Mesenchymal Stem Cell Therapy in a Rat Model for GvHD

Graft-vs-host-disease (GvHD) is an important hindrance for the usage of allogeneic bone marrow cell transplantation (alloBMT) as a treatment strategy for leukemias and other hematopoietic malignancies. Mesenchymal stem cells (MSC) can interact with the immune system and inhibit alloreactive cells. Infusions of MSC into GvHD patients have alleviated disease severity and overall survival and in recent clinical trials.

We are studying the immunoregulatory potential of MSC as a putative therapy for GvHD in an experimental animal model. Bone marrow-derived MSC from PVG rats are highly efficient in blocking PVG lymphocytes stimulated by allogeneic BN lymphocytes in mixed lymphocyte reactions. We have found a substantial contribution of indirect (without cell contact) inhibition of allostimulation by MSC in vitro, and have examined some of the possible mediating factors among rat cytokines. In our in vivo model we have transplanted BN host rats with 30×10⁶ PVG donor bone marrow (depleted for T cells), and induced GvHD by injection of 1×10⁶ peripheral T cells from PVG donors two weeks later. We have successfully reversed the lethality of GvHD in a number of diseased animals by pre-emptive and repeated infusions of MSC, improving the overall survival rate by 30%. We are furthermore able to trace injected MSC in vivo, and thereby hope to obtain important information on the migration and behaviour of those cells in the development of GvHD. Additional transplantation experiments to improve the effectiveness of the cellular treatment and test more MSC lines from different MHC-congenic rat strains are underway. Moreover, we will include a rat myelogenic leukemia (BNML) in our GvHD model based on our existing protocols and investigate the long-term outcome of MSC therapy (mortality and disease recurrence) with respect to both graft-versus-leukemia and graft-versus-host immunity.