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Strategies for targeted lymphocyte modulation to prevent organ rejection and treat autoimmune diseases
AG Schaier
Lymphocytes and their subtypes play an important role both in the pathogenesis of organ rejection and in autoimmune diseases. The migration, proliferation, apoptosis and function of lymphocytes can be influenced by the targeted use of pharmacological substances. Furthermore, the effectiveness of established substances such as mycophenolic acid can be increased by individualized therapy monitoring using pharmacodynamic measurement of IMPDH activity.
Certain subtypes of regulatory T lymphocytes make it possible to identify patients who have an increased risk of organ rejection or an autoimmune disease, thus enabling a more targeted use of immunosuppressants.
A) Pharmacodynamics: more targeted therapy through IMPDH monitoring
In addition to pharmacokinetic monitoring of MPA concentration, pharmacodynamic monitoring of IMPADH activity has also been established for patients after kidney transplantation and autoimmune patients with mycophenolic acid therapy (Schaier M, Rheumatology, 2010; Sommerer C, Br J Clin Pharmacol, 2010). Furthermore, we were able to show that proton pump inhibitors interact significantly with the absorption of the mycophenolic acid derivative MMF (Schaier M, Rheumatology, 2010).
B ) Identification of specific Treg subpopulations for individualized immunosuppression
Regulatory T cells (Tregs) are of central importance for the maintenance of feto-maternal immune tolerance during pregnancy. These immunosuppressive cells also significantly influence the acceptance of a transplanted organ.
We were able to identify major similarities with regard to changes in specific Treg subpopulations and their functional activity in pregnant women and kidney transplant recipients (Kisielewicz A, Schaier M, Clin Immunology, 2010).
Furthermore, we were able to show that the suppressive activity of the total Treg cell pool is significantly dependent on its proportion of DRlow+ and DRhigh+ Tregs and thus on its HLA-DR Mean Fluorescence Intensity (MFI) of the DR+ Treg population (Schaier M, PLoS ONE, 2012).
This HLA-DR MFI of DR+-Tregs is significantly reduced in patients with acute transplant rejection and can be used as a non-invasive marker for screening early acute transplant rejection (Schaier M, Transplant Intern, 2012).
In patients with acute rejection, steroid bolus therapy leads to an increase in highly suppressive DRhigh+ Tregs. (Seissler N, Transplant Immunol, 2012).
Patients with normal and disturbed course of pregnancy, patients with autoimmune diseases as well as kidney transplant patients with complication-free course and acute transplant rejection serve as test subjects.
These investigations could identify various known or new Treg subpopulations that are important for immune monitoring during a high-risk pregnancy or after an organ transplant.
It is possible that such immune monitoring could enable individualized immunosuppressive therapy.
Projekt-Leitung
PD Dr. med. Matthias Schaier
matthias_schaier@med.uni-heidelberg.de
+49 6221 9112 0
Persons involved
Sabine Bönisch-Schmidt
Cand. med. Christine Altenmüller
Cand. med. Angèle Leick
Cand. med. Janice Maib
Partner
Prof. Dr. Andrea Steinborn, Dept. of Gynaecology, University of Heidelberg
Prof. Dr. Claudia Sommerer, Heidelberg Kidney Center