Transplantation tolerance: gene expression profiles comparing allotolerance vs. allorejection

Abstract

An understanding of the molecular basis of immune regulation will allow development of therapies for diseases caused by immune dysregulation and for therapeutic exploitation of the immune response in transplantation of organ grafts or stem cells. To identify critical regulatory factors in immunity, we have used a mouse model wherein infectious regulatory tolerance is inducible by CD4/CD8 blockade in recipients of vascularised heart grafts. Once established, this transplantation tolerance is robust and isolated “tolerant” spleen cells show powerful immune regulatory properties, being able to impose donor-specific allotolerance upon fully immune competent naïve recipients. Here, we present a compound comparison of four gene arrays (tolerance vs. rejection, at 48 h, and at 123 h) where a relatively small number of differentially expressed genes occurred. In rejection, there was a strong progressive amplification of IFNγ and granzyme B mRNAs. In tolerance, both ELKL motif kinase and axotrophin occurred in the group of upregulated genes. Mice lacking ELKL motif kinase develop autoimmune disease, whilst axotrophin is a newly discovered stem cell gene that has only been explored in the context of neural development. This gene expression data is the first to demonstrate a link between axotrophin and regulatory tolerance and, since axotrophin, LIF, STAT3 and c-kit each function in stem cells, we propose that common mechanisms play a central role both in developmental regulation of stem cells, and in immune regulation.