Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosomeCpositive acute lymphoblastic leukemia. at several time points, JNJ-10397049 including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180?270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR V families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation. studies, inhibition of the innate immune cells activation as well as T-cell proliferation and function were noted [24, 29C32]. However, others have reported that patients treated with TKI have near-normal levels of immunological parameters and response to various cytokine stimuli [27]. Thus, the literature is usually inconsistent regarding the effects of TKIs around the immune system in the post-allo-SCT setting. We recently reported the clinical outcomes of a phase 1/2 study in CML and Ph+ ALL patients treated with nilotinb after allogeneic SCT. Nilotininb was safe and partially effective for the prevention of relapse after allo-SCT [23]. In the current study, we further explored nilotinib effect on immune reconstitution post allo-SCT. Our aim was to quantitatively characterize immune subpopulations and evaluate their function including T-cell response to mitogens, NK cytotoxic activity, and T-cell repertoire and thymic activity (TREC) at designated time points up to 1 1 year after transplantation while on nilotinib therapy. RESULTS Total cell numbers The relation between total white blood cells (WBC) and lymphocytes was analyzed directly from complete blood counts (Physique ?(Physique11 and Table ?Table1).1). Mean ( standard error) WBC at day 28 of nilotninb treatment (4014 398 cells/ml) was similar to that measured post allo-SCT and ANK3 before nilotinib treatment (4137 600 cells/ml), whereas a significant increment of WBC was observed at day 90 of nilotinib treatment (5887 771 cells/ml, = 0.04). WBC counts continued JNJ-10397049 to increase thereafter, with a mean of 9250 904 cells/ml on day 335 (Physique ?(Figure2).2). When compared to their level at day 28 of nilotinib administration, an increase in total lymphocytes was first noted at day 180 (1693.7 166.6 vs. 942.8 120.6 cells/ml, 0.001, respectively). Lymphocyte counts were maintained up to day 335 post nilotinib administration (Table ?(Table11). Open in a separate window Physique 1 Flow cytometry analysis of lymphocytes subpopulations(A) Percentage of cells expressing specific lymphocytes surface markers (CD3, CD4,CD8, CD20 and CD56). (B) Average concentration of lymphocytes subpopulations, calculated from their percentage on gated CD45pos cells. (C) CD4/CD8 ratio calculated from their concentration at each study time point. CD – cluster of differentiation. Table 1 Immune reconstitution after allo-SCT during nilotinib treatment 0.001) compared to their numbers at day 28 and at day 90 (665.3 89.8 106/ml and 633 87 106/ml, respectively). CD3pos T-cell counts were maintained at day 270 and JNJ-10397049 up to the last assessment at day 335 (Physique ?(Physique1B,1B, Table ?Table11). CD4pos T-cells The percentage of CD4pos cells began to increase at day 270 of nilotinib administration (35.8 5.3%; = 0.06) compared to values measured pre-nilotinb administration. (Physique ?(Physique1A,1A, Table ?Table1).1). CD4pos cell counts significantly increased at day 180 (457.1 87.5 106/ml; = 0.01 compared to their values at day 28 (202.8 37.7 106/ml). Counts remained stable at day 270 (490.7 77.1 106/ml) and at day 335 (434.5 44.9 106/ml), respectively (Determine ?(Figure1B1B). CD8pos T-cells The percentage of CD8pos cells remained stable from post-allo-SCT-pre-nilotinib until the last evaluation at day 335 (Physique ?(Figure1A).1A). An increase in CD8pos cells was observed after 180 days of nilotinib treatment (696.8 88 106/ml), compared to their measurement at the post-allo-SCT-pre-nilotinib time point (318.1 52 106/ml; = 0.001); (Physique ?(Physique1B,1B, Table ?Table1).1). These results effect the CD4/CD8 ratio,.
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