Liver Transplantation MDL

Liver transplantation (LTx) is the only adequate treatment for end-stage liver diseases. On the short-term it is a successful treatment, but long-term patient survival and quality of life is severely impaired by complications caused by continuous immunosuppressive treatment and hepatitis virus re-infection. These clinical problems are the basis of our research. Principal investigators in the lab are dr. Jaap Kwekkeboom and dr. Luc van der Laan. Close interaction with the liver transplant physicians in the Erasmus MC, under supervision of Prof. dr. Herold Metselaar and prof. dr. Hugo Tilanus, ensures that our research has a typically translational character.

 

 

 

Researchers involved

 

 


J. Kwekkeboom
(Jaap), PhD
Group leader[CV]
Interim Head of Laboratory


Prof. H. J. Metselaar,
(Herold), MD PhD
 [CV]


P.P.C. Boor
(Patrick), BSc,
PhD Student


O. Tapirdamaz
(Ozlem), MD,
PhD Student

A. Tjon
(Angela)
PhD student

V. Moroso
(viviana)
PhD Student

S. Mancham
(Shanta), BSc,
technician

1. Understanding immunological tolerance to liver grafts
In contrast to other solid organ grafts, LTx results in leukocyte chimerism. We observed that dendritic cells, regulatory T-cells and NK-cells detach from human liver grafts after transplantation, and migrate via the blood circulation into the recipients. By studying the characteristics of hepatic leukocytes that detach from human liver grafts during pre-transplant perfusion, we aim to elucidate how these donor-derived hepatic leukocytes may be involved in chimerism-associated transplant tolerance.
Collaboration: dr. I. Joosten, UMC St. Radboud, Nijmegen.

2. Characteristics of tolerant liver transplant recipients
We identified several genetic polymorphisms in recipient cytokine- and co-stimulatory genes that are associated with the risk of rejection after liver transplantation. Currently, we study the influence of genetic polymorphisms in innate immune receptors on rejection. The results will be used to enable identification of liver transplant recipients in which immunosuppressive drugs can be reduced, and to reveal which innate immune pathways are involved in the balance between rejection and tolerance after LTx.
Using an in-house developed highly sensitive assay, we study whether differences in frequencies of recipient T-cells that recognize donor allo-antigens via the direct pathway, are related to transplant tolerance. A sensitive assay for quantification of recipient T-cells which react to indirectly presented donor HLA molecules is being developed.
Collaboration: Prof. K. Thielemans, Free University, Brussels

3. Safe immunosuppression
We found that treatment of liver transplant recipients with Intravenous Immunoglobulins (IVIg) protects against acute rejection. Basic research revealed that IVIg inhibit allogeneic T-cell activation by at least three mechanisms: suppression of the maturation of dendritic cells (DC), stimulation of killing of DC by NK-cells, and stimulation of the suppressive capacity of regulatory T-cells. Currently, we aim to identify the active component(s) of IVIg that inhibit cellular immune reactions. Biosynthetic compounds that mimic these components may be useful as natural and safe immunosuppressive drugs.
Collaboration: dr. Th. Geijtenbeek, VUMC, Amsterdam.

4. Tolerance induction
We found that human plasmacytoid dendritic cells are potent inducers of anergy in allo-reactive memory T-cells. In addition, they induce the differentiation of Il-10 producing regulatory T-cells that suppress allogeneic memory T-cell responses. Currently, we are developing a protocol for immunotherapeutic induction of transplant tolerance using donor-derived plasmacytoid dendritic cells.

Key publications