Decreased Type 1 cytokine production has been observed in T cells of patients with untreated chronic myeloid leukemia (CML). The important role of T cells and T-cell cytokines in the long-term control of CML is well established, for example in allogeneic stem-cell graft recipients. This study examined whether or not molecularly targeted therapy with imatinib, an inhibitor of the BCR-ABL tyrosine kinase, improved endogenous T-cell function in patients resistant to or intolerant of previous IFN-alpha therapy. Intracellular cytokine staining and detection by flow cytometry was used to analyze the expression of the T1 cytokine IFN-gamma in T cells. To secure independence from changes in white blood cell counts during treatment, a constant number of T cells was purified from the peripheral blood before analysis of the proportion of IFN-gamma synthesizing T cells. Twenty-nine patients with CML were tested before and after a median follow-up of 3 month on imatinib. In addition, late follow-up (past the median time to best cytogenetic response) of 15 patients were obtained Twenty-nine age- and gender-matched individuals were used as healthy controls. The frequency of IFN-gamma producing T cells in CML patients resistant to or intolerant to previous IFN-alpha therapy was lower than in healthy individuals (p=0.0181, Mann-Whitney test). Imatinib therapy led to a significant increase over pre-treatment values (p<0.0001, Mann-Whitney test). Late follow-up indicated that the increase was sustained in patients not in major cytogenetic response. In contrast, in major responders levels returned towards values comparable to healthy individuals. In conclusion, treatment with imatinib achieves a significant increase in Type 1 (IFN-gamma) cytokine-producing T cells in patients with CML. This is consistent with the view that enhanced T-cell function is achievable in patients with CML, even in the absence of allo-mechanisms.
Background: gd T cells are a rare component of the circulating innate immune system capable of exerting anti-neoplastic activity. This population may be suitable for the adoptive immunotherapy of acute myeloid leukemia (AML). Little is known however, about the frequency and function of circulating gd T cells in AML. The aim of the study was to enumerate peripheral blood gd T cells in patients with AML and explore the feasibility of their use clinically.Methods: We compared the absolute circulating gd T cell levels in 33 AML patients before and after treatment versus 20 healthy volunteers using flow cytometry. The function of gd T cells was assessed by detection of intracelluar interferon-g (IFN-g) and cytotoxicity against leukemic blasts.Results: AML patients with high blast counts prior to induction chemotherapy had marginally decreased gd T cell levels compared with healthy controls: median 38/mL versus 83/mL; P = 0.051. Sequential gd T cell enumeration after induction showed significantly decreased counts in patients with a persistently high blast burden compared to patients with reduced but detectable residual disease (molecular maker or borderline bone marrow infiltration): median 7/mL versus 105/mL; P = 0.008. Patients with residual disease had significantly higher gd T cell counts compared to those retested after they had achieved complete remission (CR); P = 0.0025. In CR, gd T cell counts remained lower than those of healthy individuals: median 33/mL versus 83/mL, P = 0.030. We detected a sharp increase (on average, four-fold higher than values in CR) of gd T cells in patients in very early morphologic or molecular relapse. We also tested the functional properties of gd T cells from patients with AML in CR. Flow cytometric assessment of IFN-g revealed similar numbers of gd T cells expressing the T1 cytokine compared with healthy controls. We also showed that gd T cells were able to kill leukemic target cells in vitro.Conclusion: Flow cytometric assessment of gd T cells in patients with AML revealed quantitative shifts with respect to disease status. Our data suggest that gd T cells warrant further investigation as potential therapeutic agents. q
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