This week on TIBDI! Gene expression signatures of anti-TNFα non-responders are investigated, breast milk oligosaccharides regulate developing immune responses, and an anti-CD3 antibody offers hope for T cell regulation in the gut.
Inflammatory Signatures of Anti-TNFα Non-Responders
Even though anti-TNFα therapy for Crohn’s disease (CD) patients is very effective, up to 40% of patients are or become non-responders. To find out if there were differences in gene expression between these groups of patients, Dr. Raquel Franco Leal of the Hospital Clinic in Barcelona Spain examined mRNA levels of inflammatory genes in these two populations. She found that treatment with anti-TNFα effectively regulated many cytokines and chemokine genes despite the clinical outcome. However, those that achieved a clinical remission also had a number of changes in many other genes including IL1B, S100A8 and CXCL1. In contrast, refractory patients continued to have deregulated genes associated with pathways inducing IL17A. Besides introducing new drugs targets, these results reemphasize the importance of IL-17 pathways in CD.
Developing Immune Systems Need Milk
The complex immunoregulatory mechanisms needed to protect and control the human gut are developed early after birth, and are catalyzed by the colonization of the intestinal tract with bacteria. Suspecting that breast milk may protect the early intestinal tract from unwanted inflammatory responses, Dr. Y. He and colleagues investigated human milk oligosaccharides from colostrum (cHMOSs). Using human fetal intestine explants, they were able to determine that cHMOSs significantly altered immune gene expression. Their model suggests that cHMOSs attenuate pathogen-associated receptor signaling, simultaneously lowering immune cell activation and enhancing pathways needed for clearance, regulation and tissue repair.
T cells likely play an important role in inflammatory bowel disease (IBD) by maintaining inflammatory responses. Finding a way to specifically reduce or deactivate these cells in IBD patients could be a possible therapy. Dr. Anna Vossenkämper, together her colleagues, experimented with this idea using a special anti-CD3 antibody called otelixizumab, which is known to induce tolerance. Using mucosal biopsies from IBD patients, she was able to determine that otelixizumab could decrease pro-inflammatory cytokine production and lower the activity of multiple immune pathways. The antibody’s effects were determined to be dependent on IL-10 expression.
- He, Y., Liu, S., Leone, S., & Newburg, D. S. (2014). Human colostrum oligosaccharides modulate major immunologic pathways of immature human intestine, 1–14. doi:10.1038/mi.2014.20
- Leal, R. F., Planell, N., Kajekar, R., Lozano, J. J., Ordas, I., Dotti, I., et al. (2014). Identification of inflammatory mediators in patients with Crohn’s disease unresponsive to anti-TNF therapy. Gut. doi:10.1136/gutjnl-2013-306518
- Vossenkämper, A., Hundsrucker, C., Page, K., van Maurik, A., Sanders, T. J., Stagg, A. J., et al. (2014). A CD3-specific Antibody Reduces Cytokine Production and Alters Phosphoprotein Profiles in Intestinal Tissues from Patients with Inflammatory Bowel Disease. Gastroenterology, 1–48. doi:10.1053/j.gastro.2014.03.049