Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo.
Imatinib mesylate (STI571, imatinib) inhibited DNA synthesis in primary human T cells stimulated with allogeneic mature dendritic cells or phytohemagglutinin (PHA) but did not induce apoptosis. The values for the concentration that inhibits 50% (IC50) of T-cell proliferation stimulated by dendritic cells and PHA were 3.9 microM and 2.9 microM, respectively, that is, within the concentration range found in patients treated with imatinib mesylate. Interestingly, imatinib mesylate did not inhibit expression of T-cell activation markers CD25 and CD69, although it reduced the levels of activated nuclear factor-kappaB (NF-kappaB) and changed phosphorylation or protein levels of Lck, ERK1/2, retinoblastoma protein, and cyclin D3. When T cells were washed free of imatinib mesylate, they proliferated in response to PHA, demonstrating that inhibition is reversible. Treatment with imatinib mesylate led to accumulation of the cells in G0/G1 phase of the cell cycle. The in vitro observations were confirmed in vivo in a murine model of delayed-type hypersensitivity (DTH). In mice treated with imatinib mesylate, DTH was reduced in comparison to sham-injected controls. However, the number of splenic T cells was not reduced showing that, similarly to in vitro observations, imatinib mesylate inhibited T-cell response, but did not cause apoptosis. These findings indicate that long-term administration of high-dose imatinib mesylate might affect immunity.
Dietz
Allan B
AB
Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. dietz.allan@mayo.edu
Souan
Lina
L
Knutson
Gaylord J
GJ
Bulur
Peggy A
PA
Litzow
Mark R
MR
Vuk-Pavlovic
Stanimir
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D006968:Hypersensitivity, Delayed; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D010835:Phytohemagglutinins / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*
D001549:Benzamides; D010835:Phytohemagglutinins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate