Olle Korsgren's projects – TID therapy by transplantation of mesenchymal stem cells
In collaboration with Per Ola Carlsson, Dept. of Medical Sciences, Uppsala University
The hypothesis tested in these projects is that the development of TID may be halted at diagnosis by the immunomodulatory properties of mesenchymal stem cells (MSC). The development of overt TID with complete loss of endogenous insulin production would thereby be prevented and patients benefit from mild diabetes, requiring only low doses of exogenous insulin, or even return to normoglycemia without exogenous insulin.
The bone marrow contains not only hematopoietic cells, but also mesenchymal stem cells (MSC). MSC constitute only 0.001-0.01% of total nucleated cells, but have unique immunosuppressive capacities. They reduce the generation and differentiation of dendritic cells and B-cells, and down regulate NK cell cytotoxicity and proliferation. Moreover, they increase the percentage of regulatory T-cells, and suppress effector T-cell proliferation in response to nominal antigens or alloantigens.
MSC-mediated inhibition of T-cells is also associated with a reduction in inflammatory cytokine production. Several soluble factors have been implicated in the mechanism of MSC-mediated immunosuppression, including TGF-beta, HGF, prostaglandin E2, IL-10, indoleamine 2,3-dioxygenase, NO, heme oxygenase-1 and matrix metalloproteinases-2, and -9.
MSCs have immunosuppressive capacity
In experimental animal models, MSC have been shown to improve the outcome of renal, neural and lung injury by promoting a shift from pro-inflammatory to anti-inflammatory cytokines at the site of injury. Several studies indicate that MSC may protect or ameliorate experimental TID. In mice treated with daily low doses of the beta-cell toxin streptozotocin, MSC obtained from human bone marrow were found to home to and promote repair of pancreatic islets, thereby ameliorating the level of diabetes. MSC also protected from diabetes in the non-obese diabetic (NOD) mouse model by inducing regulatory T-cells in pancreatic lymph nodes.
MSC have marked immunosuppressive capacity in vivo also in humans. Life-threatening therapy-resistant grade III and IV graft vs. host disease (GvHD) of the gut and liver was dramatically suppressed in patients after MSC infusion. Promising preliminary results are also emanating from an ongoing open randomized clinical study conducted in collaboration with Prof Katarina LeBlanc, KI, Stockholm, in which the efficacy of islet transplantation with or without the support of autologous MSC is investigated. No adverse side effects of MSC treatment have yet been observed in these or other clinical studies.
Transplantation of MSCs to treat TID patients
We intend to use autologous MSC for treatment of recently diagnosed patients with TID. Such cell-based therapy is likely to simultaneously target several different immunological pathways, thereby utilizing numerous physiological mechanisms for re-establishing immune tolerance and induction of cellular repair mechanisms.
The patients will receive autologous MSC, although substantially expanded in vitro prior to transplantation, thereby avoiding potential risk of HLA immunization, transfer of viral infections and other diseases. Proof of concept has been shown in animal models of TID, and safety and potency for immune suppressive capacities of autologous MSC already tested in humans. Pending positive outcome in safety and efficacy of the proposed pilot study it can be expanded to include more patients also at other centers.
The study is an open, single center, randomized pilot study. Phenotypical analysis of lymphocytes and their antigen-specific cellular responses will be performed to identify immunological changes (immunological footprint) that could mark progression of beta cell specific autoimmunity. The detailed analysis of circulating lymphocytes and their antigen-specific cellular responses will be instrumental in the understanding of the mechanisms behind the autoimmune progression towards TID and to monitor the effect of the transplanted MSC in clinical trials.