Immunoregulation of experimental autoimmune neurirtis focuses on cell immunity
Author: Zhu, Yu
Date: 2003-02-28
Location: Hörsalen, plan 4, Novum, Huddinge Universitetssjukhus
Time: 9.30
Department: Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
View/ Open:
Thesis (762.4Kb)
Abstract
Experimental autoimmune neuritis (EAN) is a CD4+ T cell mediated autoimmune disease of peripheral nervous system (PNS). EAN can be induced in susceptible animal strains by active immunization with peripheral nerve tissue, the purified peripheral nerve myelin components P2 and PO, or synthetic P2 and PO peptides. EAN shares many of clinical, immunological, electrophysiological and morphological characteristics of Guillain-Barré syndrome (GBS), a major inflammatory demyelinating disease of the PNS in human and allows detailed study of the various effector pathways and tests novel therapeutic strategies in vivo. Therefore, EAN serves as a useful model for exploring the pathogenesis and immunotherapy of GBS.
The effects of distinct T cell subtype (CD4+ and CD8+) and B cell in EAN were examined in CD4-/-, CD8-/-, CD4-8-, B cell knockout (µMT) and wild type mice. The clinical sign, T cell response specific to PO1 80-199 and histopathological changes in CD4-/- mice were significantly lower than in wild type mice; CD8-/mice also appeared slighter clinical course, less T cell response specific to P0180-199 and slight hitopathological changes compared with wild type mice, but no significant difference between them except for the severity of disease. CD4-8-, µMT and wild type mice appeared similar in clinical courses, specific T cell response and histopathological changes. Similar levels of IgG production were found in sera from CD4-/-, CD8- /-, CD4-8- and wild type mice except for µMT mice, from which no IgG production was detectable in sera.
The roles of costimulatory molecule CD28 in EAN have been investigated in CD28-/- B6 mice and wild- type mice. All the wild-type mice developed severe EAN. None of the CD28-/- mice manifested clinical signs of disease. This was related to fewer IL-12 producing cells in sciatic nerve sections and fewer IFN-gamma secreting spleen cells in CD28-/- mice. Meanwhile, milder infiltration of such inflammatory cells into sciatic nerve tissues and less demyelination as well as lower production of specific anti-PO peptide 180-199 antibodies were found in CD28-/- mice.
To define the effects of IFN-gamma on EAN, clinical, pathological, immunological changes were evaluated in IFN-gamma receptor-deficient mutant (IFN-gammaR-/-) and wild-type mice immunized with PO peptide 180-199. IFN-gammaR-/- mice exhibited later onset, less severity of clinical disease accompanying with less infiltration of inflammatory cells and demyelination compared with wild type mice. Fewer IL- 12 producing but more IL-4 producing cells were found in sciatic nerve sections from IFN-gammaR-/- mice. However, IFN-gammaR deficiency did not affect the production of specific anti-PO peptide 180-199 antibody.
Bowman-Birk inhibitor Concentrate (BBIC) is an extract of soybeans enriched in Bowman-Birk inhibitor (BBI) capable of inhibiting the catalytic activities of several serine proteases. The immunoregulatory effects of BBIC have been evaluated in EAN. Administration of BBIC suppressed the development of clinical symptoms, and decreased inflammatory infiltrates in sciatic nerves, inhibited P2specific T cell proliferation and IFN-gamma synthesis by lymphocytes in lymph nodes from EAN rats. In vitro BBIC significantly suppressed B7.2 expression on macrophages from EAN rats, whereas B7.1 expression was slightly increased at peak of disease.
We conclude that 1) Both CD4+ T cells and CD8+ T cells are involved in the pathogenesis of EAN as helper or effector cells through their interaction, although autoreactive CD4+ T cells remain the main effectors of this disease. B cells may less contribute to perpetuating the related inflammatory demyelination. 2) CD28/B7 costimulation plays a pivotal role in either the initiation and/or effector phases of Th1-mediated EAN through both the activation of PO peptide-specific T cells and of Th-induced differentiation of B cells into Ig-secreting cells. 3) IFN-gamma contributes to the pathogenesis of EAN by promoting a Th1 cell- medicated immune response and suppressing a Th2 response. 4) BBIC has a strong ability to inhibit T cell response in EAN
The effects of distinct T cell subtype (CD4+ and CD8+) and B cell in EAN were examined in CD4-/-, CD8-/-, CD4-8-, B cell knockout (µMT) and wild type mice. The clinical sign, T cell response specific to PO1 80-199 and histopathological changes in CD4-/- mice were significantly lower than in wild type mice; CD8-/mice also appeared slighter clinical course, less T cell response specific to P0180-199 and slight hitopathological changes compared with wild type mice, but no significant difference between them except for the severity of disease. CD4-8-, µMT and wild type mice appeared similar in clinical courses, specific T cell response and histopathological changes. Similar levels of IgG production were found in sera from CD4-/-, CD8- /-, CD4-8- and wild type mice except for µMT mice, from which no IgG production was detectable in sera.
The roles of costimulatory molecule CD28 in EAN have been investigated in CD28-/- B6 mice and wild- type mice. All the wild-type mice developed severe EAN. None of the CD28-/- mice manifested clinical signs of disease. This was related to fewer IL-12 producing cells in sciatic nerve sections and fewer IFN-gamma secreting spleen cells in CD28-/- mice. Meanwhile, milder infiltration of such inflammatory cells into sciatic nerve tissues and less demyelination as well as lower production of specific anti-PO peptide 180-199 antibodies were found in CD28-/- mice.
To define the effects of IFN-gamma on EAN, clinical, pathological, immunological changes were evaluated in IFN-gamma receptor-deficient mutant (IFN-gammaR-/-) and wild-type mice immunized with PO peptide 180-199. IFN-gammaR-/- mice exhibited later onset, less severity of clinical disease accompanying with less infiltration of inflammatory cells and demyelination compared with wild type mice. Fewer IL- 12 producing but more IL-4 producing cells were found in sciatic nerve sections from IFN-gammaR-/- mice. However, IFN-gammaR deficiency did not affect the production of specific anti-PO peptide 180-199 antibody.
Bowman-Birk inhibitor Concentrate (BBIC) is an extract of soybeans enriched in Bowman-Birk inhibitor (BBI) capable of inhibiting the catalytic activities of several serine proteases. The immunoregulatory effects of BBIC have been evaluated in EAN. Administration of BBIC suppressed the development of clinical symptoms, and decreased inflammatory infiltrates in sciatic nerves, inhibited P2specific T cell proliferation and IFN-gamma synthesis by lymphocytes in lymph nodes from EAN rats. In vitro BBIC significantly suppressed B7.2 expression on macrophages from EAN rats, whereas B7.1 expression was slightly increased at peak of disease.
We conclude that 1) Both CD4+ T cells and CD8+ T cells are involved in the pathogenesis of EAN as helper or effector cells through their interaction, although autoreactive CD4+ T cells remain the main effectors of this disease. B cells may less contribute to perpetuating the related inflammatory demyelination. 2) CD28/B7 costimulation plays a pivotal role in either the initiation and/or effector phases of Th1-mediated EAN through both the activation of PO peptide-specific T cells and of Th-induced differentiation of B cells into Ig-secreting cells. 3) IFN-gamma contributes to the pathogenesis of EAN by promoting a Th1 cell- medicated immune response and suppressing a Th2 response. 4) BBIC has a strong ability to inhibit T cell response in EAN
List of papers:
I. Zhu Y, Bao L, Zhu S, Chen Z, van der Meide P, Nennesmo I, Winblad B, Ljunggren HG, Zhu J (2002). CD4 and CD8 T cells, but not B cells, are critical to the control of murine experimental autoimmune neuritis. Exp Neurol. 177(1): 314-20.
Pubmed
II. Zhu Y, Ljunggren H, Mix E, Li HL, van der Meide P, Elhassan AM, Winblad B, Zhu J (2001). CD28-B7 costimulation: a critical role for initiation and development of experimental autoimmune neuritis in C57BL/6 mice. J Neuroimmunol. 114(1-2): 114-21.
Pubmed
III. Zhu Y, Ljunggren HG, Mix E, Li HL, van der Meide P, Elhassan AM, Winblad B, Zhu J (2001). Suppression of autoimmune neuritis in IFN-gamma receptor-deficient mice. Exp Neurol. 169(2): 472-8.
Pubmed
IV. Zhu Y, Zhang GX, Ware J, Ventura E, Zhu J (2003). Bowman-Birk inhibitor concentrate suppresses ongoing experimental autoimmune neuritis in Lewis rats by inhibiting Th1 cell mediated immunity in the peripheral nerve tissue. [Manuscript]
I. Zhu Y, Bao L, Zhu S, Chen Z, van der Meide P, Nennesmo I, Winblad B, Ljunggren HG, Zhu J (2002). CD4 and CD8 T cells, but not B cells, are critical to the control of murine experimental autoimmune neuritis. Exp Neurol. 177(1): 314-20.
Pubmed
II. Zhu Y, Ljunggren H, Mix E, Li HL, van der Meide P, Elhassan AM, Winblad B, Zhu J (2001). CD28-B7 costimulation: a critical role for initiation and development of experimental autoimmune neuritis in C57BL/6 mice. J Neuroimmunol. 114(1-2): 114-21.
Pubmed
III. Zhu Y, Ljunggren HG, Mix E, Li HL, van der Meide P, Elhassan AM, Winblad B, Zhu J (2001). Suppression of autoimmune neuritis in IFN-gamma receptor-deficient mice. Exp Neurol. 169(2): 472-8.
Pubmed
IV. Zhu Y, Zhang GX, Ware J, Ventura E, Zhu J (2003). Bowman-Birk inhibitor concentrate suppresses ongoing experimental autoimmune neuritis in Lewis rats by inhibiting Th1 cell mediated immunity in the peripheral nerve tissue. [Manuscript]
Issue date: 2003-02-07
Rights:
Publication year: 2003
ISBN: 91-7349-446-1
Statistics
Total Visits
Views | |
---|---|
Immunoregulation ...(legacy) | 698 |
Immunoregulation ... | 86 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Immunoregulation ... | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 268 |
thesis.pdf | 48 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 337 |
China | 52 |
Germany | 48 |
Sweden | 42 |
South Korea | 15 |
Russia | 11 |
Ireland | 9 |
Denmark | 7 |
Finland | 7 |
United Kingdom | 7 |
Top cities views
Views | |
---|---|
Romeo | 36 |
Beijing | 23 |
Sunnyvale | 20 |
Kiez | 17 |
Seoul | 15 |
Dublin | 9 |
London | 7 |
University Park | 7 |
Ashburn | 6 |
Ballerup | 6 |