COLORADO SPRINGS — The “absolutely astounding” recent success in treating Crohn's disease by feeding patients live ova of the pig whipworm opens the door to an exciting new approach to treating autoimmune diseases, J. John Cohen, M.D., declared at a meeting of the Colorado Chapter of the American College of Physicians.
Crohn's disease is characterized by a marked imbalance between T helper cell type 1- and T helper cell type 2- derived cytokine activity. Worm therapy aimed at blunting the proinflammatory T helper cell 1 (Th1) overactivity that defines the disease proved remarkably effective and safe in the groundbreaking initial 24-week open-label study conducted at the University of Iowa.
“I've got no idea whether pig whipworm eggs are going to catch on in clinical practice, but we're now beginning to realize that whether the Th1 or Th2 response dominates in response to a particular antigen determines what the outcome of your infection is going to be. And it looks from this study like we're at the very beginning of being able to manipulate the direction in which the body's immune responses will go,” said Dr. Cohen, professor of immunology at the University of Colorado, Denver.
The Iowa study, led by digestive diseases division head Robert W. Summers, M.D., and funded by the Crohn's and Colitis Foundation of America, involved 29 patients with severe longstanding Crohn's disease who consumed pig whipworm ova every 3 weeks. At 24 weeks' follow-up, the disease response rate was nearly 80%, and the remission rate was 72% (INTERNAL MEDICINE NEWS, July 1, 2004, p. 65).
Patient compliance was high. There were no treatment side effects, even among the 14 patients on concurrent immunosuppressive therapy with corticosteroids and/or azathioprine. In fact, subgroup analysis suggested patients on immunosuppressive drugs responded better to worm therapy, as did those with an intact terminal ileum. The Iowa group noted that the observed response rates were far greater than would be expected with placebo and concluded that their data warrant a definitive, double-blind, placebo-controlled trial (Gut 2005;54:87-90).
“I think this is an incredible paper,” Dr. Cohen said.
He explained that this novel therapeutic approach followed from the epidemiologic observation that inflammatory bowel disease is largely confined to the developed world, where helminthic colonization is uncommon, and is rare in developing nations, where a great many people carry parasitic worms in the gut.
Cytokines produced by Th1 cell activation—namely interleukin 2 and interferon-γ—suppress Th2 cells, while the Th2 cytokines (interleukins 2, 5, and 10) exert an anti-inflammatory effect by suppressing Th1. Helminthic infection triggers a powerful Th2 response, both in animal studies and now in the Iowa study participants with Crohn's disease.
Worm infection also appears to activate T regulatory cells. These cells, which comprise about 5% of all T helper cells, produce transforming growth factor-β, which markedly suppresses other T cells' immune responses.
“A large focus of future research will be on how to deliver antigen specifically to T regulatory cells to downregulate unwanted immune responses. In the meantime, that's where the worms come in,” Dr. Cohen said.
Swallowing the ova of the pig whipworm, Trichuris suis, results in brief, self-limited colonization in humans without causing disease. The ova used in the study were collected from pathogen-free pigs and treated to render them free of bacteria.
In a commentary that accompanied the Iowa study, Graham Radford-Smith, M.D., of Royal Brisbane and Women's Hospital, hailed it as “important and innovative.” But he offered a cautionary note: Animal studies as well as a single recent clinical case report suggest helminthic coinfection with Campylobacter jejuni and perhaps other pathogens may result in septicemia and other serious adverse effects. This raises the possibility that candidates for worm therapy might need to be screened for carriage of selected pathogens.
Such concerns could be bypassed by identifying worm antigens that are responsible for the therapeutic effect and then administering the purified molecules orally. One possible candidate is the schistosome oligosaccharide lacto-N-neotetraose, according to Dr. Radford-Smith (Gut 2005;54:6-8).