Mechanisms of immune dysfunction in stem cell transplantation

High dose therapy (HDT) and stem cell transplantation (SCT) results in alterations in the immunologic network, thymic re-education and the induction of peripheral tolerance. The changes to the immunoregulatory cascade and tolerance induction associated with autotransplants have been investigated in a series of studies focused on leukocyte reconstitution and function following HDT and autologous SCT. In these studies, we observed a significant decrease in the CD4:CD8 T cell ratio post-transplantation compared to normal peripheral blood (PB) donors due to a decrease in CD4 cells. In addition, T cell function (phytohemagglutinin (PHA) mitogenesis) was consistently depressed compared to samples obtained from normal PB donors. The loss of T cell function was associated with an increased frequency of circulating monocytes, their expression of Fas ligand (FasL) and a high frequency of apoptotic CD4 T cells. Indeed, 28‐51% of circulating CD4 T cells were observed to be apoptotic during the first 100 days following HDT and SCT. These studies suggest that ‘primed’ or activated Fas CD4 lymphocytes interact with FasL monocytes, resulting in apoptosis, leading to the preferential 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 activated with a predominantly type 2 phenotype, which may also contribute to the maintenance of the immunosuppressive condition. Therefore, there is the potential to regulate immune recovery by stem cell product manipulation or post-transplantation cytokine administration. © 2000 International Society for Immunopharmacology. Published by Elsevier Science Ltd. All rights reserved.