In vitro susceptibility of CD4+ and CD8+ T cell subsets to fludarabine

Gamberale, Romina; Galmarini, Carlos M.; Fernández-Calotti, Paula; Jordheim, Lars Petter; Sánchez-Ávalos, Julio César; Dumontet, Charles; Geffner, Jorge; Giordano, Mirta

doi:10.1016/j.bcp.2003.07.008

Cited by 23 publications

(25 citation statements)

References 26 publications

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“…59 Moreover, chemotherapy applied to patients with CLL includes drugs such as fludarabine, cyclophosphamide, or alemtuzumab, which are cytotoxic for T cells and have been shown to alter ratios of CD4 ϩ to CD8 ϩ T cells in vitro. 60 Overall, we assessed T reg cells in 73 patients with CLL and 42 healthy individuals. In addition to presenting clear evidence of a stage-dependent increase of T reg cells in this leukemia, we observed, for the first time in humans, a significant impact of chemotherapy, particularly fludarabine-based therapy regimens, on the frequency and function of CD4 ϩ CD25 hi T cells.…”

Section: Introductionmentioning

confidence: 99%

Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine

Beyer

Kochanek

Darabi

et al. 2005

Blood

431

325

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Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequencies of CD4 ؉ CD25 hi regulatory T cells (T reg cells) have been described as an additional mechanism reducing immunity. We assessed 73 patients with B-cell chronic lymphocytic leukemia ( IntroductionHuman and murine CD4 ϩ CD25 ϩ T cells contain cells that suppress antigen-specific T-cell immune responses. [1][2][3][4][5] These naturally occurring regulatory CD4 ϩ CD25 ϩ T cells originate from the thymus and play a central role in the maintenance of peripheral tolerance by suppression of autoreactive T-cell populations. In murine models, regulatory T cells (T reg cells) prevent autoimmune and inflammatory diseases 1,6,7 and inhibit antitumor immune responses. [8][9][10][11][12] Although a truly unique marker for T reg cells is still not available, several molecules have been associated with these cells including cytotoxic T lymphocyte-associated protein 4 (CTLA4), [13][14][15][16] glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR, TNFRSF18), 17,18 Forkhead box P3 (FOXP3), [19][20][21] Lselectin (CD62L, SELL), 22,23 and OX40 antigen (CD134, TNFRSF4). 23,24 In humans, T reg cells are enriched within the CD4 ϩ CD25 hi population, whereas CD4 ϩ CD25 lo T cells represent mainly previously activated T helper cells. 25 These CD4 ϩ CD25 hi T reg cells inhibit proliferation and cytokine release by conventional CD4 ϩ CD25 Ϫ T cells. 26 Decrease of these cells was found in patients with autoimmune diseases, 27-31 whereas an increase of T reg cells in patients after allogeneic bone marrow transplantation was associated with a reduced graft-versus-host disease. [32][33][34][35] In patients with malignant melanoma, 36 Hodgkin lymphoma, 37 or ovarian, 38,39 gastric, 40,41 lung, 39,42 breast, 43,44 and pancreatic cancer 43 inhibitory CD4 ϩ CD25 ϩ T cells are also increased. In an elegant study, Curiel et al 38 demonstrated that functional T reg cells were enriched in ascites from women with ovarian cancer, migrated toward CCL22 expressed by tumor cells and tumor-associated macrophages, and specifically inhibited antitumor immunity. Moreover, within this setting, the increase of T reg cells predicted poor survival. 38 Only recently, studies assessing a potential influence of chemotherapy on T reg cells have been initiated. In mice, low-dose cyclophosphamide decreased the number of T reg cells. 45 Based on these observations we were interested in understanding whether CD4 ϩ CD25 hi T cells are also increased and possess inhibitory capacities in B-cell chronic lymphocytic leukemia (CLL) and, if so, to assess the frequency and function in the context of stage of disease and prior therapy. CLL, the most common type of leukemia in the Western hemisphere, 46 is characterized by clonal proliferat...

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Section: Introductionmentioning

confidence: 99%

Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine

Beyer

Kochanek

Darabi

et al. 2005

Blood

431

325

View full text Add to dashboard Cite

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“…Lymphocyte populations were purified as described previously (Gamberale et al, 2003) and the purity of each population was found to be .95 %. CD19 + B cells were further cultured with phorbol-myristate-acetate (PMA) (50 nM) and ionomicine (5 mg ml 21 ) for 48 h with the aim of amplifying this minor cell type circulating in the peripheral blood.…”

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confidence: 99%

GB virus C quasispecies detected in plasma and lymphocyte subsets in a natural human infection

Ruiz

Giordano

Rivero

et al. 2010

Journal of General Virology

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Genomic heterogeneity and quasispecies composition of GB virus C (GBV-C) within plasma and lymphocyte subsets in a naturally infected blood donor were investigated. For this purpose, fragments from the 59 untranslated region (59 UTR) and the E2 gene recovered from plasma, B and T lymphocytes, were cloned and sequenced. A total of 63 clones was analysed: 95.2 % of them (n560) -obtained from plasma and cells -were assigned to genotype 2b, while only three derived from plasma corresponded to genotyope 3. The G215A transition within this region was present in 90.9 % of the clones from B lymphocytes, but absent in the remaining cell compartments (P,0.01). Apparently, most of the circulating GBV-C quasispecies in this blood donor were related to the viral population infecting CD8 + T cells, and B cells to a lesser extent. This is the first report showing the quasispecies nature of GBV-C in lymphocyte subsets within peripheral blood mononuclear cells.

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“…24 Immunomodulation due to an altered CD4-to-CD8 ratio and changes in the T cell repertoire has also been observed following fludarabine therapy. 25,26 Thus, infectious events occur relatively frequently in patients receiving fludarabine. Klasa et al, 27 who compared fludarabine with CVP in patients with recurrent low-grade lymphoma, reported that 36% of patients in the fludarabine arm developed infectious complications, with 11% experiencing World Health Organization Grade 3 or 4 infection.…”

Section: Toxicitymentioning

confidence: 99%