Fas-FasL-mediated CD4+ T-cell apoptosis following stem cell transplantation.
We report the preferential expression of Fas on CD4+ T cells and Fas ligand (FasL) on monocytes and their potential role in the selective loss of CD4+ T cells in breast cancer patients undergoing high-dose chemotherapy and peripheral blood stem cell transplantation (PSCT). A high frequency of apoptotic CD4+ T cells (28-51%) is observed during the first 100 days after PSCT concomitant with a significant increase in monocyte frequency and FasL expression (11.6-23%) on monocytes. The preferential expression of Fas on CD4+ T cells (73-92%) in the peripheral blood (PB) of these patients is associated with a significantly higher frequency of CD4+ T-cell apoptosis compared with CD8+ T cells (28-47%) and CD4+ T cells (46 +/- 5.7%) in normal PB. These data suggest that "primed" Fas+ CD4+ lymphocytes interact with activated monocytes that express FasL, resulting in apoptosis, leading to deletion of CD4+ T cells, an inversion in the CD4:CD8 T-cell ratio, and immune dysfunction. The prevention of CD4+ T-cell apoptosis and improved immune reconstitution by the manipulation of PB stem cell products, blockade of Fas-FasL interactions, or cytokine support after transplantation may be important adjuvant immunotherapeutic strategies in patients undergoing high-dose chemotherapy and PSCT.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198-5660, USA.
R K
RK
Singh
M L
ML
Varney
S
S
Buyukberber
K
K
Ino
A G
AG
Ageitos
E
E
Reed
S
S
Tarantolo
J E
JE
Talmadge
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003131:Combined Modality Therapy; D053222:Fas Ligand Protein; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D013997:Time Factors; D019014:fas Receptor / Q000502:physiology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor