Forschung
Transplantation Immunology LabImmunobiology labNon-invasive biomarkers, that detect early allograft rejection or injuryTransplantation Immunology Lab
Team: Mark Daniels, Diana Gil, Barbara Hausmann, Gideon Hönger, Michel Mallaun, Dieter Naeher, Dominique Roubaty, Adam Schrum, Emma Teixeiro, Ed PalmerWhile transplantation has been successfully used to treat many types of organ failure, it is limited in the long term by the immune system’s intolerance of the graft. Graft rejection is initiated by T lymphocytes and reflects the immune systems’ pre-occupation with eliminating cells, which are “non-self”. Our goal is to use our knowledge of T cell biology to extend the time that transplanted organs can be maintained.
The T cell receptor: a decision maker for the T lymphocyte
T cell tolerance is established in the thymus, where negative selection eliminates self-reactive T cells. On the other hand, positive selection generates functional T cells specific for foreign antigens (including transplantation antigens). The molecular bases of positive and negative selection are not understood and we are actively working to understand this central issue in T cell immunology. The central question is how the T cell receptor’s affinity for an antigen determines whether a developing T cell will be positively or negatively selected. We are using a combination of genetics, cellular immunology, biochemistry and microscopy to address this question.
Life and Death for peripheral T cells
In the presence of foreign antigen, peripheral T cells divide, develop effector functions and eventually undergo activation induced cell death (AICD). Another focus in the laboratory is to better define how the T cell receptor independently signals T cell proliferation and AICD and how the ratio between division and death controls T cell homeostasis.
Transplantation tolerance
We have also developed a model of graft rejection by transplanting MHC-disparate skin onto mice, whose T cells express an allo-reactive TCR. This model allows one to follow the graft-rejecting T cells, through the activation and effector phases. Using this experimental system we are developing and testing strategies for inducing peripheral tolerance to the grafted skin.
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Immunobiology lab
Team: Olivier Gasser, Thomas Schmid, Ineke Oehri, Gideon Hönger, Gabriela Zenhäusern, Christoph HessHLA class I restricted CD8 T cells are an essential component of the protective immune response against a variety of viral infections. An effective host response to infection depends on production of functional CD8 T cells and their attraction to sites of viral replication.
Our lab is interested in factors that determine an efficient CD8 T cell response in humans. Specifically we are investigating migration/homing properties of CD8 T cell subsets formed during the process of activation and differentiation.
The molecular mechanisms that control CD8 T cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Efficient migration of cytotoxic CD8 T cells into sites of infection is intimately linked to their function. We are investigating expression, regulation and function of inflammatory T cell chemokine receptors (e.g. CXCR3, CCR5, CX3CR1, and CXCR1) expressed on antigen-specific and bulk CD8 T cell subsets with effector function.
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Non-invasive biomarkers, that detect early allograft rejection or injury
Project Stefan Schaub, MDAt present, repeated measurements of serum creatinine are used to monitor the allograft function non-invasively, but creatinine levels can underestimate the extent of allograft rejection or injury. In contrast, an allograft biopsy allows detailed analysis of the pathology, however, sampling errors can occur and biopsies cannot be performed frequently (e.g. weekly) due to the associated costs, inconvenience, and possible complications. Non-invasive biomarkers, that detect early allograft rejection or injury and can be measured repeatedly, may allow for timely therapeutic interventions preventing ongoing allograft damage. The aim of our study is to detect urine proteins that are associated with allograft rejection using an unbiased mass-spectrometry based proteomic approach. We recently identified cleaved urinary ß2-microglobulin as a promising biomarker for acute tubular injury related to rejection. The greatest utility of non-invasive urine biomarkers may be to determine that they are normal, and by inference that the allograft is devoid of rejection and/or injury. This may allow for safe tapering of immunosuppression, whereas abnormal values may warrant further investigation (i.e. allograft biopsy).
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