Oral mucosal lamina propria progenitor cells as a novel and preferential source for treatment of Graft Vs Host Disease

Graft-Versus-Host-Disease (GVHD) is characterised by a direct attack on the patient?s body by immune cells present within transplanted donor blood stem cells. This disease is a major barrier to transplantation in that it leads to a high death rate. Bone marrow stem cells (BMSCs) can suppress this attack on the patient and reduce the incidence/severity of GVHD but there are problems with using these cells. We have identified within the mouth a novel population of progenitor (stem-like) cells (oral PCs) which are powerful suppressors of immune responses and are more effective than BMSCs, possibly due to something they secrete. This research will investigate in depth how these cells are able to exert their superior suppression on immune cells and how they are different to BMSCs. We will also utilise cutting edge technologies to identify what the soluble factors are so that these cells/factors can ultimately be utilised to help patients. Importantly, oral PCs have distinct advantages for therapeutic applications in that they come from an area of the mouth that is easily accessible and which will heal rapidly with no/minimal resultant scar formation for the patient. We believe that the increased potential of these oral PCs will make them a favoured source of cells for transplantation with blood stem cells in the treatment of GVHD and potentially a number of other diseases where the immune response is dysfunctional.

Mortality due directly to chronic GVHD remains one of the major obstacles in allogeneic haematopoietic stem cell (HSC) transplantation. Research suggests that co-transplantation of mesenchymal stem cells (MSCs) during HSC transplantation results in a significant decrease in acute and chronic GVHD. However, MSC heterogeneity means that trial results are variable and also large cell numbers are required to deliver an immunosuppressive effect which can sometimes initiate an immune response. We have recently demonstrated the existence of a novel, neural crest-derived PC population resident within the lamina propria of the oral mucosa which have a unique immunomodulatory capacity. These clonally-derived oral mucosal lamina propria-progenitor cells (OMLP-PCs) have the ability to lower lymphocyte proliferation back to base levels in the presence of alloantigens, in a contact-independent manner and at ratios as low as 0.001% of OMLP-PCs to allogeneic lymphocytes (levels much lower than for MSCs). This suggests that OMLP-PCs may work via a different mechanism(s) to MSCs and would be potentially more potent/effective than MSCs in the treatment of GVHD. This application will complete the in vitro characterisation of the immunosuppressive potential of OMLP-PCs in direct comparison to MSCs and identify the soluble factors involved in this response. Ultimately this project is aimed at translating our basic research findings into innovative and improved pre-clinical developments for the treatment of GVHD.