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Spontaneous tolerance: experience with the rat liver transplant model
Bettina Dresske1, Xionbing Lin, Dong-Sheng Huang
1Department of General and Thoracic Surgery, University of Kiel, Arnold-Heller-Strasse 7, 24105 Kiel, Germany. dresske@t-online.de
Human Immunology
|October 9, 2002
Summary
Passenger leukocytes within liver allografts are crucial for inducing spontaneous liver tolerance in rats. Removing these leukocytes via irradiation prevents tolerance, but restoring them with donor cells re-establishes acceptance, highlighting their role in graft survival.
Area of Science:
- Immunology
- Transplantation Biology
- Graft Tolerance Mechanisms
Background:
- Spontaneous liver tolerance in allogeneic transplantation is linked to soluble MHC class I antigens and passenger leukocytes (PL).
- The precise role of PL and intra-graft defense mechanisms in long-term liver allograft acceptance requires further elucidation.
Purpose of the Study:
- To delineate the specific contribution of "passenger leukocytes" (PL) to liver allograft tolerance.
- To investigate the local intra-graft defense mechanisms in long-term accepted liver allografts.
Main Methods:
- Orthotopic liver transplantation in Lewis (LEW) and DA rats, with and without whole-body irradiation (WBI) to deplete PL.
- Characterization of Fas/FasL expression and apoptotic cell death using immunohistochemistry and TUNEL staining.
- Analysis of gene expression via reverse transcriptase-polymerase chain reaction (RT-PCR) for Fas and FasL.
Main Results:
- Irradiation-induced depletion of PL abrogated liver allograft tolerance, while syngeneic PL reconstitution restored it.
- Tolerized allografts showed increased FasL expression on hepatocytes and high proliferating cell counts, suggesting active immune modulation.
- Apoptotic lymphocytes were abundant in the portal tract of tolerized grafts, indicating FasL-mediated elimination of effector cells.
Conclusions:
- Non-resident passenger leukocytes significantly contribute to liver allograft acceptance and spontaneous tolerance induction.
- The FasL/Fas pathway on graft hepatocytes mediates peripheral deletion of alloreactive lymphocytes, a key tolerogenic mechanism.
- Liver tolerance is primarily induced within the graft itself, mediated by its resident non-parenchymal cells.