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A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis

View Article: PubMed Central - PubMed

ABSTRACT

Helminth parasites secrete molecules that potently modulate the immune responses of their hosts and, therefore, have potential for the treatment of immune-mediated human diseases. FhHDM-1, a 68-mer peptide secreted by the helminth parasite Fasciola hepatica, ameliorated disease in two different murine models of autoimmunity, type 1 diabetes and relapsing-remitting immune-mediated demyelination. Unexpectedly, FhHDM-1 treatment did not affect the proliferation of auto-antigen specific T cells or their production of cytokines. However, in both conditions, the reduction in clinical symptoms was associated with the absence of immune cell infiltrates in the target organ (islets and the brain tissue). Furthermore, after parenteral administration, the FhHDM-1 peptide interacted with macrophages and reduced their capacity to secrete pro-inflammatory cytokines, such as TNF and IL-6. We propose this inhibition of innate pro-inflammatory immune responses, which are central to the initiation of autoimmunity in both diseases, prevented the trafficking of autoreactive lymphocytes from the periphery to the site of autoimmunity (as opposed to directly modulating their function per se), and thus prevented tissue destruction. The ability of FhHDM-1 to modulate macrophage function, combined with its efficacy in disease prevention in multiple models, suggests that FhHDM-1 has considerable potential as a treatment for autoimmune diseases.

No MeSH data available.


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Administration of FhHDM-1 reduces inflammation and demyelination in the CNS in relapsing remitting (RR)-EAE.Histological analysis of brain tissue from (a–c) FhHDM-1- or (d–f) PBS-treated EAE mice at 15 day post induction. Paraffin embedded sections were analysed for demyelination by luxol fast-blue/haematoxylin and eosin staining. (a) and (d) show the cerebellum (Cb), with an enlargement of the area from the black rectangle shown in (b,e), respectively. The white arrow in (b) shows an inflammatory infiltrate that is retained within the perivascular space, with no evidence of surrounding demyelination; this was only seen in the FhHDM-1-treated mice. The asterisks in (e) indicate foamy macrophages. (c,f) show the area near the hippocampus (H) and the lateral ventricle (LV) of the brain, with the white arrows indicating a large area of cellular infiltration and demyelination in (f).
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f3: Administration of FhHDM-1 reduces inflammation and demyelination in the CNS in relapsing remitting (RR)-EAE.Histological analysis of brain tissue from (a–c) FhHDM-1- or (d–f) PBS-treated EAE mice at 15 day post induction. Paraffin embedded sections were analysed for demyelination by luxol fast-blue/haematoxylin and eosin staining. (a) and (d) show the cerebellum (Cb), with an enlargement of the area from the black rectangle shown in (b,e), respectively. The white arrow in (b) shows an inflammatory infiltrate that is retained within the perivascular space, with no evidence of surrounding demyelination; this was only seen in the FhHDM-1-treated mice. The asterisks in (e) indicate foamy macrophages. (c,f) show the area near the hippocampus (H) and the lateral ventricle (LV) of the brain, with the white arrows indicating a large area of cellular infiltration and demyelination in (f).

Mentions: Typically, infection with helminth parasites leads to a polarized and potent Thelper (Th)2 type immune response and chronic infection is associated with the differentiation of regulatory T cells (Tregs)1122. It is these regulatory responses that are proposed to suppress the development of the detrimental auto-antigen specific Th1 and Th17 responses that mediate autoimmune disease2324. Indeed, the protection afforded by FhES in both NOD and EAE mouse models has been attributed to both the secretion of Th2 cytokines and the inhibition of autoantigen specific Th1 type immune responses1718. To examine if this was the mechanism of protection mediated by FhHDM-1, draining lymph nodes were harvested from both PBS and FhHDM-1 treated EAE mice when the first peak of disease occurred in the PBS-treated mice (day 15 after disease induction), and PLP139-151-specific T cell responses were measured. Despite the observation that FhHDM-1 treated mice displayed less severe clinical symptoms (1.3 ± 0.8) than PBS treated animals (4.1 ± 0.4), and less inflammation and demyelination in the CNS (Fig. 3), there was no apparent difference in the quantity of cytokines or phenotype of immune response produced in response to the auto-antigen (Fig. 4a,b). There was no significant alteration in the levels of the disease mediating pro-inflammatory cytokines, IFNγ, TNF or IL-17 (Fig. 4a), and no increase in the levels of IL-4, IL-5 or IL-10, all of which were negligible in the EAE mice (not shown). Furthermore, analyses of PLP139-151-specific responses, among T cells from resident lymph nodes from surviving relapsing remitting (RR)-EAE mice also showed no differences in cytokine production or proliferative responses between PBS and FhHDM-1 treatments (Fig. 4c,d). These results indicated that disease protection by FhHDM-1 was not mediated by the inhibition of auto-antigen specific inflammatory T cell responses or a switch towards a Th2 phenotype. Additionally, FhHDM-1 did not modulate immune responses to injected KLH (Supplementary Fig. 1), thereby verifying that the peptide did not generally suppress antibody production or T helper cell responsiveness.


A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis
Administration of FhHDM-1 reduces inflammation and demyelination in the CNS in relapsing remitting (RR)-EAE.Histological analysis of brain tissue from (a–c) FhHDM-1- or (d–f) PBS-treated EAE mice at 15 day post induction. Paraffin embedded sections were analysed for demyelination by luxol fast-blue/haematoxylin and eosin staining. (a) and (d) show the cerebellum (Cb), with an enlargement of the area from the black rectangle shown in (b,e), respectively. The white arrow in (b) shows an inflammatory infiltrate that is retained within the perivascular space, with no evidence of surrounding demyelination; this was only seen in the FhHDM-1-treated mice. The asterisks in (e) indicate foamy macrophages. (c,f) show the area near the hippocampus (H) and the lateral ventricle (LV) of the brain, with the white arrows indicating a large area of cellular infiltration and demyelination in (f).
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Related In: Results  -  Collection

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f3: Administration of FhHDM-1 reduces inflammation and demyelination in the CNS in relapsing remitting (RR)-EAE.Histological analysis of brain tissue from (a–c) FhHDM-1- or (d–f) PBS-treated EAE mice at 15 day post induction. Paraffin embedded sections were analysed for demyelination by luxol fast-blue/haematoxylin and eosin staining. (a) and (d) show the cerebellum (Cb), with an enlargement of the area from the black rectangle shown in (b,e), respectively. The white arrow in (b) shows an inflammatory infiltrate that is retained within the perivascular space, with no evidence of surrounding demyelination; this was only seen in the FhHDM-1-treated mice. The asterisks in (e) indicate foamy macrophages. (c,f) show the area near the hippocampus (H) and the lateral ventricle (LV) of the brain, with the white arrows indicating a large area of cellular infiltration and demyelination in (f).
Mentions: Typically, infection with helminth parasites leads to a polarized and potent Thelper (Th)2 type immune response and chronic infection is associated with the differentiation of regulatory T cells (Tregs)1122. It is these regulatory responses that are proposed to suppress the development of the detrimental auto-antigen specific Th1 and Th17 responses that mediate autoimmune disease2324. Indeed, the protection afforded by FhES in both NOD and EAE mouse models has been attributed to both the secretion of Th2 cytokines and the inhibition of autoantigen specific Th1 type immune responses1718. To examine if this was the mechanism of protection mediated by FhHDM-1, draining lymph nodes were harvested from both PBS and FhHDM-1 treated EAE mice when the first peak of disease occurred in the PBS-treated mice (day 15 after disease induction), and PLP139-151-specific T cell responses were measured. Despite the observation that FhHDM-1 treated mice displayed less severe clinical symptoms (1.3 ± 0.8) than PBS treated animals (4.1 ± 0.4), and less inflammation and demyelination in the CNS (Fig. 3), there was no apparent difference in the quantity of cytokines or phenotype of immune response produced in response to the auto-antigen (Fig. 4a,b). There was no significant alteration in the levels of the disease mediating pro-inflammatory cytokines, IFNγ, TNF or IL-17 (Fig. 4a), and no increase in the levels of IL-4, IL-5 or IL-10, all of which were negligible in the EAE mice (not shown). Furthermore, analyses of PLP139-151-specific responses, among T cells from resident lymph nodes from surviving relapsing remitting (RR)-EAE mice also showed no differences in cytokine production or proliferative responses between PBS and FhHDM-1 treatments (Fig. 4c,d). These results indicated that disease protection by FhHDM-1 was not mediated by the inhibition of auto-antigen specific inflammatory T cell responses or a switch towards a Th2 phenotype. Additionally, FhHDM-1 did not modulate immune responses to injected KLH (Supplementary Fig. 1), thereby verifying that the peptide did not generally suppress antibody production or T helper cell responsiveness.

View Article: PubMed Central - PubMed

ABSTRACT

Helminth parasites secrete molecules that potently modulate the immune responses of their hosts and, therefore, have potential for the treatment of immune-mediated human diseases. FhHDM-1, a 68-mer peptide secreted by the helminth parasite Fasciola hepatica, ameliorated disease in two different murine models of autoimmunity, type 1 diabetes and relapsing-remitting immune-mediated demyelination. Unexpectedly, FhHDM-1 treatment did not affect the proliferation of auto-antigen specific T cells or their production of cytokines. However, in both conditions, the reduction in clinical symptoms was associated with the absence of immune cell infiltrates in the target organ (islets and the brain tissue). Furthermore, after parenteral administration, the FhHDM-1 peptide interacted with macrophages and reduced their capacity to secrete pro-inflammatory cytokines, such as TNF and IL-6. We propose this inhibition of innate pro-inflammatory immune responses, which are central to the initiation of autoimmunity in both diseases, prevented the trafficking of autoreactive lymphocytes from the periphery to the site of autoimmunity (as opposed to directly modulating their function per se), and thus prevented tissue destruction. The ability of FhHDM-1 to modulate macrophage function, combined with its efficacy in disease prevention in multiple models, suggests that FhHDM-1 has considerable potential as a treatment for autoimmune diseases.

No MeSH data available.


Related in: MedlinePlus