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Table 1 Experimental and clinical studies of helminth-derived therapies in autoimmune diseases

From: Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications

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

  1. 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.