Imatinib impairs CD8+ T lymphocytes specifically directed against the leukemia-associated antigen RHAMM/CD168 in vitro.
The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate is highly effective in the front-line treatment of chronic myeloid leukemia (CML) and is increasingly used in patients with residual disease or relapse after allogeneic stem cell transplantation (allo-SCT). Since an impairment of anti-viral CD8+ T-lymphocyte function by imatinib has been described, we question whether imatinib also affects specific anti-leukemic CD8+ T lymphocytes generated from the peripheral blood of healthy donors, and of CML patients after allo-SCT. Here, we assessed CD8+ T-cell expansion and function from healthy donors and patients with CML. The release of IFN-gamma and granzyme B by CD8+ T-lymphocytes specific for R3, a recently described T-cell epitope peptide derived from a leukemia-associated antigen designated RHAMM/CD168 (receptor for hyaluronic acid mediated motility), was inhibited by imatinib in a dose-dependent fashion (range: 1-25 microM). These T cells were able to lyse cognate peptide labeled T2 cells and CD34+ CML progenitor cells. This lysis was inhibited by imatinib. The inhibitory effect was not associated with an increased rate of apoptosis of T cells and reversible after removal of imatinib. In the light of these findings, clinical administration of imatinib might result in the reduction of efficacy of the graft-versus-leukemia effect or other T-cell-based immunotherapies.
Chen
Jinfei
J
Third Department of Internal Medicine, University Ulm, Robert-Koch-Str 8, 89081 Ulm, Germany.
Schmitt
Anita
A
Chen
Baoan
B
Rojewski
Markus
M
Ringhoffer
Mark
M
von Harsdorf
Stephanie
S
Greiner
Jochen
J
Guillaume
Philippe
P
Döhner
Hartmut
H
Bunjes
Donald
D
Schmitt
Michael
M
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001549:Benzamides; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D016326:Extracellular Matrix Proteins / Q000276:immunology*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D000068877:Imatinib Mesylate; D018189:Immunomagnetic Separation; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014184:Transplantation, Homologous
D000970:Antineoplastic Agents; D001549:Benzamides; D018984:Epitopes, T-Lymphocyte; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D010879:Piperazines; D011743:Pyrimidines; C098946:hyaluronan-mediated motility receptor; D000068877:Imatinib Mesylate