Immunopathology & Immune Tolerance

Our research focus is on the development of new pharmacological treatment options for chronic inflammatory diseases that arise from dysregulated immune system in the skin, the gastrointestinal tract, the musculoskeletal or central nervous system. Although the respective diseaseas such as rheumatoid arthritis or multiple sclerosis are clearly distinct entities and differ considerably in their clinical manifestations they, share a loss of immunological self tolerance as a common pathogenic feature. Conventional treatments strive at interfering with the effector pathways fueled by an imbalanced adaptive and innate immune system using glucocorticoids, cytotoxic agents or antagonists of critical cytokines. Accordingly, therapeutic efficacy is closely associated with undesired unspecific immunosuppression. Targeting of T and/or B lymphocytes in an antigen specific manner to induce regulatory cells for re-establishment of a state of unresponsiveness to self in the immune system without need for broad immunosuppression to counteract pathogenic autoimmunity is currently being explored.

Core competencies:

Experience in drug development in the field of Rheumatic diseases: animal models of arthritis, clinical studies
Pphase I - IV
Biomarker development
In vitro differentiation of immune cells
Recombinant production of antigens/immune receptors
Functional immune assays
T- and B cell epitope mapping
Preclinical studies in the experimental model of collagen II induced arthritis (CIA)

Tabbed contents

Expand all Close all

Services

The innovation platform offers consulting services in the area of development of innovative immunomodulatory therapies and, depending on the respectively identified needs of the costumer, solutions combined with specific service offers in cooperation with the areas of drug discovery, preclinical research and clinical research.

Selected Projects

Therapeutic immunomodulation of rheumatoid arthritis using recombinant MHCII peptide complexes

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic joint disease that leads to joint destruction and inflammation-associated systemic comorbidities via an immune-mediated chronic inflammatory process. Despite improved immunosuppressive therapeutic options, the medical need for personalized, long-term effective and tolerable treatment strategies continues. A therapeutic immune modulation adapted to the patient's MHC genotype by the therapeutic application of MHCII/collagen II (CII) peptide complexes for the induction of regulatory T cells is currently being developed in the experimental arthritis model of collagen type II arthritis (CIA) as well as in functional studies of lymphocyte subpopulations from human blood samples in vitro. In addition, the molecular mechanisms underlying the pharmacological effects are characterized.

Establishment of a humanized mouse model of CII induced arthritis to evaluate the effectiveness of therapeutic vaccinations with human MHCII peptide complexes

For the preclinical development of human allele-specific MHCII peptide complexes, the availability of new humanized models of arthritis to evaluate the therapeutic potential of promising drug candidates is critical. In cooperation with Prof. Rikard Holmdahl (Medical Inflammation Research, Karolinska Institute, Stockholm), humanized mouse lines are established that have a physiological expression of human DR molecules; ensured by a “knock-in” of the ectodomain of the non-polymorphic DRA gene in combination with either the RA-associated DRRB1 allele: * 0401 (dominant RA-associated allele in Caucasians) or the protective * 0402 allele (for specificity control). In these mouse lines, the therapeutic effects of the human allele-specific MHCII peptide complexes will be evaluated upon arthritis induction by immunization with human CII.

Establishment of immune monitoring of induced regulatory T cells and characterization of regulatory B cell subpopulations in the peripheral blood of RA patients.

With regard to the clinical development of a therapeutic immunomodulatory vaccination, the establishment of a standardized immune monitoring of the T cell phenotype specifically induced by the active substance is important. Accordingly, flow cytometric determinations of surface markers (e.g. PD1, Lag3 etc.) and bead-based immunoassays to characterize the cytokine profile of the responder cell population are performed. Fluorescence-labeled MHCII-peptide-tetramer complexes allow the detection and sorting of specific T cells for transcriptome analyzes (RNAseq), which enable differences in the expression profile to be recorded at the individual cell level in order to identify suitable biomarkers using biostatistical analysis methods. In addition, antigen-specific regulatory B cells (Breg) in the peripheral blood of RA

patients are currently being analyzed with regard to their potential importance as target structures for immunomodulatory interventions.

Partner:
Cooperation partner mRNA Seq: Dr. Kai Sohn, Fraunhofer IGB Stuttgart
Cooperation partner Breg: Prof. Rikard Holmdahl, Medical Inflammation Research, Karolinska Institute, Stockholm

Selected Publications

Janczi T, Böhm BB, Fehrl Y, DeGiacomo P, Kinne RW, Burkhardt H.
ADAM15 in apoptosis resistance of synovial fibroblasts: Converting Fas/CD95 death signals into the activation of prosurvival pathways by calmodulin recruitment.
Arthritis Rheumatol. 2019 Jan;71(1):63-72
doi: 10.1002/art.40667

Zhong J, Scholz T, Yau ACY, Guerard S, Hüffmeier U, Burkhardt H, Holmdahl R.
Mannan-induced Nos2 in macrophages enhances IL-17-driven psoriatic arthritis by innate lymphocytes.
Sci Adv. 2018 May 16;4(5):eaas9864
doi: 10.1126/sciadv.aas9864

Ge C, Tong D, Liang B, Lönnblom E, Schneider N, Hagert C, Viljanen J, Ayoglu B, Stawikowska R, Nilsson P, Fields GB, Skogh T, Kastbom A, Kihlberg J, Burkhardt H, Dobritzsch D, Holmdahl R.
Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
JCI Insight. 2017 Jul 6;2(13): e93688
doi: 10.1172/jci.insight.93688

Sehnert B*, Burkhardt H*, Wessels JT, Schröder A, May MJ, Vestweber D, Zwerina J, Warnatz K, Nimmerjahn F, Schett G, Dübel S, Voll RE. (*shared last authorship).
NF-κB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-κB in immune-mediated diseases.
Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16556-61
doi: 10.1073/pnas.1218219110

Hüffmeier U, Uebe S, Ekici AB, Bowes J, Giardina E, Korendowych E, Juneblad K, Apel M, McManus R, Ho P, Bruce IN, Ryan AW, Behrens F, Lascorz J, Böhm B, Traupe H, Lohmann J, Gieger C, Wichmann HE, Herold C, Steffens M, Klareskog L, Wienker TF, Fitzgerald O, Alenius GM, McHugh NJ, Novelli G, Burkhardt H*, Barton A*, Reis A* (*shared last authorship).
Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.
Nat Genet. 2010 Nov;42(11):996-9
doi: 10.1038/ng.688