lab, learning about leukocyte trafficking, I became interested in why patients with ulcerative colitis would have their disease limited to the colon. Would leukocytes have specific things that targeted them to the colon and not to the small intestine? Do these lymphocytes or T cells have a receptor that might be guiding them to the colon rather than the small intestine?”

Pursuing that question led to some interesting findings.

“Several years ago we did some microarray studies and we found G-protein coupled receptor 15 (GPR15) to be highly upregulated in the colon of the mouse. Very little is known about GPR15 because it is an orphan receptor; it had been previously described as an HIV co-receptor. We got some GPR15 transgenic mice from a group at NYU that had GPR15 frozen embryos, and recovered the frozen mouse embryos in response to our proposal and request to evaluate GPR15 in colon lymphocyte homing. “

Working with these new transgenic mice, Habtezion and Butcher soon discovered an anomaly. “Even though GPR15 was highly expressed on regulatory T cells in the mouse colon, when we started to look at the human colon it was very different. We did not find GPR15 to be expressed in the human colon regulatory T cells, and we were quite surprised that the expression pattern was so different between the species, especially because we use the mouse model to study IBD in humans.“

Soon thereafter, Habtezion transitioned to her own lab and continued to study the unexpected mouse-man difference together with the Butcher lab.  “We started to look closely at the gene expression and that led us to discover differences in the transcription factors that regulate how T cells become either effector T cells or T-regs. Here there was a difference between the mouse and the human with a point mutation that disrupts GATA3 binding to GPR15 enhancer activation in the mouse. This was the first example of how defined differences in transcription factor binding could lead to species differences in targeting functionally distinct T cell populations.”

A research group in London led by Richard Jenner had already looked at transcription factors but not at GPR15. They had published their findings in PNAS in 2009. Contacted by the Habtezion and Butcher labs, “they went back and looked in their gene sequence analysis and they were able to help us confirm our findings. It was a nice collaboration with this group that works on gene sequence analysis of transcription factors as master regulators of T cell differentiation independent of trafficking receptors.”

The results of Habtezion’s research were published in Nature Immunology in December. According to Habtezion, the co-senior author, “the three important findings in this paper are: 1) that GPR15 can be expressed in effector T cells that can mediate colitis in a mouse; 2) although highly expressed in mouse T regs, that doesn’t seem to be the case in humans (we looked at different tissue specimens including IBD patients and colon cancer patients); 3) this led us to look at transcription factors that regulate these T cells to become either T regs or TH2 cells in the two species, and that’s where we found that there were quite dramatic differences between mouse and human.”

Is there likely to be a clinical application for this finding? Habtezion believes so.

“Sometime in the future we may find that GPR15 is a target for therapeutic intervention treating colitis. Before we have anything to take to the clinic, however, we need to do more study using human samples and identify the ligand for GPR15. There’s a lot more work to be done.”

A recent editorial in Nature Immunology seems to echo the possibility of a clinical application targeting GPR15.

Read full article here.

Posted on: January 9 2020

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