Helminth infections and their metabolic products suppress autoimmune demyelinating disease in Multiple Sclerosis (MS) and in its laboratory model EAE. Helminth infection ameliorates clinical score in EAE laboratory model and in MS patients in association with an increase in the number of regulatory T cells and strong Th2 responses also alters the regime of Th1/Th2; Th3 to IL-4, IL-10, IL-12, TGF-β, and IFN-γ production, Th7 and the IL-7/IL-7R signaling, and Th9/IL-9 signaling Th-17 responsive secreting CD4 T cells (Th17 cells) in CNS of MS and EAE. Parasite-driven protection is associated with regulatory T cell induction and anti-inflammatory cytokine secretion increases TGF-β and IL-10 levels of expression of TLR2. Different immunomodulatory properties are involved during the helminth infection as an alternative therapeutic application. A clinical trial with Trichuris suis ova (TSO) have shown as potential alternative treatment of MS patients that can be used as a treatment for Multiple sclerosis. 

MS Multiple Sclerosis; EAE Experimental autoimmune encephalomyelitis;TGF-β Transforming growth factor (TGF)-β; CNS central nervous system; HES Hypereosinophilic syndrome; TLR2 Toll-like receptor 2; TSO Trichuris suis ova;  CD4+ T helper cells or T4 cells;  CD8+  Cytotoxic T cells; GM-CSF Granulocyte-macrophage colony-stimulating factor ; IL-2 Interleukin-2; IL-4 Interleukin 4; IL-7 Interleukin 7; IL-9 Interleukin 9;IL-15 Interleukin-15;  IL-21 Interleukin 21; Tfh T follicular helper (TFH) cells; Th-1 Type 1 helper (TH1) cells; Th-2 T helper 2 (T H 2) cells; Th-3 TGF-β-producing Ag-specific CD4+ T cells; Th-7 pathogenic T helper type 17 (T(H)17) cells; Th-9 T helper type 9 cells, CD4+IL-9+IL-13−IFNγ − ; Th-17 T helper 17 (Th17) cells; IFN-γ Interferon gamma; SEA soluble egg antigens; NTs neurotrophins;; IL-10 Interleukin 10; CD25+CD4+ FoxP3+ CD4 + CD25 + Foxp3 + natural regulatory T (nTreg) cells; ELISPOT enzyme linked  immuno sorbent  spot (ELISpot) assay; Th T helper cells (Th cells); TFs  Transcription factors (TFs);  RORγt The nuclear receptor retinoid-related orphan receptor gamma t (RORγt); Treg Regulatory T (T Reg) cells; IL-7R interleukin-7 receptor; IL-23 Interleukin 23 (IL-23); IL-23R interleukin-23 receptor; STAT3 signal transducer and activator of transcription 3; γδ Gamma Delta (γδ) T Cells;  Tregs Regulatory T cells (Tregs); PCR polymerase chain reaction (PCR); IL-12p40 IL-12p40 is a subunit of IL-12 and IL-23; HES H. polygyrus adult excretory–secretory (HES);   IL-4Rα interleukin (IL)-4 receptor alpha (IL-4Rα);  GATA3+  transcription factor GATA-binding protein 3 (GATA3) positive; ST2 member of the interleukin 1 receptor family with 2 main isoforms;  IL-17A Interleukin-17 (IL-17, also known as IL-17A); IL-33 Interleukin-33 (IL-33); IL-25 Interleukin-25 (IL-25); TSLP Thymic stromal lymphopoietin (TSLP);  RMS  Relapsing-remitting MS; rRNA ribosomal RNA (rRNA); ESL1 excretory-secretory products (ES L1); TLR2 Toll-like receptors (TLRs); IL-12 Interleukin-12 (IL-12);  DCs dendritic cell (DC); SPs Soluble products; HIM helminth infectted MS; HIT helminth immunotherapy (HIT);  TAM  TAM receptors are a family of  receptor  tyrosine kinases;  GAS6 growth arrest-specific gene 6; CD11bhigh CD11bhighB cells are a heterogeneous  sub population  of B cells; TLRs Toll-like receptors (TLRs); TSO Trichuris suis ova.

Helminth parasites infect almost one-third of the world's population in tropical regions. Currently, there is much interest to study in helminth-associated immune regulation suppresses autoimmune demyelinating disease in multiple sclerosis (MS) and in its laboratory model (EAE) [1]. It is believed that auto-reactive T helper cells, particularly the Th1 and Th17 subsets, enter and are re-activated in the central nervous system (CNS) resulting in the recruitment of additional T cells and macrophages to establish inflammatory lesions. These lesions result in loss of myelin, damaging oligodendrocyte and axon result as seen symptoms in MS patients [2]. CD4+ T helper cells initiate MS disease where B cells, CD8+ T cells, and natural killer cells have been implicated drivers of disease pathogenesis [3]. T cells which secrete IL-17 or IL-17 and IFN-gamma infiltrate the CNS prior to the onset of clinical symptoms of EAE, where they may mediate CNS inflammation, in part, through microglia activation. The role of Th17/Th1 Th17 cells plays an essential role in autoimmune CNS inflammation, perhaps mainly in the initial phases of the disease. Th1 cells likely contribute to pathogenesis, with their role possibly more pronounced later in disease [4, 5].  CD4+ T helper cells are well-established as important for initiating demyelinating disease pathogenesis and Th1 cytokines, including IL-12 and the Th17-driving cytokine IL-23, as well as GM-CSF and IL-1, are responsible for the disease via an IL-23-independent pathway in a severe form [6, 7]. 

Immune response of helminth infection and demyelinating disease

The IL-2 family includes IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines. IL-2 family members participate in autoimmune demyelinating diseases by CD4+ and CD8+ T cells and play a crucial role in immunity. Helminth, such as Strongyloides stercoralis during infection in humans, shows IL-2, IL-7 and IL-15 levels significantly increased, whereas IL-4 and IL-9 levels were significantly decreased following anthelmintic treatment [8]. IL-21's role in establishing Th2 mediated immunity has been documented in studies of mice infected with Nippostrongylus brasiliensis, Heligmosomoides polygyrus, and Schistosoma mansoni. 

The importance of IL-21 in Th2 mediated immunity has been shown to play a role in sustaining Tfh responses in the context of parasitic infections in S. mansoni and H. polygyrus infection Th2 response by releasing IL-4 [9-12].  Th1/Th2 response: Helminthes down regulate the pro-inflammatory Th1 cytokines including, interleukin-12 (IL-12), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), while promoting the production of regulatory Th2 cytokines such as IL-10, IL-4, IL-5 and IL-13. Protective immunity against intestinal helminthes is associated with development of type 2 responses. However, in some host-intestinal helminthes combinations of local Th1 responses are initiated inducing chronic levels. Cytokines produced by T helper (Th) cells are of critical importance for the outcome of many infectious diseases. The Th1/Th2 dichotomy has proven useful in the analysis of immune responses to infections. 

It was believed that helmetinths only suppress T-helper Type 1 (Th1) cells and induce T-helper Type 2 (Th2) cells. The regulatory effects of parasitic worms of autoimmune diseases caused by Th1 cells are only explained by this hypothesis. Despite this, helminthes also control diseases that are caused by Th2; the suppression of various types of parasitic worms is always in favor of regulatory T (Treg) cells. EAE model of MS direct showed suppression by chronic Schistosoma mansoni infection. Inflammatory cells, specifically macrophages, infiltrate the CNS in S. mansoni infected immunized mice significantly less than uninfected mice (13). Soluble egg antigens (SEA) from Schistosoma japonicum suppressed EAE through up-regulating T helper-2 (Th2) immune responses. In schistosome-infected mice, the production of IFN-γ, nitric oxide, and tumor necrosis factor alpha by splenocytes was significantly decreased compared to uninfected mice [14]. While immune cells, especially Th2 cells, can produce and secrete a variety of NTs (Neurotrophins) resulting in neuroprotective immunity, NTs can also modulate immune responses by augmenting Th2 responses and down regulate Th1 responses. Moreover, in the central nervous system of chronic schistosomiasis, NGF is increased [15]. 

Th3 response: Th3 cells are subset of T lymphocytes known as immunoregulatory and immunosuppressive functions. The primarily function of Th3 is secreting the anti-inflammatory cytokine transforming growth factor beta (TGF-β). Role of TGF-β1 in the differentiation of naïve CD4+ T cells into Th1, Th2, Th17, Treg, and Tfh cells. TGF-β1 negatively regulates the differentiation of naïve CD4+ T cells into Th1 and Th2 cell subsets by affecting the expression of lineage-defining transcription factors and cytokines. It promotes the differentiation and expansion of Th17, Treg, and Tfh cells. Th3 has been described as CD4+FOXP3- regulatory T cells in both mice and humans. Th3 cells were first described as oral toleration in the EAE, and later, CD4+CD25-FOXP3-LAP+ cells were induced in the gut by oral antigen through T cell receptor (TCR) signaling. The association between parasite infection and immune responses in multiple sclerosis has been observed in patients with associated eosinophilia. The development of IL-10 and TGF-β as well as the induction of CD25+CD4+ FoxP3+ T cells, suggest that regulatory T cells induced during parasite infections can affect the progression of MS. Interleukin (IL)-4, IL-10, IL-12, transforming growth factor (TGF) -beta, and interferon-gamma production by myelin basic protein-specific peripheral blood mononuclear cells were studied by enzyme-linked immunospot (ELISPOT), where FoxP3 and Smad7 increase production of IL-10 and TGF-β together with induction of CD25+ CD4+ FoxP3+ T cells. This suggests that regulatory T cells induced during parasite infections alter the course of MS [16]. 

Th7 response: Interleukin-7 (IL-7), a molecule known for its growth-promoting effects on progenitors of B cells, remains one of the most extensively studied cytokines. It plays a vital role in health maintenance and disease prevention, and the congenital deficiency of IL-7 signaling leads to profound immunodeficiency. IL-7 contributes to host defense by regulating the development and homeostasis of immune cells, including T lymphocytes, B lymphocytes, and natural killer (NK) cells. In EAE, T-cell-mediated autoimmune disease involving effector T helper (Th) subsets such as Th and Th7. Recently, Th7 cells have been shown to play a major role in many autoimmune and other inflammatory diseases. The development of Th subsets is controlled by the transcription factors (TFs). TFS are required for Th17 cell development essential by RORγt and STAT3. Transcription factors attenuate play a major role in the development of other Th or regulatory T cell (Treg) lineages such as T-bet and Foxp3 with the Th17 TFs [17]. The IL-7/IL-7R signaling axis is involved in cell survival, and any disruption of this pathway has been linked to an increased risk of MS. Th17 cells from mice with EAE express high levels of IL-7Rα compared with Th1 cells. IL-7/IL-7R signaling is implicated in the dynamics of Th17 and Th1 cells during CNS autoimmunity [18]. 

Th9 response: Th9 cells are a sub-population of CD4+T cells that produce interleukin-9 (IL-9). This sub-population of CD4+ cells of T helper type 9 cells, CD4+IL-9+IL-13−IFNγ.  They play a role in defense against helminth infections and in autoimmunity. The secretion of IL-9 from Th9 cells is a signature cytokine that contributes to multiple classes of inflammatory diseases. Schistosomiasis is characterized by important roles played by Th1, Th2, Th17, Treg, and Tfh cells. There was a substantial increase in Th9 cell proliferation and IL-9 levels compared to normal controls in mice infected with S. japonicum [19]. IL-9 binds to a heterodimeric receptor consisting of the IL-9 receptor (IL-9R) and a common γ chain also presents in IL-2, IL-4, IL-7, and IL-15 receptor complexes. IL-9 affects the activity of multiple cell types in the immune compartment and central nervous system (CNS).   IL-9 initially implicated in type 2 inflammations in EAE and MS [20]. 
Th17 response: Th17 (T helper 17 cells) is a subset of pro-inflammatory T helper cells, related to T regulatory cells. Th17s actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17s cells play an important role in maintaining mucosal barriers as protective and non-pathogenic Th17 cells termed as Treg17 cells. Helminth infection or helminth-derived protects against the development of autoimmune diseases associated with anti-inflammatory innate immune responses whereas IL-17-secreting γδ T cells play a key pathogenic role in CNS autoimmune disease. IL-17-secreting CD4 T cells (Th17 cells) are found at high levels in CNS lesions of MS patients and similarly in the brain and spinal cord of EAE induced mice. Gamma-delta provides an early source of IL-17 and promoting development of Th17 cells. Human Th17 cells can be identified as CCR2+ CCR5- memory CD4+ T cells. 
Patients with concurrent natural helminth infections and MS condition (HIMS) had an increased expression of the negative regulatory TAM receptors in antigen-presenting cells their agonist GAS6 in circulating CD11bhigh and CD4+ T cells compared to patients with only MS. The Th17 subset was reduced in patients with HIMS with a subsequent down regulation of its pathogenic genetic program. Moreover, these CD4+ T cells promoted lower levels of the co- stimulatory molecules CD80, CD86, and CD40 on dendritic cells compared with CD4+ T cells from patients with MS, an effect that was GAS6-dependent. In HIMS patients, IL-10+ cells showed higher levels of GAS6 expression levels than Th17 cells, and preventing GAS6 binding resulted in an expansion of Th17 effector genes. Various human autoimmune diseases such as MS relay on the IL-23/Th17 axis for their pathogenesis.  CCR2 on Th17 cells could be a potential therapeutic target in MS [21-25]. 

Helminth infections and their products suppress demyelinating disease Helminthes evoke immune regulatory pathways often involving dendritic cells, regulatory T cells, and macrophages that help to control the disease. Helminth infection in experimentally induced EAE mice with Schistosoma mansoni showed regulatory macrophages capable of modulating CNS inflammation [26]. EAE mice immunizing with egg antigens from either S. mansoni or S. japonicum suppressed disease progression by inducing Th2-deviation and IL-4 production and also reduce MOG-specific Th1 and Th17 cytokines. Schistosoma mansoni eggs penetrate the endothelium and migrate to the intestinal lumen of mice to continue the lifecycle. This process is dependent on an intact host CD4 T helper (Th) cell response to egg antigens [27-28]. The ameliorating effect of S. mansoni ova treatment is regulated by STAT6 in a critical manner. Real-time PCR results showed that transcript levels of IL-12p40, but not IFN- γ, were dramatically reduced in the spinal cords. Immune response is also associated with the pathology of allergic diseases such as asthma, particularly when Schistosoma mansoni or its products influences the development of atopic asthma [29]. 

Heligmosomoides polygyrus, another intestinal helminth parasite, is also ameliorating EAE when using excretory/secretory products (HES). The disease severity in an IL-4Rα-dependent manner with increased Tregs, GATA3+ and ST2+ cells and reduced RORγt+ and IL-17A cell responses, and lower myeloid cell infiltration into the CNS.  The therapeutic effect of the nematode of L4 stage shows almost completely attenuates the clinical severity and pathological signs of EAE [30]. Dicrocoelium dendriticum (Dicrocoeliidae, Platyhelminthes) eggs showed prophylactic effect with a significant decrease in IL-17 and an increase in TGF-β cytokine in the treatment group compared to the EAE control group. The mRNA expression of disease-associated cytokines decreased, and the anti-inflammatory cytokines increased [31]. 

Although most of helminths (trematode, cestode and nematode) ameliorate the severity in autoimmune diseases, but not all parasites are protected in case of multiple sclerosis, diabetes, and inflammatory bowel diseases [32]. Helminth parasite molecules have unique advantages for the treatment of immunological disorders. For examples, soluble products of T. suis, S. mansoni and T. spiralis suppress TNF-α and IL-12 secretion by TLR-activated human DCs.  Where T. suis and S. mansoni strongly enhance expression of OX40L, filarial parasite product which is antigen-specific T cells hypo-responsiveness is mediated particularly by regulatory cytokines IL-10 and TGF-β. 

Multiple sclerosis therapy with helminth infection 

The possibility of treating multiple sclerosis with live helminths or helminth products has been explored in animal models, natural human infections, and phases 1 clinical trial. Helminth therapy has been considered safe and has generally been favorable in clinical, magnetic resonance imaging, and immunological outcomes so far but adverse effects are always possible, particularly with live parasitic administration [33, 34]. Helminth colonization alters the intestinal microbiota composition that leads to suppression of intestinal inflammation. When epithelial cells are exposed to potentially threatening external stimuli such as allergens, bacteria, viruses, and helminths, they instantly produce "alarmin" cytokines, namely, IL-33, IL-25, and TSLP.  These alarmins strongly stimulate type-2 immune cells, including eosinophils, mast cells, dendritic cells, type-2 helper T cells, and type-2 innate lymphoid cells [35]. In animal models and human studies also, helminths or their antigens have shown to be protected against severe autoimmune and allergic disorders by declining the intensity of inflammatory reactions and improve the clinical symptoms of the patients as potential application [36,37] 

The immunogenic vaccines comprised of a self-antigen plus a Th2 adjuvant either free or conjugated. Such vaccines alleviate autoimmunity by switching the immune response against the self-antigen from a damaging pro-inflammatory Th1/Th17 to an anti-inflammatory Th2 immunity. Glatiramer is effective in the treatment of multiple sclerosis but not shown efficacy in other autoimmune diseases. The development of a vaccine to treat and/or prevent autoimmune conditions while inducing anti-inflammatory immunity and does not abrogate pro-inflammatory Th1/Th17 immunities. The immune response against Schistosoma mansoni requires different mechanisms of memory T cells to manipulate immunomodulatory pathogen to protect the host from the infection [38-41]

It is important to understand the helminth-associated changes in gut microbiota composition and parasitic worms. This has a link to imbalances in gut microbial communities in RMS patients when subjected to placebo treatment. Bacterial 16S rRNA high-throughput sequencing results revealed a significant decreased in alpha diversity in the faecal microbiota of PBO compared to Necator americanus infected subjects. There was a significant difference in the bacterial taxa with putative immune-modulatory functions between study cohorts. Para-bactericides were significantly expanded in the faecal microbiota of Necator americanus-infected individuals. This concept supports the parasite-associated alterations in gut microbial composition contribute to the immune-modulating properties of hookworm parasites [42]. In another helminth parasite, Trichinella spiralis infection or application of its muscle larvae excretory-secretory products (ESL1) was achieved through activation of Th2 and regulatory responses in EAE. Serum samples from MS patients were tested in Western blot, suggesting potential immunomodulatory capacity and involvement in the parasite's provoked amelioration of EAE [43]. The immunogenic vaccines are comprised of a self-antigen plus a single Th2 adjuvant, either free or conjugated.  By altering the immune response towards the self-antigen from harmful pro-inflammatory Th1/Th17 to beneficial anti-inflammatory Th2 immunity, autoimmunity is reduced. Another type of vaccines is the DNA vaccines where cells transiently express the self-antigen encoded by DNA, induces Th2 immunity. DNA vaccines can benefit from the presence of an adjuvant that elicits a systemic sole Th2 immunity to enhance initially weak immune response characteristic of these vaccines.  With this concept, possibility of treating multiple sclerosis with live helminths or helminth products has been explored in animal models, natural human infections and phases 1 clinical trial. 
Toll like receptor response in Helminth infection AND Multiple Sclerosis

Toll-like receptor 2 is also known as TLR2, a protein is encoded by the TLR2 gene in humans and designated as CD282 (cluster of differentiation 282). TLR2 plays a role in the immune system on both B cells and dendrite cells (DC) were significantly higher in MS patients.  Stimulation of myelin-specific T cell lines with a TLR2 agonist induced inhibition of T cell proliferation shows suppression of IFN-γ, IL-12, and IL-17 secretion and increase in IL-10 production.

Helminth parasite infection alters the regulation function and levels of the receptors. Parasite-driven protection was associated with regulatory T cell induction and anti-inflammatory cytokine secretion as increased TGF-β and IL-10 levels. All functional effects mediated by TLR2 were abrogated when MyD88 gene expression was silenced; indicate that helminth-mediated signaling changes in cytokine secretion in a MyD88-dependent manner [44]. Exposed to TLR2 agonists or to soluble egg Ag (SEA) from Schistosoma mansoni resulted in significant TLR2 up-regulation. SEA decreased the production of IL-1beta, IL-6, IL-12, and TNF-alpha in DCs induced by LPS, while it increased the production of TGF-beta and IL-10. Similarly, after exposure to SEA, anti-CD40-activated B cells increased IL-10 production. DCs stimulation by SEA and TLR2 agonists induced increase phosphorylation of the MAPK ERK. This proves critical in developing novel therapeutic approaches for the treatment of autoimmune diseases such as MS [45].

Human monocyte-derived dendritic cells (DCs) show remarkable phenotypic changes upon direct contact with soluble products (SPs) of Trichuris suis, a pig whipworm that is experimentally used in therapies to ameliorate inflammation in patients with Crohn's disease and multiple sclerosis. These changes may contribute to the observed induction of a T helper 2 (Th2) response and the suppression of Toll-like receptor (TLR)-induced Th1 and Th17 responses by human DCs primed with T. suis SPs. The interaction of DCs with T. suis glycans likely involves mannose-type glycans, rather than fucosylated glycans, which differs from DC binding to soluble egg antigens of the human worm parasite, Schistosoma mansoni. The interaction of T. suis glycans with CLRs of human DCs may be essential for the ability of T. suis to suppress a pro-inflammatory phenotype of human DCs. Patients with concurrent natural helminth infected MS (HIMS) had an increased expression of the negative regulatory TAM receptors in antigen-presenting cells and their agonist GAS6 in circulating CD11bhigh and CD4+ T cells compared to patients with only MS. The Th17 subset was reduced in patients with HIMS. Glycans of T. suis SPs contribute significantly to the suppression of the lipopolysaccharide (LPS)-induced expression in DCs of a broad variety of cytokines and chemokines, including important pro-inflammatory mediators such as TNF-α, IL-6, IL-12, lymphotoxin α (LTA), C-C Motif Ligand (CCL)2, C-X-C Motif Ligands (CXCL)9 and CXCL10 [46]. 

Multiple Sclerosis relapsing remitting patients presenting parasite infections were observed during the time period of anti-parasite treatment, showing a significant increase in the IFN-γ and IL-12 producing cells and decrease in TGF-β and IL-10 secreting cells, as well as CD4+CD25+FoxP3+ Treg cells. To better understand the link between parasite infections and the course of multiple sclerosis (MS), study of the role of TLRs in helminth product recognition by dendritic cells (DCs) and B cells. Helminth molecules exert potent regulatory effects on both DCs and B cells through TLR2 regulation conducted via different signaling pathways [47]. TLR2 was significantly higher in infected-MS patients compared with uninfected MS subjects or healthy controls. Moreover, cells exposed to TLR2 agonists or to soluble egg Ag (SEA) from Schistosoma mansoni resulted in significant up-regulation of TLR2.

The impact of helminth infections on the course of multiple sclerosis 

Some research highlights that the prevalence of MS is lower in areas where parasitic infections are more common due to a reduction in parasite exposure and improved hygienic conditions favor the development of MS.  This concept supports those parasitic infections play a protective role in MS. In Argentina a gastrointestinal helminth species evidence for helminth-induced protection in MS patients. Such patients showed significant increase in the number of IFN-γ and IL-12 producing cells, and a fall in the number of TGF-β and IL-10 secreting cells, as well as CD4+CD25+FoxP3+ Treg cells after three months anti-helminth treatment began. Trichiruis suis and Necator americanus were used in multiple clinical trials, based on their favorable infection safety profile. According to these observations on parasite infections associated with MS, parasite regulation of host immunity can affect the course of MS [48]. 

Clinical trials on pig whipworm have been identified as non-pathogenic in human subjects. MS patients treated with TSO experience a continuous increase in serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens up to 12 months post-treatment. While stable and comparable frequencies of total CD4+ and CD8+ T cells were detected in placebo and TSO-treated patients with an increase of activated HLA-DR+CD4+ T cells in TSO-treated patients only. Frequencies of Gata3+ Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3+ Treg frequencies varied greatly between individuals. Therefore, Trichuris suis ova (TSO) has introduced as a potential alternative treatment of MS patients reported as modest clinical efficacy [49].

Gratefully acknowledged to Dr. V. K. Mahadik, Director, R. D. Gardi Medical College for the encouragements, and to establish and develop research in biomedical sciences.

Helminth infections and their metabolic products alter the regime of Th1/Th2 and suppress demyelinating disease in Multiple Sclerosis (MS) and its laboratory model EAE. Parasite-driven protection was associated with regulatory T cell induction and anti-inflammatory cytokine secretion increases TGF-β and IL-10 levels of expression of TLR2. The Th1/Th2 paradigm of CD4+ T helper cell subsets can provide the basis for the development of new types of drugs for the treatment development of Th1 and/or Th17 cells. It is also important to understand about the helminth-associated changes in gut microbiota composition and parasitic worms have a link to imbalances in gut microbial communities in RMS patients. DNA vaccines can benefit from the presence of an adjuvant that elicits a systemic sole Th2 immune response as characteristic of the vaccine. Clinical studies have shown that Trichuris suis ova (TSO) are a non-pathogenic in human subjects and could be a potential alternative treatment for Multiple Sclerosis patients.