tetano
Editor, Senior Moderator
Blood. 2013 May 29. [Epub ahead of print]
Tyrosine kinase inhibitors impair B cell immune responses in CML through off-target inhibition of kinases important for cell signaling.
de Lavallade H, Khoder A, Hart M, Sarvaria A, Sekine T, Alsuliman A, Mielke S, Bazeos A, Stringaris K, Ali S, Milojkovic D, Foroni L, Chaidos A, Cooper N, Gabriel I, Apperley J, Belsey S, Flanagan RJ, Goldman J, Shpall EJ, Kelleher P, Marin D, Rezvani K.
Source
Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom;
Abstract
Tyrosine kinase inhibitors (TKI) have significant off-target multi-kinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase CML patients on imatinib, or second-line dasatinib and nilotinib and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared to controls (IgM titer 79.0 vs. 200 U/ml, p=0.0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B-cells. In vitro co-incubation of B-cells with plasma from CML patients on TKI or with imatinib, dasatinib or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B cell signaling and survival. These data indicate that TKI, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.
PMID:
23719297
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23719297
Tyrosine kinase inhibitors impair B cell immune responses in CML through off-target inhibition of kinases important for cell signaling.
de Lavallade H, Khoder A, Hart M, Sarvaria A, Sekine T, Alsuliman A, Mielke S, Bazeos A, Stringaris K, Ali S, Milojkovic D, Foroni L, Chaidos A, Cooper N, Gabriel I, Apperley J, Belsey S, Flanagan RJ, Goldman J, Shpall EJ, Kelleher P, Marin D, Rezvani K.
Source
Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom;
Abstract
Tyrosine kinase inhibitors (TKI) have significant off-target multi-kinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase CML patients on imatinib, or second-line dasatinib and nilotinib and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared to controls (IgM titer 79.0 vs. 200 U/ml, p=0.0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B-cells. In vitro co-incubation of B-cells with plasma from CML patients on TKI or with imatinib, dasatinib or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B cell signaling and survival. These data indicate that TKI, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.
PMID:
23719297
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23719297