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Comparative Study
. 2008 Jul;22(5):639-46.
doi: 10.1016/j.bbi.2007.11.001. Epub 2008 Jan 2.

The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) therapy

Andrew W Taylor  1 , Nobuyoshi Kitaichi
Affiliations
Comparative Study

The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) therapy

Andrew W Taylor et al. Brain Behav Immun. 2008 Jul.

Abstract

The neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) plays an important role in immune privilege by its suppression of inflammation, and its induction of regulatory T cells. This finding led us to test the possibility that we can use alpha-MSH to suppress autoimmune diseases, and promote re-establishment of immune tolerance to autoantigens. To test this possibility, SJL mice with experimental autoimmune encephalomyelitis (EAE) were injected with alpha-MSH at the first signs of paralysis. The alpha-MSH-treated mice in comparison with untreated EAE mice had a profound diminishment in the severity and tempo of EAE. The spleen cells in alpha-MSH-treated EAE produced TGF-beta in response to PLP-antigen stimulation in contrast to untreated mice spleen cells that produced IFN-gamma. When the alpha-MSH-treated EAE mice were reimmunized there was a delay of a week before the second episode of EAE. Although this delay maybe because of the induction of TGF-beta-producing spleen cells by the alpha-MSH-treatment, it was not adequate to suppress IFN-gamma-production by PLP-antigen stimulated spleen cells from untreated mice, nor able to suppress the eventual second episode of EAE. Therefore, the injection of alpha-MSH at the onset of paralysis is extremely effective in diminishing the severity and tempo of EAE, and the subsequent induction of potential PLP-specific Treg cells suggests that an alpha-MSH therapy could be attempted as part of a therapeutic regiment to impose immunoregulation and immunosuppression on an autoimmune disease of the central nervous system.

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Figures

Fig. 1
Fig. 1
A single treatment with α-MSH suppresses EAE. The SJL mice were immunized to induce EAE as described in the methods and were monitored every day for symptoms of paralysis. On the first day of paralysis symptoms (Day 0) one group of mice were injected with 50 µg of α-MSH ip (+α-MSH) and another group of mice were injected with PBS (−α-MSH). Both groups were monitored for another 7 days. The groups consisted of 16 mice injected with α-MSH, and 14 injected with PBS. Presented are the mean EAE scores of the group ± the SEM for each day, and are the pooled results of three separately run experiments. The α-MSH-treatment statistically (P ≤ 0.01) changed the curve of EAE scores over time.
Fig. 2
Fig. 2
Treatment with α-MSH changes the cytokine profile of PLP (130–151) antigen stimulated immunity in the spleen. The mice were immunized to induce EAE, and as in Fig. 1 one group was treated with α-MSH (+α-MSH) and one group was not (−α-MSH). The mice were monitored for an additional 7 days, and their spleen cells were collected. The cultured spleen cells were stimulated by adding PLP (130–151) antigen (+Ag) to the cultures. The cultures were incubated for 48 h, and the culture media was assayed for IFN-γ, TGF-β, and IL-4. In addition the cells were assayed for proliferation 72 h after adding antigen. Presented are the mean concentration of the cytokine ± SEM of two experiments of five pooled mouse spleen cells per group in each experiment. Proliferation is presented as stimulation index ± SEM relative to antigen stimulated spleen cells from untreated EAE mice. There was a significant change in the production of IFN-γ and TGF-β with an increase in proliferation by the PLP-stimulated spleen cells from α-MSH-treated EAE mice.
Fig. 3
Fig. 3
A single treatment with α-MSH delays the onset of a second induced episode of EAE. The SJL mice were immunized to induce EAE, treated with or without α-MSH as in Fig. 1. The mice were monitored to detect the day that the α-MSH-treated mice reach almost complete recovery (Day 0), and the mice of both α-MSH-treated and untreated EAE mice were reimmunized with PLP (130–151) in synthetic adjuvant. The mice were monitored for a second episode of EAE and possible recovery. Each group consisted of 15 mice. Presented are the mean EAE scores of the group ± the SEM for each day, and are the pooled results of three separately run experiments. The α-MSH-treatment statistically (P ≤ 0.01) changed the curve of EAE scores over time with extremely significant differences (P < 0.002) before day 7 and after day 12.
Fig. 4
Fig. 4
Spleen cells from α-MSH-treated EAE mice appear to be regulatory cells but cannot suppress IFN-γ production by PLP-antigen stimulated spleen cells from untreated EAE mice. The mice were immunized to induce EAE, and as in Fig. 1. The mice were monitored for 7 days, and the spleen cells were collected. Equal numbers of spleen cells from the α-MSH-treated EAE mice (mouse group A), and untreated EAE mice (mouse group B) were mixed in culture and stimulated by adding PLP (130–151) antigen to the spleen cell cultures. The cultures were incubated for 48 h, and the culture media was assayed for IFN-γ, and TGF-β. Presented are the mean concentration of the cytokine ± SEM of two experiments of five pooled mouse spleen cells per group in each experiment. There was significant production of TGF-β with the addition of spleen cells from the α-MSH-treated EAE mice, but there was no effect on IFN-γ production by the PLP-stimulated spleen cells from untreated EAE mice.
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