Immune-regulatory networks and disease initiation

(Projects A07, A09, A11, A12, B04, B08)

In the recent years we learned a lot about disease initiation in MS by investigating molecular mechanisms of lymphocyte priming and myeloid cell activation in the systemic immune compartment and within the CNS. We currently need to show how the perturbation of immune regulation at a specific site in the systemic compartment has an impact on immune responses in remote niches such as the CNS. In this cluster we want to take the analysis of large human data sets to the next level by applying two complementary strategies: First, we will integrate multiple data sets including clinical data, imaging data and immune phenotyping data to identify algorithms that describe solid endpoints of the disease phenotype and/or course of MS patients. Second, we will in reverse and refined translational approaches model distinct pathogenic cascades in experimental systems to feed a mechanistic underpinning of prognostic markers and potential therapeutic targets. By these means we aim at understanding how functional specializations of immune cells in the systemic immune compartment and in the CNS are causally linked to relevant clinical outcomes. To learn more about the individual project please look here . . .

Immune Cell Trafficking

(Projects B01, B03, B15)

CNS infiltration of immune cells is one of the most prominent hallmarks of MS pathology and has been key to some of the most efficacious immune-modulatory therapies as well. The analysis of mechanisms by which immune cells are attracted to and migrate into and back from the CNS has been a major area of research in MS – and in this CRC.
These studies have shown that the process of transmigration is more complicated than previously thought. There are several different trafficking routes into the CNS, each of them comprising a different set of endo- and epithelial cells with their own and unique expression of (adhesion) molecules: They are subject to dynamic changes under homeostatic versus pathological conditions (e.g., during acute and chronic neuroinflammation). To obtain a more comprehensive understanding of the transmigration process, subsequent studies will investigate the migratory behaviour of distinct immune-cell subpopulations and relate it to their cell surface molecules, cytokine production or transcription signatures.
This cluster combines 1) long-standing expertise in working with primary human cells of various tissues, employing physiological flow in vitro models of the brain barriers and 2) large-scale next-generation sequencing (e.g., adaptive immune receptor or snRNA-seq) with algorithm-based analy-sis to answer questions of tissue- or antigen-specificity. Observations generated by analysing hu-man clinical samples are reverse translated into experimental murine models of MS to dissect pathways and mechanisms, and to delineate causal relationships. Treatment of MS patients with immunomodulatory drugs and their influence on immune cell-brain barrier interactions serves as a human in vivo paradigm to study CNS immune surveillance (e.g., during MS remission), a proposed lack thereof (e.g., in PML cases) or pathology-associated infiltration (e.g., during a MS relapse). To learn more about the individual projects, please look here.

Immune-Mediated Damage and Repair

(A03, B05, B06, B07, B09, B10, B12, B13, B14)

Our capabilities to measure and control the dysregulation of peripheral immune activation in multiple sclerosis have continued to improve within the last years. This is evidenced by the increasing number of approved drugs that mainly act outside the central nervous system (CNS). Despite this, our understanding of the inflammatory reaction within the CNS compartment are relatively limited – and as a result our abilities to monitor and interfere with it.
This is particularly relevant for advanced stages of MS. There the control of progressive tissue inflammation and the repair of resulting damage to neurons and oligodendrocytes have remained major unmet medical needs. The overarching goal of this subclus-ter is to tackle these unmet needs and work towards providing an improved mechanistic under-standing, refined biomarkers and new therapeutic targets for diseaseprogression in MS. We want to achieve this by using approaches that rely on i) innovative models of CNS inflammation and progressive pathology and ii) longitudinal MS patient cohorts with multidimensional clinical, imaging and biological analysis. Key aspects of neuronal, glial and immune pathology underlying chronic CNS inflammation will be addressed by the following projects. To learn more about the individual project please look here.

Cluster “Environment”

(A01, A08, A10)

The impact of environmental influences such as dietary factors on initiation and progression of var-ious autoimmune diseases, including MS, is now widely acknowledged. From a therapeutic point of view, targeted modulation of nutritional factors represents a promising approach for a personalized intervention that supports conventional treatment regimes. In the previous funding periods, this re-search subcluster has focussed on two major “environment” axes: the gut-CNS-axis and the skin-CNS-axis. Now we want to to introduce a molecular understanding of the impact of environmental cues on immune responses not only at body surface areas (mucosal immunity, skin immunity) but in the systemic immune compartment and at remote tissues (including the CNS).
In detail, the identification of molecular pathways into which environmental factors feed, and by that means control tissue responses, is a key vision of this subcluster. Methodologically, the environment subcluster will highly developed model systems and patient cohorts in order to refine and validate mechanistic pathways in a bidirectional translational approach, identifying and validating novel therapeutic principles and targets by combining forward, reverse and refined translation. The environmental subcluster has the vision to equip correlations between environmental cues and disease outcome with mechanistic underpinnings that will not only improve lifestyle counselling of patients but eventually provide druggable targets and validated biomarkers for the impact of environmental factors on the disease outcome in patients. To learn more about the individual project please look here.

Clinical Translation Unit

(Z02, V)

The overall aim of this platform is to support various translational aspects of the CRC128. In particular, we pursue the following approaches:Provide a platform for „proof-of-concept“ clinical studies (association with project A08)

• Provide a platform for „proof-of-concept“ clinical studies (association with project A08)
• Present a translational platform for support of single scientific projects in order to strengthen their translational aspects (examples are A01, A08, A09, B03, B07)
• Provide a service platform in terms of infrastructure as well as biomaterial collection for use in individual scientific projects (examples are A08, A09, A10, B01, B08)

More about our team can be found here . . .