**9. Concluding remarks**

602 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

secretory function

Egg i.p. A IFN-↓, IL-4↑, STAT6 dependent Elliott et al., 2003 Worm Ag i.p. AIFN-↓, IL-17↓, TGF-↑, IL-10↑ Ruyssers et al., 2009

Egg i.p. A IFN-↓, IL-10↑、TLR4↓ Zhao et al., 2009

13/TGF- independent

Infection (mixed) A TNF-↓ Bodammer et al., 2011

dependent, IL-10/STAT6 dependent

*Trichinella spiralis* Worm Ag i.r. A IL-1↓, iNOS↓, IL-13↑, TGF-↑ Motomura et al., 2009 *Schistosoma mansoni* Infection A IL-2↑, IL-4↑ Moreels et al., 2004

*Acanthocheilonema viteae* Cystatin i.p. A IL-10 producing M Schnoeller et al., 2008 *Toxascaris leonina* Galectin homologue i.p. A TGF-↑, IL-10↑ Kim et al., 2010

*Hymenolepis diminuta* Infection E Reardon et al., 2001

*Heligmosomoides polygylus* Infection A IL-17↓, IL-10 independent Elliott et al., 2004; Elliott et al.,

*Schistosoma japonicum* Egg i.p. A IFN-↓, IL-4↑, IL-10↑, Treg↑ Mo et al., 2007

Sutton et al., 2008

Hunter et al., 2005; Hunter et al., 2010; Johnston et al., 2010

Smith et al., 2007

2008

Colitis model Helminth Treatment Effect Proposed mechanism Refs

TNBS/DNBS-induced colitis *Ancylostoma caninum* Worm Ag i.p. A Ruyssers et al., 2009 *Heligmosomoides polygyrus* Infection A Mast cell-mediated, Neural control of

*Hymenolepis diminuta* Infection A TNF-↓, IL-10↑, IL-4↑, AAM-

DSS-induced colitis *Ancylostoma ceylanicum* Worm Ag / ES Ag i.p. A IFN-↓, IL-17↓, TNF-↓ Cançado et al., 2011

*Schistosoma mansoni* Infection (male only) A M dependent, Treg/IL-10/IL-4/IL-

Infection (mixed) N Egg Ag i.p. N

Egg Ag i.p. N

Oxazolone colitis *Hymenolepis diminuta* Infection E IL-5↑, Eosinophils↑ Wang et al., 2010

Colitis in TGF-RII DN mice *Heligmosomoides polygylus* Infection N TGF- signal dependent Ince et al., 2009 Rag/IL-10-/- Tcell transfer *Heligmosomoides polygylus* Infection A Modulation of DC function Hang et al., 2010

**8. Clinical trials of parasitic helminths against immunological disorders** 

The administration of non-pathogenic or hypo-virulent parasitic worms could be considered for the treatment of immunological disorders. Several clinical trials using parasitic worms have been and are currently being conducted. Significant therapeutic effects have been confirmed in some of these studies. Weinstock's group conducted trials with *Trichuris suis* (porcine whipworm) ova (TSO) against CD (Summers et al., 2005a) and UC (Summers et al., 2005b), and demonstrated significant efficacy. TSO is also being tested for MS and promising results have been obtained in a phase I trial (Fleming et al., 2011). Regarding allergic disorders, Bager et al. (2010) found no therapeutic effect of TSO on allergic rhinitis. However, Summers et al. (2010) critically commented on the report that it was premature to conclude that TSO is ineffective on allergic rhinitis because the TSO treatment was too late and not sufficient. *Necator americanus* (Hookworm) is also under clinical trials for asthma (Feary et al., 2010) and CD (Croese et al., 2006). The advantage of this worm is its long life in the host (at least 6 years) and no need for repeated inoculation (Elliott and Weinstock, 2009). The parasite was well-tolerated without severe adverse effects on asthmatic patients, but a safe dosage of the parasites (10 infective larvae) did not show significant therapeutic efficacy

↓:down-regulation, ↑:up-regulation A: Amelioration, E: Exacerbation, N: No effect

Table 4. Effects of parasitic helminths on experimental colitis.

Piroxicam-induced colitis in IL-10 deficient mice

(Feary et al., 2010).

There are two ways of developing parasite-based biomedicines for clinical use. One approach is the direct applications of non-pathogenic/hypo-virulent viable helminths to patients, as introduced in section 8. In addition to TSO and hookworms, other hypo-virulent helminths could be considered for human application. However, before clinical trials, sufficient accumulation of epidemiological and experimental evidence of their therapeutic efficacy is required. Hypo-virulent intestinal nematodes (e.g. *Trichostrongylus* spp.), intestinal trematodes (e.g. *Metagonimus* sp.) and intestinal tapeworms (e.g. *Hymenolepis diminuta*) may become candidates for such studies in the future. It is also essential that the parasites can be maintained in domestic or experimental animals. This is because parasites that infect only humans cannot be maintained and expanded efficiently for clinical use. Another way of developing parasite-based biomedicines comes from the identification of effector molecules of parasites. Considerable numbers of immunomodulatory molecules have been identified from helminths (Harnett W & Harnett MM, 2010). The majority have shown therapeutic effects on experimental autoimmunity or allergy. Some investigators reported that viable parasites were superior to administration of the antigens of parasites (Hunter et al., 2010; Bodammer et al., 2011; Osada et al., 2010) in therapeutic efficacy. In addition, there is still considerable controversy over the roles of regulatory cells (e.g. Treg, Breg or AAMΦ) and regulatory cytokines (e.g. IL-4, IL-10, TGF-β) in helminth-induced immunomodulation. Therefore, further investigation is needed to elucidate the immunomodulatory mechanisms of viable parasite infections, and new findings obtained there should help to establish an optimal screening system for anti-autoimmune/antiallergic substances from parasitic helminths.
