title: Measurable immune dysfunction and telomere attrition in long-term allogeneic transplant recipients.
abstract: This study was conducted to determine if the accelerated telomere attrition that occurs as a consequence of allogeneic stem cell transplantation leads to measurable functional defects. Telomere lengths in mononuclear leukocytes obtained from 15 long-term allogeneic stem cell transplant recipients and their respective donors were determined by Southern hybridization and densitometric analysis. Functional assays evaluated the ability of these cells to proliferate in response to a mitogenic stimulus and to differentiate under appropriate cytokine stimulation. Lymphocyte proliferation in response to phytohemagglutinin was determined by measurement of (3)[H]thymidine uptake. The ability of circulating myeloid cells to differentiate was determined after incubation of peripheral blood mononuclear cells with IL-3 and GM-CSF. A total of 13 patients demonstrated telomeric loss, ranging from 0.1 to 3.7 kbp. Strikingly, lymphocytes from 14 of the 15 patients demonstrated a significant decrease in proliferation when compared to their respective donors (68%+/-22, P=0.001). All patients demonstrated at least a 50% decrease in the number of myeloid colony-forming units when compared to their respective donors (P<0.0001). A decreased ability of hematopoietic cells to proliferate and differentiate is phenotypically consistent with an aged immune system. This may correlate with diminished clinically relevant immune responses to infection or vaccination, as seen in the elderly.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. n_lewis@fccc.edu
authors.forename: N L
authors.initials: NL
authors.lastname: Lewis
authors.forename: M
authors.initials: M
authors.lastname: Mullaney
authors.forename: K F
authors.initials: KF
authors.lastname: Mangan
authors.forename: T
authors.initials: T
authors.lastname: Klumpp
authors.forename: A
authors.initials: A
authors.lastname: Rogatko
authors.forename: D
authors.initials: D
authors.lastname: Broccoli
mesh_terms: D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation / Q000592:standards*; D002454:Cell Differentiation / Q000187:drug effects; D016922:Cellular Senescence; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000503:physiopathology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology; D023461:Myeloid Progenitor Cells; D038042:Myelopoiesis; D036102:Peripheral Blood Stem Cell Transplantation / Q000592:standards*; D010835:Phytohemagglutinins / Q000494:pharmacology; D017741:Survivors; D016615:Telomere / Q000276:immunology* / Q000648:ultrastructure; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D010835:Phytohemagglutinins