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.
Talmadge
J E
JE
Department of Pathology and Microbiology, University of Nebraska, 987660 Nebraska Medical Center, Omaha, NE 68198-7660, USA. jtalmadg@unmc.edu
Singh
R
R
Ino
K
K
Ageitos
A
A
Buyukberber
S
S
D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000628:therapy; D016516:CD4-CD8 Ratio; D016207:Cytokines / Q000096:biosynthesis; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology
D000970:Antineoplastic Agents; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D012333:RNA, Messenger