Subclinical CNS Inflammation as Response to a Myelin Antigen in Humanized Mice
- 647 Downloads
Multiple sclerosis is a demyelinating autoimmune disease of the CNS. Its animal model experimental autoimmune encephalomyelitis is commonly induced by active immunization with myelin antigens. To investigate human immune responses against myelin antigens in vivo we established a new subclinical experimental autoimmune encephalomyelitis model in humanized mice. NOD/Scidγc−/− animals were transferred with peripheral blood mononuclear cells from healthy human donors and immunized with myelin antigens in complete Freund’s adjuvant and antigen-pulsed autologous dendritic cells. Human T cells recovered from these animals reacted specifically to the soluble domain of myelin oligodendrocyte glycoprotein and secreted proinflammatory cytokines. Furthermore, immunized animals developed subclinical CNS inflammation with infiltrating CD4+ and CD8+ T cells and production of encephalitogenic cytokines. Thus, this model of myelin-induced CNS inflammation by human T cells may allow testing of new human-specific therapeuticals for multiple sclerosis.
KeywordsEAE Humanized mice MOG NSG moDC
monocyte-derived dendritic cells
myelin oligodendrocyte glycoprotein
ionized calcium binding adaptor molecule 1
We thank André Heinen, Petra Adams and Nicole Roder for excellent technical support. This work was supported by the DFG via TR128 to FK (TP A03) and to AW (TP A07).
Disclosure of conflicts of interest
The authors have no conflict of interest. The manuscript contains a part of the medical thesis of Morad Zayoud.
- Babbe H, Roers A, Waisman A, Lassmann H, Goebels N, Hohlfeld R, Friese M et al (2000) Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 192:393–404PubMedCrossRefGoogle Scholar
- Brehm MA, Cuthbert A, Yang C, Miller DM, DiIorio P, Laning J et al (2010) Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation. Clin Immunol 135(1):84–98PubMedCrossRefGoogle Scholar
- Pette M, Fujita K, Wilkinson D, Altmann DM, Trowsdale J, Giegerich G et al (1990) Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple-sclerosis patients and healthy donors. Proc Natl Acad Sci U S A 87(20):7968–7972PubMedCrossRefGoogle Scholar
- van Rijn RS, Simonetti ER, Hagenbeek A, Hogenes MC, de Weger RA, Canninga-van Dijk MR et al (2003) A new xenograft model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2−/− gammac−/− double-mutant mice. Blood 102(7):2522–2531PubMedCrossRefGoogle Scholar