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A two-step model for the induction of organ-specific autoimmunity
A Limmer1, T Sacher, J Alferink
1Division of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
Novartis Foundation Symposium
|October 7, 1998
Summary
Peripheral tolerance prevents autoimmunity, but anergic T cells can be dangerous. Reversing tolerance in mice required a second step—inflammation—to trigger liver autoimmunity, suggesting a two-step process for autoimmune disease development.
Area of Science:
- Immunology
- Autoimmunity
- Transplantation Immunology
Background:
- Peripheral tolerance is crucial for preventing autoimmune diseases.
- Anergic T cells, though tolerant, pose a potential risk for autoimmunity.
- Liver-specific tolerance models are essential for studying autoimmunity mechanisms.
Purpose of the Study:
- To investigate if reversing peripheral tolerance in vivo directly causes autoimmunity.
- To determine the conditions necessary for autoimmunity development after tolerance reversal.
- To explore the implications for autoimmune disease treatment and tumor therapy.
Main Methods:
- Utilized transgenic mice with established tolerance to a foreign MHC class I antigen (Kb) in the liver.
- Reversed tolerance by administering tumor cells expressing Kb and interleukin-2.
- Induced liver inflammation using irradiation or Listeria infection to condition the target organ.
Main Results:
- Reversed T cells could reject Kb-positive grafts but did not attack the Kb-positive liver spontaneously.
- Liver inflammation (conditioning) was necessary to induce massive T cell infiltration and liver damage in reversed mice.
- Autoimmunity requires both activation of antigen-specific T cells and conditioning of the target organ.
Conclusions:
- Autoimmunity development is a multi-step process, necessitating both T cell activation and target organ conditioning.
- Understanding the factors involved in target organ conditioning, potentially including adhesion molecules, is critical.
- These findings have significant implications for developing therapies for autoimmune diseases and cancer.