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Type-2 Immunity During Therapeutic Helminth Infection


Clinical and laboratory studies have demonstrated that helminth infection can ameliorate intestinal inflammation driving inflammatory bowel diseases (IBD). Nonetheless, the cellular and molecular mechanisms mediating the benefits of helminth exposure remain poorly understood. Host immune strategies that have evolved to tolerate chronic helminth infection, including mechanisms for tissue repair and the mitigation of inflammatory pathology, are likely at play. These mechanisms are largely orchestrated by T-helper (TH)2 cells.

The studies described here investigate the immunologic mechanisms underlying helminthic therapy. First, in an ulcerative colitis patient who achieved clinical remission after infecting himself with Trichuris trichiura, we described the induction of a TH2 response in the colonic mucosa following helminth exposure as well as the expression of IL-22, a cytokine known to promote intestinal barrier functions. The severely impaired mucus production in the inflamed colon was restored, suggesting that disease remission was associated with repair of the mucosal barrier. Similarly, in juvenile rhesus macaques suffering from chronic idiopathic colitis, a putative model for IBD, we found that symptomatic improvement following T. trichiura exposure was associated with a mucosal TH2 response and reduced bacterial attachment to the intestinal epithelium.

We also explored the role of retinoic acid (RA), a vitamin A metabolite that regulates T cell function and is vital for mucosal epithelial maintenance, during helminth infection in mice. RA synthesis was induced during Schistosoma mansoni infection and played a critical role in the TH2 response. Alternatively-activated macrophages were found to be an important source of RA synthesis in this context.

The findings presented here support the broad conclusion that TH cell responses in the intestinal mucosa elicited by helminth infection, including the canonical TH2 cytokines as well as IL-22, support mucosal barrier functions that avert pathogenic inflammatory responses to commensal bacteria. The innate immune response elicited by helminth infection drives RA synthesis, which is critical for the development of TH2 immunity. These studies provide insights into the mechanisms underlying helminthic therapy, and support the development of IBD therapies that target mucosal repair.

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