Functional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation

• Published in: Blood 2003-10, Vol.102 (8), p.2892-2900
• Main Authors: Rezvani, Katayoun, Grube, Matthias, Brenchley, Jason M., Sconocchia, Giuseppe, Fujiwara, Hiroshi, Price, David A., Gostick, Emma, Yamada, Ko, Melenhorst, Jan, Childs, Richard, Hensel, Nancy, Douek, Daniel C., Barrett, A. John
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Bone marrow, stem cells transplantation. Graft versus host reaction; CD3 Complex - biosynthesis; CD8 Antigens - biosynthesis; CD8-Positive T-Lymphocytes - metabolism; Cell Line; DNA, Complementary - metabolism; Flow Cytometry; Hematologic and hematopoietic diseases; HLA-A Antigens - blood; HLA-A2 Antigen; Humans; Immunologic Memory; Leukemia - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Peptides - chemistry; Phenotype; Polymerase Chain Reaction; RNA - metabolism; Stem Cell Transplantation; T-Lymphocytes - metabolism; Time Factors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-01-0150

Antigens implicated in the graft-versus-leukemia (GVL) effect in chronic myeloid leukemia (CML) include WT1, PR1, and BCR-ABL. To detect very low frequencies of these antigen-specific CD8+ T cells, we used quantitative polymerase chain reaction (qPCR) to measure interferon-γ (IFN-γ) mRNA production by peptide-pulsed CD8+ T cells from HLA-A*0201+ healthy volunteers and from patients with CML before and after allogeneic stem cell transplantation (SCT). Parallel assays using cytomegalovirus (CMV) pp65 tetramers demonstrated the IFN-γ copy number to be linearly related to the frequency of tetramer-binding T cells, sensitive to frequencies of 1 responding CD8+ T cell/100 000 CD8+ T cells. Responses to WT1 and PR1 but not BCR-ABL were detected in 10 of 18 healthy donors. Responses to WT1, PR1, or BCR-ABL were observed in 9 of 14 patients with CML before SCT and 5 of 6 after SCT, often to multiple epitopes. Responses were higher in patients with CML compared with healthy donors and highest after SCT. These antigen-specific CD8+ T cells comprised central memory (CD45RO+CD27+CD57–) and effector memory (CD45RO–CD27–CD57+) T cells. In conclusion, leukemia-reactive CD8+ T cells derive from memory T cells and occur at low frequencies in healthy individuals and at higher frequencies in patients with CML. The increased response in patients after SCT suggests a quantitative explanation for the greater effect of allogeneic SCT.