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We will combine our 20 year knowledge on the immunomodulatory properties of mesenchymal stromal cell (MSC) transplantation with results from 2 separate projects on neuroinflammation, i.e. multiple sclerosis (MS) and fatigue/cognitive dysfunction after hematopoietic stem cell transplantation (HSCT).We believe that stroma – immune – neuronal crosstalk is defective and that activated perivascular stroma in the CNS is deficient in trophic signals, secretes profibrotic matrix molecules and cytokines that propagate neuroinflammation. In MS, we will continue our characterization of fibrotic perivascular stroma of brain tissue and MSC from MS patients.After HSCT, we have identified patients with cognitive dysfunction, hypoactivation of the prefrontal cortex and decreased immune regulatory proteins and immune subsets in the CNS. We believe that deficiency of trophic signals from the perivascular stroma activate microglia and alloreactive T-cells in the CNS and disrupt synaptic function.In transgenic mice where transcription factor Ebf2 is GFP marked and Ebf2-CreER x Rosa26-DTA mice where MSC can be selectively eliminated by Tamoxifen, we will induce neuroinflammation and study the stroma in the early inflammatory events. Possible reversal of neuroinflammation will be studied after intranasal adoptive transfer of MSC.It is not until we understand the respective contributions of stroma, immune subsets and neurons that we can design targeted therapies in various neuroimmune disorders.

Some blood cancers are only cured with blood stem cell transplantation. In the course of time, the transplanted blood cells may attack the patient's body and an inflammatory reaction may occur, a graft-versus-host reaction (so-called Graft-versus-Host Disease

GvHD). Many improvements have been made in the treatment of stem cell transplant patients, but long-term survival is limited by severe GvH reactions and leukemia recurrences. Our research aims to improve the environment in the patient with combined cell therapies so that GvHD is suppressed while the new immune system is allowed to mature as quickly as possible to prevent leukemia recurrence. We have previously shown, in test tubes and clinical studies, that connective tissue stem cells (mesenchymal stem cells

MSC) inhibit inflammation. We want to understand the interaction between connective tissue and immune cells, how they communicate with each other via direct contact and via complement and coagulation systems, in healthy tissue and diseased tissue. Our hypothesis is that the balance is eliminated in chronic GvHD, a condition characterized by fibrosis in mucous membranes and connective tissue, with little inflammatory spread. We therefore want to study in detail the connective tissue stem cells, ffa from the oral cavity, in the development of chronic GvHD, the cytokine profile of the cells and interaction with immune cells. In order to make the MSC a safe future patient treatment, we work internationally to create routines for how the MSC should be grown and characterized in the laboratory before they are given to patients. In several clinical studies, we evaluate the ability of MSC to prevent and treat immune responses, a new concept that may be important for many disease states. At the same time, we study how connective tissue stem cells, and the cytokine profile in blood, in patients treated with MSC are affected by the treatment to better understand the natural balance between inflammation and anti-inflammation in healthy and diseased tissue.

Certain types of blood cancer are only cured with blood stem cell transplantation. In the bone marrow there are both blood and connective tissue stem cells (mesenchymal stem cells

MSC) which can form bone, cartilage, fat and nourish blood cells. MSC is few in the body but can be grown in the laboratory to many millions of cells. We have previously shown that MSC inhibits inflammation. The MSC differs from blood cells by its ability to hide from the immune system and can be transplanted even between different tissue types. We have isolated the MSC from more than 150 people and given over 100 infusions to patients, mainly to suppress life-threatening transplant reactions and to speed up healing of organs damaged by chemotherapy. The mechanism by which the MSC partly hides the immune system and partly inhibits white blood cells is incompletely understood. We now want to study in more detail, partly in test tubes and partly in animal models, how the MSCs given to patients improved on MSC treatment differ from the MSCs given to patients who have not improved. We also want to study whether the GvH disease patients suffered from differing in the patients who responded and did not respond. We have previously studied how the indirect immune system interacts with the MSC. We now want to focus on how early The direct immune system interacts with connective tissue in the body during the onset of GvH disease, and partly how it is affected by MSC treatment, so that the cell types together counteract inflammation. We also want to understand how the blood reacts when the MSC is injected into the bloodstream to patients. In order to make the MSC a safe future patient treatment, we work internationally to create routines for how the MSC should be grown and characterized in the laboratory before they are given to patients. In several international studies, which we lead, MSC's ability to prevent and treat immune responses is evaluated, a new concept that may be important for many disease states.