T cells from patients with Hodgkin's disease have a defective T-cell receptor zeta chain expression that is reversible by T-cell stimulation with CD3 and CD28

Renner, Christoph; Ohnesorge, Sascha; Held, Gerhard; Bauer, Stefan; Jung, Woo Kyung; Pfitzenmeier, JP; Pfreundschuh, M

doi:10.1182/blood.v88.1.236.236

Cited by 70 publications

(34 citation statements)

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“…Not all T lymphocytes isolated from the tumour environment or from the PB of patients with cancer are dysfunctional, and restoration of proliferative and cytolytic functions have been reported to occur in the presence of cytokines, such as interleukin (IL)‐2 (Whiteside, 1994; Tartour et al , 1995; Rabinowich et al , 1996a), IL‐7 or IL‐12 (Whiteside, 1999) or when the T cells are cross‐linked with anti‐CD3. For example, PB T lymphocytes from patients with untreated Hodgkin's disease show decreased levels of TCR zeta chain which, after combined CD3 and CD28 cross‐linking in vitro , upregulate their zeta chain protein expression to normal levels within 48 h (Renner et al , 1996). Only limited data are available for the in vivo effects of IL‐2 on expression of the zeta chain in T cells obtained from patients with cancer.…”

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confidence: 99%

Impaired expression of the CD3‐zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis

et al. 2000

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In patients with myeloid malignancies, cell-mediated immunity is often suppressed, being most profound in those with advanced disease. Such immune dysfunction, as demonstrated in many patients with chronic lymphocytic leukaemia (CLL) and myelodysplastic syndrome (MDS), may, at least in part, be due to altered expression of the CD3-zeta chain, which is an important component of the T-cell receptor (TCR). We speculated that impaired expression of the TCR-zeta chain would be evident in peripheral blood T cells of patients with chronic myeloid leukaemia (CML) and that such an abnormality would result in an increased ex vivo susceptibility to apoptosis. In this study, we demonstrated that, compared with normal controls, zeta chain expression was significantly downregulated in all of the T-cell subsets (P < 0.009) in more than 90% of CML patients. In addition, there was a significantly lower expression of the CD3-epsilon chain (P < 0.001) in patients than in controls. In those patients with abnormal zeta chain expression, the proportion of lymphocytes with spontaneous DNA fragmentation, as determined by terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labelling (TUNEL) assays, was also significantly higher (P < 0.002) than controls. From all of the patients tested, it was possible to upregulate partially zeta chain expression and hence to reduce the susceptibility to apoptosis by cross-linking the T cells with interleukin (IL)-2, interferon (IFN)-alpha or immobilized CD3. In addition, such cross-linked T cells showed a significantly higher capacity to proliferate than the native CML T cells.

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confidence: 99%

Impaired expression of the CD3‐zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis

et al. 2000

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“…These results, together with the evidence that effective LAK cells may be generated from leukaemic patients in disease remission (Lauria et al, 1994), are in contrast to the defective killing capacity of LAK effectors generated from AML patients at diagnosis (Foa et al, 1991a). T and cytotoxic cells in®ltrating or associated with solid and haematological malignancies present several functional defects in molecules involved in the triggering of effector functions (Tursz et al, 1982;Ruco et al, 1983;Frydecka, 1985;Foa et al, 1990;Nakagomi et al, 1993;Lai et al, 1996;Kono et al, 1996); these abnormalities may be secondary to the presence of the tumour (Whiteside, 1999) and are usually reversible after activation of these effectors Renner et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Expansion of cytotoxic effectors with lytic activity against autologous blasts from acute myeloid leukaemia patients in complete haematological remission

Torelli¹,

Guarini²,

Palmieri³

et al. 2002

Br J Haematol

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Summary. New therapeutic approaches are needed to improve the cure rates in acute myeloid leukaemia (AML). The present study was designed to investigate whether: (1) cytotoxic lymphocytes could be expanded from AML patients in complete remission; (2) their signal transduction machinery was preserved; (3) these cells were capable of producing cytokines involved in the cytolytic process; and (4) these cells showed cytotoxic activity against allogeneic and autologous blasts. By co-culturing blood mononuclear cells with feeder cells, we obtained an average 5á3-fold increase in the total cell number and a 35-fold increase in natural killer (NK) cells. Expression of the f chain and of tyrosine kinases of the Src and Syk-ZAP families involved in the triggering of NK functions was analysed on expanded cells. The results demonstrated a signal transduction apparatus preserved and quantitatively similar to that of normal donors. After phorbol myristate acetate and ionomicin stimulation, the ability of expanded cells to produce interferon c and tumour necrosis factor a was documented. Patients' expanded cells showed a cytotoxic activity against target lines and allogeneic blasts which was similar to that of normal donors. Puri®cation experiments indicated that the NK cell fraction was responsible for most of the lytic effect. More signi®cantly, these cells also exerted a lytic effect against autologous blasts that could be further enhanced following incubation with low-dose interleukin 2. These ®ndings document the possibility of expanding cytotoxic effectors with preserved signal transduction machinery and autologous killing capacity from AML patients in remission, and suggest a new potential immunotherapeutic strategy for the management of early disease recurrence or of residual disease.

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“…There are as yet only a few reports on the distribution of Tcell signalling molecules in human cancer. Decreased levels have been reported in tumour-infiltrating lymphocytes (TIL) and/or PBT cells from patients with renal cell carcinoma (CD3z) (Finke et al, 1993), colorectal carcinoma (CD3z, p56 lck ) (Nakagomi et al, 1993), melanoma (CD3z, p56 lck ) and Hodgkin's disease (Renner et al, 1996), whereas normal levels have been reported in TIL from patients with non-Hodgkin's lymphoma (CD3z, p56 lck , p59 fyn , ZAP-70) (Wang et al, 1995). Unlike solid tumours, MM is a disease where malignant cells at different stages of maturation and large amounts of tumour-derived idiotype circulate in the peripheral blood (Billadeau et al, 1992(Billadeau et al, , 1993; therefore MM PBT cells are a suitable population for investigating the effect of tumour cells on the molecular organization of the CD3/TCR complex.…”

Section: Discussionmentioning

confidence: 99%

“…Splenic T cells from tumourbearing mice are deficient in the expression of CD3z, p56 lck and p59 fyn and display abnormal protein tyrosine phosphorylation and calcium flux after activation through the TCR/CD3 complex (Mizoguchi et al, 1992;Salvadori et al, 1994). Deficiency of CD3z and p56 lck has also been reported in tumour-infiltrating lymphocytes (TIL) and peripheral blood T lymphocytes (PBT) from patients with renal cell carcinoma (Finke et al, 1993), colorectal carcinoma (Nakagomi et al, 1993), melanoma and Hodgkin's disease (Renner et al, 1996). Other reports, however, have disagreed with the view that structural alterations of the CD3/TCR signal transduction machinery represent a general phenomenon in cancer leading to tumour-specific T-cell incompetence (Wang et al, 1995;Levey & Srivastava, 1995).…”

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confidence: 98%

Distribution of T‐cell Signalling Molecules in Human Myeloma

et al. 1997

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It is controversial whether altered levels of TCR/CD3-associated signalling molecules play a role in the T-cell dysfunction of cancer patients. In multiple myeloma (MM), peripheral blood T (PBT) lymphocytes are functionally impaired by prolonged exposure to tumour cells, and so we investigated the organization of the TCR/CD3-associated signal transduction machinery. The aim of this study was two-fold: first, to investigate the levels of CD3zeta, p56(lck), p59(fyn), ZAP-70, protein kinase C-alpha (PKC-alpha) and phospholipase C-gamma (PLC-gamma) in MM PBT cells; second, to determine whether levels of expression were correlated with clinical or prognostic factors. Forty-four MM patients were studied and 25 age-matched normal donors served as controls. On average, PKC-alpha was the only significantly decreased (P<0.001) signalling molecule, whereas levels of CD3zeta, p56(lck), p59(fyn), PLC-gamma and ZAP-70 were not statistically different. However, there was wide variation between individual patients, and levels for each single protein also varied. A 75% or greater decrease in protein expression was observed, ranging from 8% (p59(fyn)) to 68% (PCK-alpha) of MM patients. When patients were grouped according to the cut-off values of prognostic factors such as the serum levels of C reactive protein (CRP), beta2-microglobulin (beta2M), neopterin (NPT) and the labelling index (LI%) of bone marrow (BM) plasma cells, the only difference observed was the lower PKC-alpha expression in patients with high serum NPT values. None of the T-cell signalling molecule levels was affected by the duration of tumour exposure, calculated on the number of years and/or months that had elapsed since diagnosis, or by disease status. In conclusion, there was a significant decrease of PCK-alpha in MM T cells; however, neither this decrease nor the heterogenous levels of the other T-cell signalling molecules were clearly correlated with prognosis, duration of tumour exposure, and disease status.

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T cells from patients with Hodgkin's disease have a defective T-cell receptor zeta chain expression that is reversible by T-cell stimulation with CD3 and CD28

Cited by 70 publications

References 0 publications

Impaired expression of the CD3‐zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis

Impaired expression of the CD3‐zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis

Expansion of cytotoxic effectors with lytic activity against autologous blasts from acute myeloid leukaemia patients in complete haematological remission

Distribution of T‐cell Signalling Molecules in Human Myeloma

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