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Modulation of immune responses in experimental autoimmune encephalomyelitis

thesis
posted on 2024-09-02, 19:43 authored by Maja Wållberg

The aim of this thesis work has been to elucidate mechanisms for modulation of the immune response in experimental autoimmune encephalomyelitis (EAE), the animal model for the human disease multiple sclerosis (MS).

MS is a degenerative disorder of the central nervous system (CNS) believed to be of autoimmune origin, meaning that components of the immune system attack the tissue in the CNS causing inflammation and destruction. The underlying cause for the attack against self tissue remains unclear, and probably depends on several factors acting together. Genetic as well as environmental risk factors have been suggested. To date there is no cure for MS. That several factors act together to cause MS of course makes it more difficult to solve the mystery of the disease's etiology. However, if several factors need to synergise in order for disease to occur, one should be able to prevent disease by just removing one of them.

In a mouse model for MS, myelin oligodendrocyte glycoprotein (MOG)-induced EAE, we have studied very diverse ways of influencing the pathogenic immune response to CNS antigens, both in disease-preventing and disease-promoting ways.

In the first two studies, we have studied mechanisms for induction of antigen-specific tolerance. Through intra-peritoneal injection of MOG adsorbed to the weak adjuvant alum, we induced a benevolent type of immunity that protected the mice from developing EAE upon later challenge with MOG in the strong adjvant complete Freund's adjuvant (CFA) normally used to induce EAE. The protective effect was mediated through antigen-specific production of TGF-beta, and T cells producing this cytokine could also down-regulate the immunostimulatory properties of antigen presenting cells (APCs) in vitro.

In the third study, we investigated the impact of infection with Trypanosoma brucei brucei (Tbb) on the development of EAE. We discovered that concurrent infection abrogated development of EAE and that infected animals, in concordance with previous studies, were severely immunosuppressed. This immunosuppression was determined to be caused at least in part by parasite-induced APCs, which were deficient in their capacity to activate T cells. This in turn was in part attributed to increased production of IL-10 in the APCs from Tbb-infected hosts. IL10 from APCs from infected mice could down-regulate the function of control APCs in co-cultures, and APCs from infected mice could mitigate or prevent EAE in MOG-CFA immunised mice when transferred 7 days after immunisation.

The fourth and final study in this thesis concerns the properties of the antigen itself, in our case MOG. We investigated how the formation of adducts on lysine residues through incubation with malondialdehyde (MDA), a reactive dialdehyde formed during lipid peroxiadation in the body, affects the immunogenicity and encephalitogenicity of the protein. We determined that the MDA adducts did render MOG more immunogenic, and that this increase in immunogenicity was caused by increased uptake of the modified protein into APCs. Increased uptake was mediated by scavenger receptors of class A. MDA modified MOG was more encephalitogenic than was non-modified MOG, and interestingly it was also more efficient when used in the protective protocol described in the first two studies in this thesis. Additionally, pulsing of bone marrow derived macrophages (BMMphi) with MDA-MOG resulted in upregulation of transcription of the pro-inflammatory cytokines IL-12 and IL-23 as well as their receptors, indicating yet another mechanism for the increased immunogenicity of the modified protein.

List of scientific papers

I. Wallberg M, Wefer J, Harris RA (2003). Vaccination with myelin oligodendrocyte glycoprotein adsorbed to alum effectively protects DBA/1 mice from experimental autoimmune encephalomyelitis. Eur J Immunol. 33(6): 1539-47.
https://doi.org/10.1002/eji.200323772

II. Wallberg M, Harris RA (2005). MOG-alum-induced regulatory T cells down-regulate APC function through secretion of TGF beta. [Manuscript]

III. Wallberg M, Harris RA (2005). Coinfection with Trypanosoma brucei prevents experimental autoimmune encephalomyelitis in DBA/1 mice through induction of suppressor APCs. International Immunology. [Accepted]
https://doi.org/10.1093/intimm/dxh253

IV. Wallberg M, Bergquist J, Achour A, Breji E, Harris RA (2005). Malondialdehyde-modification of Myelin Oligodendrocyte Glycoprotein leads to increased encephalitogenicity and vaccine efficacy. [Submitted]

History

Defence date

2005-05-04

Department

  • Department of Medicine, Solna

Publication year

2005

Thesis type

  • Doctoral thesis

ISBN-10

91-7140-335-3

Number of supporting papers

4

Language

  • eng

Original publication date

2005-04-13

Author name in thesis

Wållberg, Maja

Original department name

Department of Medicine

Place of publication

Stockholm

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