Limits...
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.


Related in: MedlinePlus

Administration of FhHDM-1 prevents T1D in NOD mice.(a) Female NOD/Lt mice were injected i.p. for a total of six times with FhHDM-1, FhCL1 (10 μg in 100 μl sterile PBS), or sterile PBS (100 μl) on alternate days beginning at 4 weeks of age. Mice were then monitored over 30 weeks, assessed for blood glucose weekly, and diagnosed as diabetic after two consecutive measurements >14 mmol/L. Data shown is a combination of four independent experiments. A Tarone-Ware nonparametric test comparing the Kaplan-Meier estimates of survivor function was used to assess significance. (b) Pancreas isolated from mice at 13 weeks of age (n = 9) were graded for insulitis on a scale of 0–4; whereby 0 = healthy islet or mild peri-insular mononuclear cell infiltration, 1 = infiltration up to 25% of islet mass, 2 = infiltration up to 50% of islet mass, 3 = infiltration from 50% up to 75% of islet mass, and 4 = less than 25% of islet mass present. The proportion of islets with each grade of insulitis is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5121616&req=5

f1: Administration of FhHDM-1 prevents T1D in NOD mice.(a) Female NOD/Lt mice were injected i.p. for a total of six times with FhHDM-1, FhCL1 (10 μg in 100 μl sterile PBS), or sterile PBS (100 μl) on alternate days beginning at 4 weeks of age. Mice were then monitored over 30 weeks, assessed for blood glucose weekly, and diagnosed as diabetic after two consecutive measurements >14 mmol/L. Data shown is a combination of four independent experiments. A Tarone-Ware nonparametric test comparing the Kaplan-Meier estimates of survivor function was used to assess significance. (b) Pancreas isolated from mice at 13 weeks of age (n = 9) were graded for insulitis on a scale of 0–4; whereby 0 = healthy islet or mild peri-insular mononuclear cell infiltration, 1 = infiltration up to 25% of islet mass, 2 = infiltration up to 50% of islet mass, 3 = infiltration from 50% up to 75% of islet mass, and 4 = less than 25% of islet mass present. The proportion of islets with each grade of insulitis is shown.

Mentions: Because we have previously shown that FhES can prevent autoimmune disease in mice17, the same treatment regime was chosen to assess the efficacy of FhHDM-1 and FhCL1 in preventing T1D in NOD mice. The parasite derived proteins were administered to female NOD mice by intraperitoneal injection beginning at 4 weeks of age (co-incident with the priming of auto-reactive T cell populations and initiation of insulitis), and continued on alternate days for a total of 6 treatments (10 μg/injection). The incidence of diabetes in the vehicle only (PBS treated) cohort was 84%, as expected (Fig. 1a). Administration of FhCL1 afforded no significant protection, with a disease penetrance of 90% observed. By contrast, 50% of mice treated with FhHDM-1 were protected against T1D (p < 0.0001 as compared to PBS treated cohorts; Fig. 1a) and remained normoglycaemic at 30 weeks of age (24 weeks after the final injection of FhHDM-1; experimental endpoint). The protection afforded by FhHDM-1 was comparable to that observed using FhES17. Examination of H&E stained sections of pancreas isolated from FhHDM-1-treated mice at 13 weeks of age showed a consistent and significant (p < 0.001) reduction in islet inflammation compared to PBS treated mice (Fig. 1b), which is in keeping with the ability of the peptide to prevent autoimmune diabetes.


A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis
Administration of FhHDM-1 prevents T1D in NOD mice.(a) Female NOD/Lt mice were injected i.p. for a total of six times with FhHDM-1, FhCL1 (10 μg in 100 μl sterile PBS), or sterile PBS (100 μl) on alternate days beginning at 4 weeks of age. Mice were then monitored over 30 weeks, assessed for blood glucose weekly, and diagnosed as diabetic after two consecutive measurements >14 mmol/L. Data shown is a combination of four independent experiments. A Tarone-Ware nonparametric test comparing the Kaplan-Meier estimates of survivor function was used to assess significance. (b) Pancreas isolated from mice at 13 weeks of age (n = 9) were graded for insulitis on a scale of 0–4; whereby 0 = healthy islet or mild peri-insular mononuclear cell infiltration, 1 = infiltration up to 25% of islet mass, 2 = infiltration up to 50% of islet mass, 3 = infiltration from 50% up to 75% of islet mass, and 4 = less than 25% of islet mass present. The proportion of islets with each grade of insulitis is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121616&req=5

f1: Administration of FhHDM-1 prevents T1D in NOD mice.(a) Female NOD/Lt mice were injected i.p. for a total of six times with FhHDM-1, FhCL1 (10 μg in 100 μl sterile PBS), or sterile PBS (100 μl) on alternate days beginning at 4 weeks of age. Mice were then monitored over 30 weeks, assessed for blood glucose weekly, and diagnosed as diabetic after two consecutive measurements >14 mmol/L. Data shown is a combination of four independent experiments. A Tarone-Ware nonparametric test comparing the Kaplan-Meier estimates of survivor function was used to assess significance. (b) Pancreas isolated from mice at 13 weeks of age (n = 9) were graded for insulitis on a scale of 0–4; whereby 0 = healthy islet or mild peri-insular mononuclear cell infiltration, 1 = infiltration up to 25% of islet mass, 2 = infiltration up to 50% of islet mass, 3 = infiltration from 50% up to 75% of islet mass, and 4 = less than 25% of islet mass present. The proportion of islets with each grade of insulitis is shown.
Mentions: Because we have previously shown that FhES can prevent autoimmune disease in mice17, the same treatment regime was chosen to assess the efficacy of FhHDM-1 and FhCL1 in preventing T1D in NOD mice. The parasite derived proteins were administered to female NOD mice by intraperitoneal injection beginning at 4 weeks of age (co-incident with the priming of auto-reactive T cell populations and initiation of insulitis), and continued on alternate days for a total of 6 treatments (10 μg/injection). The incidence of diabetes in the vehicle only (PBS treated) cohort was 84%, as expected (Fig. 1a). Administration of FhCL1 afforded no significant protection, with a disease penetrance of 90% observed. By contrast, 50% of mice treated with FhHDM-1 were protected against T1D (p < 0.0001 as compared to PBS treated cohorts; Fig. 1a) and remained normoglycaemic at 30 weeks of age (24 weeks after the final injection of FhHDM-1; experimental endpoint). The protection afforded by FhHDM-1 was comparable to that observed using FhES17. Examination of H&E stained sections of pancreas isolated from FhHDM-1-treated mice at 13 weeks of age showed a consistent and significant (p < 0.001) reduction in islet inflammation compared to PBS treated mice (Fig. 1b), which is in keeping with the ability of the peptide to prevent autoimmune diabetes.

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