Table 1.
Experimental and clinical studies of helminth-derived therapies in autoimmune diseases
| Inflammatory bowel disease | Mice | Trichinella spiralis [141,147,153] | Attenuates DNBS-induced colitis |
| ↑ IL-4, IL-13, TGF-β and ↓ IFN-γ, IL-1β, MPO activity, iNOS expression | |||
| Schistosoma mansoni [142,143,145] | Prevents or attenuates TNBS- and DSS-induced colitis | ||
| ↑ IL-4, IL-10, F4/80+ macrophages and ↓ IFN-γ | |||
| Heligmosomoides polygyrus [122,123] | Prevents Rag IL-10−/− T-cell transfer model of colitis | ||
| ↑ tolerogenic DC and ↓ IFN-γ, IL-17 | |||
| Hymenoleptis diminuta [144,148] | Attenuates DNBS-induced colitis | ||
| ↑ IL-10 | |||
| Schistosoma japonicum [146] | Attenuates TNBS-induced colitis | ||
| ↑ IL-4, IL-5, IL-13, Treg, and ↓ IFN-γ | |||
| Clonorchis sinensis [135] | Attenuates DSS-induced colitis | ||
| ↑ IL-10, IL-10+ F4/80+ macrophages and ↓ TNF-α | |||
| Human | TSO [149-152] | CD: open-label study: 79.3% responded, 72.4% remitted at 24 weeks | |
| UC: placebo-controlled trial: 43.3% responded 12 weeks versus 16.7% in placebo group; no significant difference in remission rates | |||
| CD: phase 2 TRUST-I trial: no significant differences between TSO and placebo groups | |||
| Necator americanus [155] | Improvement CDAI in 5/9 patients at 20 weeks and 3/5 at 45 weeks | ||
| Mild adverse events | |||
| Multiple sclerosis | Mice | Schistosoma mansoni [158,160,162] | Reduces incidence and attenuates EAE |
| ↑ IL-4, IL-10, TGF-β and ↓ IFN-γ, TNF-α, IL-12, and CNS inflammatory cell infiltration | |||
| Trichinella spiralis [104,121,157,163] | Attenuates EAE | ||
| ↑ IL-4, IL-10, TGF-β, Treg, tolerogenic DC and ↓ IFN-γ, IL-17 | |||
| H. polygyrus [129] | Prevents EAE by transfer of B-cells from IL-10−/− infected mice | ||
| Trichinella pseudospiralis [106] | Delays and attenuates EAE ↑ IL-4, IL-5, IL-10 and ↓ TNF-α, IFN-γ, IL-1β, IL-6, IL-17 | ||
| Schistosoma japonicum [164] | Attenuates EAE | ||
| ↑ IL-4 and ↓ IFN-γ and CNS inflammation | |||
| Fasciola hepatica [161] | Attenuates EAE ↑ IL-10, tolerogenic DC, M2-macrophages, IL-10 secreting T-cells and ↓ IFN-γ, IL-17 | ||
| Taenia Crassiceps [159] | Attenuates EAE | ||
| ↑ IL-4, IL-10, M2-macrophages and ↓ TNF-α, IL-17, iNOS expression and CNS inflammation | |||
| Human | Hymenoleptis nanan, Trichuris trichura, Ascaris lumbricoides, Strongyloides stercolaris, Enterobius vermicularis [131,165,166] | 12 naturally infected MS patients and 12 controls, follow-up 7.5 years | |
| ↓ relapses, disability scores, MRI activity, and ↑ IL-10, TGF-β, Treg, Breg and ↓ IFN-γ, IL-12 in infected patients | |||
| Anti-helminthic treatment ↑ clinical and radiological activity | |||
| TSO [167] | 5 patients with relapsing-remitting MS | ||
| ↓ mean number of new MRI lesions | |||
| Rheumatoid arthritis | Mice | Acanthocheilonema vitae (ES-62) [108,128,169,171-173] | Reduces incidence and attenuates CIA |
| ↑ IL-10, late IL-22, tolerogenic DC, Breg and ↓ TNF-α, IFN-γ, IL-6, IL-17, early IL-22, IgG2a | |||
| Immunomodulatory effects related to PC moiety | |||
| Schistosoma mansoni [107] | Attenuates CIA | ||
| ↑ IL-4, IL-10 and ↓ TNF-α, IFN-γ, IL-1β, IL-6, IL-17A, IgG2a | |||
| Hymenoleptis diminuta [174] | Attenuates Freund’s complete adjuvant-induced arthritis | ||
| Protection abrogated in mice lacking T- and B-cells or IL-4Rα or IL-10 | |||
| Fasciola.hepatica [175] | Reduces incidence and attenuates CIA | ||
| ↑ IL-10, TGF-β, tolerogenic DC, Treg and ↓ TNF-α, IL-17A, IgG2a | |||
| Schistosoma japonicum [176] | Attenuates CIA | ||
| ↑ IL-10, Treg, IgG1 and ↓ TNF-α, IFN-γ, IL-1β, IL-6 Th-17 cells, IgG2a | |||
| Heligmosomoides polygyrus and N. brasiliensis [177] | Reduces incidence and attenuates spontaneous arthritis in MRL/lpr mice | ||
| ↑ IL-4, IgG1 | |||
| Type-1 diabetes | Mice | Schistosoma mansoni [111-113,178,179] | Reduces incidence or prevents diabetes in NOD mice |
| ↑ IL-4, IL-5, IL-10, IL-13, TGF-β, tolerogenic DC, Treg, V alpha 14i NKT cells | |||
| Prevents class switch from IgM to IgG anti-insulin autoantibodies | |||
| ω1 glycoprotein secreted by S. mansoni ova responsible for its effects | |||
| Heligmosomoides polygyrus [109,180] | Prevents and reduces severity of diabetes in NOD mice | ||
| ↑ IL-4, IL-10, IL-13, Treg and ↓ pancreatic insulitis | |||
| Trichinella spiralis [109] | Prevents diabetes in NOD mice | ||
| ↑ IL-4 and ↓ pancreatic insulitis. No change in IL-10 and IFN-γ | |||
| Litomosoides sigmodontis [110,115] | Prevents diabetes in immunocompetent and IL-4 deficient NOD mice | ||
| ↑ IL-4, IL-5, IgG1, Treg and ↓ pancreatic insulitis | |||
| Dirofilaria immitis [181] | Prevents diabetes in NOD mice | ||
| ↑ IgE. Prevents class switch from IgM to IgG anti-insulin autoantibodies | |||
| Celiac disease | Human | Necator americanus [183,184] | No significant change in symptom severity at the gluten challenge following treatment |
| ↓ IFN-γ, IL17A | |||
| Systemic lupus erythematosus | Mice | Schistosoma mansoni [185] | Change glomerulonephritis phenotype from diffuse proliferative to membranous pattern |
| ↑ IL-4, IL-5, IL-10, and TGF-β | |||
| Graves’ disease | Mice | Schistosoma mansoni [186] | Prevent Grave’s disease development |
| ↓ IFN-γ, IgG2a, anti-TSHR antibodies | |||
| Psoriasis | Mice | Schistosoma mansoni [187] | Prevent psoriatic skin lesions in fsn/fsn mice |
| ↑ IL-13 and ↓ IFN-γ |
Breg, B-regulatory cells; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; CIA, Collagen-induced arthritis; CNS, Central nervous system; DC, Dendritic cell; DNBS, Dinitrobenzene sulfonic acid; DSS, Dextran-sodium-sulfate; EAE, Experimental autoimmune encephalitis; iNOS, Inducible nitric oxide synthase; IFN, Interferon; IL, Interleukin; MPO, Myeloperoxidase; MRI, Magnetic resonance imaging; MS, Multiple sclerosis; NKT cells, Natural killer T-cells; NOD, Non-obese diabetic; PC, Phosphorylcholine; TGF, Transforming growth factor; Th, T-helper cells; TNBS, Trinitrobenzene sulfonic acid; TNF, Tumor necrosis factor; Treg, T-regulatory cells; TSHR, Thyroid stimulating hormone receptor; TSO, Trichuris suis ova; UC, Ulcerative colitis.