Research Report 2010 - MDC

Kirsten Falk andOlaf RötzschkeStructure of the GroupGroup LeaderDr. Kirsten FalkDr. Olaf RötzschkeScientistsDr. Mireille StarkeDr. Markus KleinewietfeldGraduate andundergraduate studentsSabine HöpnerShashank GuptaKatharina DickhautReiner MailerAlexander SternjakCellular Immunology of Autoimmunereactions – Controlling the Balancebetween Effector and Suppressor T cellsDirection and strength of the immune response is largely controlled by the equilibrium betweeneffector and suppressor T cells. While effector T cells drive proinflammatory reactions toeradicate pathogens and transformed cells, suppressor T cells prevent autoimmune reactions aswell as the collateral damage by keeping the effector cells in check. It is now generally acceptedthat regulatory T cells (Treg) are a key suppressor population responsible for the maintenance ofperipheral tolerance. Characteristic marker of Treg cells is the transcription factor Foxp3. Specificaim of the group is to understand the composition and function of Treg subsets and to exploretheir role for future immune interventions in autoimmune diseases and cancer.Antigen-specific Recruitment of Treg cells andTreg-based cell therapiesCooperation with the SFB650, Berlin, the BMBF networkproject ‘BIOTIA’, and the ‘Singapore Immunology Network’(SIgN), SingaporeTreg cells may offer a novel perspective for the treatmentof autoimmune diseases as the antigen-specificrecruitment of these cells could result in dominant protectionfrom the autoimmune attacks. In several experimentalanimal models we have demonstrated thatrepeat antigens consisting of linear copies of a T cellepitope are particularly effective to inducing this effect.This applies for the treatment of multiple sclerosis-likeautoimmune disease (EAE), as well as for experimentalautoimmune neuritis (EAN) and an animal model oftype I diabetes (T1D). Recent studies further suggestthat the strategy is also widely used by parasites suchas plasmodium spec to mediate immune evasion. In a“bionics approach” tolerogenic repeat regions identifiedin the malaria parasite plasmodium falciparum are currentlybeing tested in the autoimmune model of multiplesclerosis.in the context of the BIOTIA network.In another approach the group has developed a methodthat provides access to ‘untouched’ human Treg cells. Ithas been documented numerous times in mice that theadoptive transfer of Treg cells is a very effective celltherapeuticapproach to treat inflammatory diseasesand syndromes. Translation of these approaches intoclinical praxis however was hindered by the lack of suitablecell isolation techniques. The new approach allowsnow obtaining highly pure populations of human Tregcells particularly suitable for therapeutic applications Ina mouse model of ‘graft vs. host disease’ (GvHD), thecells have been proven already to be capable of controllingthe disease. In a joint project with SIgN, a clinicalphase I trial has been launched in Singapore, in which‘untouched’ Treg cells will be used to treat GvHD inleukaemia patients.Extracellular ATP and CD39+ Treg cellsCooperation with Santa Lucia Foundation, Rome, Italy, theGRK 1258, Berlin and SIgN, SingaporeAs indicator of ‘non-natural’ (necrotic) cell death ATP isreleased through the damaged cell membrane into theextracellular space. It triggers various proinflammatoryreactions such as the maturation of dendritic cells (DC)and the regulation the inflammasome-mediatedrelease IL-1. The latter is also known as ‘endogenous134 Cancer Research