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Immunoregulation and immunotherapy in experimental autoimmune neuritis

thesis
posted on 2024-09-02, 18:46 authored by Li-Ping Zou

Experimental autoimmune neuritis (EAN) is a CD4+ T cell mediated autoimmune disease of the peripheral nervous system (PNS). EAN represents an animal model for studying the immunopathogenesis and immunotherapy of Guillain-Barré syndrome (GBS). EAN can be induced by active immunization with peripheral nerve tissue, the purified peripheral nerve myelin components P2 or P0 and their synthetic peptides. EAN can be transferred to naive recipients by syngeneic P2- or P0-specific CD4+ T cell line. The pathogenesis of EAN comprises blood-nerve barrier breakdown, autoreactive T and B cells activation which then cross the blood-nerve barrier, infiltration of the PNS by activated T cells and macrophages, and focal demyelination of nerve roots predominantly around venules. CD4+ Th I cells are involved in the pathogenesis of EAN by releasing inflammatory cytokines, such as interleukin2 (IL-2) and interferon-[gamma] (IFN-[gamma]), which can activate macrophages that directly attack the myelin sheath through phagocytosis and release injurious factors and proinflammatory cytokines. Th2 cells produce cytokines such as IL4, IL-6 and IL-10 that facilitate B cells to produce anti-peripheral nerve myelin antibodies. Antibodies may be involved in the PNS tissue damage in EAN. On the other hand, Th2-related cytokines IL-4 and IL-10, as well as Th3 cell released transforming growth factor-ß (TGF-ß), can inhibit Th1 cell functions.

Nasal administration of immunodominant and neuritogenic P2-peptide 57-81 effectively suppressed the severity and shortened clinical EAN and prevented clinical EAN relapse in a dose dependent manner. This was associated with T cell hyporesponsiveness, downregulated IFN-[gamma] rnRNA expression and upregulated TGF-ß rnRNA expression in lymph node mononuclear cells (paper I).

The neuritogenic peptides 180-199 and 56-71 of P0 protein prevented and attenuated ongoing EAN following nasal administration. Both peptides effectively decreased the severity and shortened clinical EAN. This was associated with T and B cell hyporesponsiveness, reflected by downregulated IFN-[gamma] secretion and macrophage function, as well as upregulated IL-4 secretion and TGF-ß rnRNA expression in the sciatic nerve (paper II).

Interferon-ß (IFN-ß) clearly ameliorated EAN, suppressed both T and B responses and strongly decreased the numbers of infiltrating CD4' cells, macrophages and other inflammatory cells, as well as a significantly reduced MHC class II antigen expression and monocyte chemotactic protein-I (MCP-1) production in the PNS (paper III).

We estimated that nasal administration of recombinant rat interleukin-4 (rrIL-4) in dose ranges of 0.1-1 [my]g/rat/day in the initial phase of EAN, decreased the severity and duration of clinical EAN. This treatment also gave hyporesponsiveness of T cells, down regulation of Th1 cell responses IFN-[gamma] but increased levels of specific IgG 1. Low grade inflammation and reduced regional demyelination in the sciatic nerve were seen in rrIL-4 treated rats (paper IV).

The maximum number of macrophage inflammatory protein- I [alpha] (MIP- I a) positive cells in the sciatic nerve was seen on day 14 post immunization (p.i.), which correlated with the development of severe clinical signs. Administration of an anti-MIP-1[alpha] antibody suppressed clinical signs of EAN and inhibited inflammation and demyelination in the sciatic nerve. Peak numbers of MCP-I positive cells in the sciatic nerve were detected on day 7 p.i. (i.e. the onset of clinical EAN). Administration of an anti-MCP-I antibody caused a delay of onset of EAN. The numbers of MIP-2 positive cells reached a maximum on day 21 p.i. Anti-MIP-2 antibody failed to suppress clinical signs of EAN and inflammation and demyelination in the sciatic nerve (paper V).

EAN was strongly suppressed by Rolipram and associated with down-regulation of myelin antigen-induced T cell responses and production of IFN-[gamma] and TNF-[alpha]. Extension of this treatment resulted in the prevention of clinic EAN relapse. There was no relationship between clinical EAN relapse and high levels of TNF-[alpha] in serum (paper VI).

In conclusion, administration of organ-specific autoantigens, rrIL-4 and IFN-ß, as well as Rolipram, prevented EAN and EAN relapse, suppressed clinical signs and histopathological changes in EAN. These effects were associated with antigen specific T cell hyporesponsive, downregulated Th I cell responses, and upregulated Th2 cell responses. Nasal administration of small amounts of antigens provides a highly efficient approach for inducing tolerance as well as an accessible portal for antigens and cytokines.

List of scientific papers

I. Zou LP, Zhu J, Deng GM, Levi M, Wahren B, Diab A, Hillert J, Link H (1998). Treatment with P2 protein peptide 57-81 by nasal route is effective in Lewis rat experimental autoimmune neuritis. J Neuroimmunol. 85(2):137-145.
https://pubmed.ncbi.nlm.nih.gov/9630162

II. Zou LP, Ma DH, Levi M, Wahren B, Wei L, Mix E, van der Meide PH, Link H, Zhu J (1999). Antigen-specific immunosuppression: nasal tolerance to P0 protein peptides for the prevention and treatment of experimental autoimmune neuritis in Lewis rats. J Neuroimmunol. 94(1-2):109-121.
https://pubmed.ncbi.nlm.nih.gov/10376943

III. Zou LP, Ma DH, Wei L, van der Meide PH, Mix E, Zhu J. (1999). IFN-beta suppresses experimental autoimmune neuritis in lewis rats by inhibiting the migration of inflammatory cells into peripheral nervous tissue. J Neurosci Res. 56(2):123-130.
https://pubmed.ncbi.nlm.nih.gov/10494101

IV. Deretzi G, Zou LP, Pelidou SH, Nennesmo I, Levi M, Wahren B, Mix E, Zhu J (1999). Nasal administration of recombinant rat IL-4 ameliorates ongoing experimental autoimmune neuritis and inhibits demyelination. J Autoimmun. 12(2):81-89.
https://pubmed.ncbi.nlm.nih.gov/10047428

V. Zou LP, Pelidou SH, Abbas N, Deretzi G, Mix E, Schaltzbeerg M, Winblad B, Zhu J (1999). Dynamics of production of MIP-1alpha, MCP-1 and MIP-2 and potential role of neutralization of these chemokines in the regulation of immune responses during experimental autoimmune neuritis in Lewis rats. J Neuroimmunol. 98(2):168-175.
https://pubmed.ncbi.nlm.nih.gov/10430050

VI. Zou LP, Deretzi G, Pelidou SH, Levi M, Wahren B, Quiding C, van der Meide P, Zhu J (2000). Rolipram suppresses experimental autoimmune neuritis and prevents relapses in Lewis rats. Neuropharmacology. 39(2):324-333.
https://pubmed.ncbi.nlm.nih.gov/10670428

History

Defence date

1999-12-16

Department

  • Department of Neurobiology, Care Sciences and Society

Publication year

1999

Thesis type

  • Doctoral thesis

ISBN-10

91-628-3918-7

Number of supporting papers

6

Language

  • eng

Original publication date

1999-11-25

Author name in thesis

Zou, Li-Ping

Original department name

Department of Clinical Neuroscience, Occupational Therapy and Elderly Care Research (NEUROTEC)

Place of publication

Stockholm

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