Mechanisms of immune dysfunction in stem cell transplantation

High dose therapy (HDT) and stem cell transplantation (SCT) results in alte rations in the immunologic network, thymic re-education and the induction o f peripheral tolerance. The changes to the immunoregulatory cascade and tol erance induction associated with autotransplants have been investigated in a series of studies focused on leukocyte reconstitution and function follow ing HDT and autologous SCT. In these studies, we observed a significant dec rease in the CD4:CD8 T cell ratio post-transplantation compared to normal p eripheral blood (PB) donors due to a decrease in CD4(+) cells. In addition, T cell function (phytohemagglutinin (PHA) mitogenesis) was consistently de pressed compared to samples obtained from normal PB donors. The loss of T c ell function was associated with an increased frequency of circulating mono cytes, their expression of Fas ligand (FasL) and a high frequency of apopto tic CD4(+) T cells. Indeed, 28-51% of circulating CD4(+) T cells were obser ved to be apoptotic during the first 100 days following HDT and SCT. These studies suggest that 'primed' or activated Fas(+) CD4(+) lymphocytes intera ct with FasL(+) monocytes, resulting in apoptosis, leading to the preferent ial deletion of CD4(+) T cells, a decrease in the CD4:CD8 T cell ratio and depressed T cell function. Further, as discussed herein, the T cells are ac tivated with a predominantly type 2 phenotype, which may also contribute to the maintenance of the immunosuppressive condition. Therefore, there is th e potential to regulate immune recovery by stem cell product manipulation o r post-transplantation cytokine administration. (C) 2000 International Soci ety for Immunopharmacology. Published by Elsevier Science Ltd. All rights r eserved.