Abstract
Various regimens used for hematopoietic stem cell mobilization have been optimized to mobilize a maximum number of CD34+ hematopoietic stem cells (HSC) into the peripheral blood. However, the effects of mobilization regimens on other bone marrow derived cell populations have not been carefully examined. Since T cells from HSC grafts play an important role in anti-tumor responses, we studied T cell function in 11 adult patients with hematological malignancies undergoing mobilization for autologous stem cell transplantation (SCT). Mobilization regimens consisted of G-CSF alone (3 patients) or in combination with: GM-CSF (1 patient), chemotherapy (2), GM-CSF and chemotherapy (3), or AMD3100 (2). T cell function was determined using ImmuKnow (Cylex) assay, an FDA approved test, which measures immune cell function in whole blood by quantifying the amount of ATP released by PHA-stimulated CD4+ T helper (Th) cells. Prior to mobilization treatment, average Th reactivity was 242±128 ng ATP/ml (normal range: 200–525 ng ATP/ml). With mobilization, Th reactivity increased gradually in all patients, reaching peak reactivity values (>525 ng ATP/ml) on day 4–6 of treatment. Efficient stem cell mobilization (≥10 CD34+ cells/ul of blood) was accomplished in 8 out of 11 patients. These 8 patients exhibited an average Th peak reactivity level of 701±126 ng ATP/ml. Stem cell mobilization failed in the remaining 3 patients (<10 CD34+ cells/ul). Two of these patients had received AMD3100 (a CXCR4 inhibitor) and G-CSF, and showed unusually high ATP levels (>1000 ng/ml). Chi-Square analysis indicated that there was an inverse correlation between CD34 stem cell counts and peak ATP levels (p=0.01). However, there was no direct relationship between the number of CD3+ or CD3+CD4+ T cells and Th reactivity. Immunophenotypic studies performed in 4 patients with CD34 counts ≥10 cells/ul and 2 patients with CD34 counts <10 cells/ul indicated that the agents used for stem cell mobilization triggered the expansion of CD4+CD25+ T cell population. However, the vast majority of these T cells did not co-express FoxP3, the characteristic marker of regulatory T cells, consistent with the enhanced T cell reactivity detected in these patients. It, therefore, results that mobilization agents have a “priming” effect on CD4+ T helper cells, inducing their robust activation. This effect may lead to improved anti-tumor surveillance and might contribute to the higher rate of complete remission and overall survival observed in patients with hematological malignancies, who have received autologous SCT in addition to chemotherapy. Thus, monitoring of T cell reactivity by Immuknow assay might help tailor therapy to maximize the patient’s potential to mount an immune response against the tumor and, at the same time, obtain efficient stem cell mobilization.
Modulation of PKM activity affects the differentiation of TH17 cells
