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Biomedical subjects

E Legrand

Publications and source records attributed to E Legrand.

At least 109 records · Page 6Linked to original sources

Impairment of monocyte functions in advanced head and neck cancer.

Depression of cell-mediated immunity is well established in most malignancies and especially in head and neck cancers, and much information is available concerning the defect in helper T lymphocyte function. We now report on impairment of the monocyte-macrophage system. Compared with normal controls we found that patients displayed, on one hand, an increased number of peripheral blood monocytes and, on the other hand, a smaller percentage of HLA-DR+ monocytes. Such peripheral blood monocytes normally failed to secrete factors, including interleukin 1 (IL-1). In addition, we observed that the in vivo induced blastogenesis of peripheral blood lymphocytes from patients, which is spontaneously depressed, is partly restored by medium containing IL-1. We cannot exclude, however, that the observed monocyte dysfunction involves other cytokines. Whether such an immune deficiency is due to secondary malnutrition or to the malignancy (or both) remains unclear.

Adult↗

Detection of CD1 positive cells in the peripheral blood of patients suffering from cancer-associated malnutrition.

The immunological phenotyping of peripheral blood mononuclear cells (PBMC) was assayed in a series of 22 patients suffering from severe cancer-associated malnutrition. A marked decrease of the T-lymphocyte subsets (CD3+, CD4+, CD8+) and of the CD20+ B lymphocytes occurred; there was however an increased percentage of monocytes but their absolute number was normal. Interestingly, 5% of the PBMC expressed "activated T-cell antigens". The specificity of two different monoclonal antibodies (MoAbs) towards CD1 epitopes (OKT6 and D47) was assessed by indirect immunofluorescence (IIF): about 5% of CD1+ thymocytes were detected with no antigen (Ag) cross reactivity with the small subset of activated T cells. It is hypothesized that some relationship may exist between such cells and malnutrition and/or cancer.

Adult↗

Thymic lymphosarcomas obtained by X-rays in association with a weakly leukemogenic virus: cellular studies.

The association in C57BL/6 mice of a subleukemogenic radiation dose (1.75 Gy X 2) which induces 7% of thymic lymphosarcomas (TL) with the injection of a weakly oncogenic B-tropic retrovirus responsible for 5% of TL resulted in a higher incidence of TL (31%) than expected from a simple cumulative effect when the viral injection preceded the irradiations (VX protocol). When virus was injected after irradiation (XV protocol) TL incidence (19%) was not significantly different from that of a cumulative phenomenon. The B-tropic virus used (1223) was isolated from RadLV-Rs extract and cloned. The TL incidence correlates with the presence of virus firstly in the thymus and bone marrow (BM) during the preleukemic period, secondly in the cell lines established in vitro from TL obtained in both protocols. This suggests that B-tropic viruses derepressed by 4 radiation doses of 1.75 Gy might be similarly implicated in the mechanism of radio-induced TL. This hypothesis is further supported by the evidence that BM restoration inhibited leukemogenesis in processes induced either by 4 radiation doses of 1.75 Gy or by the association of 2 radiation doses and viral injection whereas it has no effect on TL induced by highly oncogenic thymotropic viruses. Transplantation of BM cells from animals which had been submitted shortly before to leukemogenic VX protocol failed to induce donor type TL or leukemias in irradiated recipients suggesting that preleukemic cells either are not present or cannot be detected. However a high incidence of recipient TL was observed indicating that viruses were transferred with the grafted cells.

Animals↗

Murine thymic lymphomas after infection with a B-ecotropic murine leukemia virus and/or X-irradiation: proviral organization and RNA expression.

The role of retroviruses in murine radioleukemogenesis was reinvestigated using a protocol associating the injection of a non-pathogenic retrovirus (T1223/B virus) and a subleukemogenic dose of X-radiation (2 X 1.75 Gy). Using the Southern blotting technique we studied MuLV proviral organization and RNA expression in thymic lymphomas induced by the combined effect of virus and irradiation or irradiation alone. A recombinant provirus was detected in the chromosomal DNA of every tumor induced by associating virus and radiation whereas it was unconstantly found in radio-induced tumors. In every instance, the provirus was not integrated at a common site. No relationship was observed between viral RNA expression and tumor induction. Trisomy 15 was observed in all metaphases irrespective of the protocol of tumor induction. The G-banding technique revealed an extra-band in several thymic lymphomas induced by irradiation and T1223/B virus injection.

Animals↗

Autologous monoclonal antibodies recognize tumour-associated antigens in X-irradiated C57BL/6 mice.

X-irradiation of C57BL/6 mice induces thymic lymphosarcomas which sometimes contain retroviruses which upon injection into normal mice mimic the effect of the irradiation. We examined whether specific antigenicities, viral or cellular, were expressed by tumour cells that could be recognized by antibodies from the irradiated animals. We developed monoclonal antibodies (MAbs) using splenocytes of the diseased animal. The reactivity of such MAbs towards thymoma cell lines established in vitro was investigated by means of an ELISA. At least 10 antibody specificities were detected on the 13 tumours investigated, allowing separation of the MAbs into three classes: those recognizing the autologous tumour, heterologous tumours as well as normal thymic tissue, those specific for the autologous tumour, and those specific for one tumour, but not ones of autologous origin. The last two classes corresponded to specific tumour-associated antigens. Our panel of MAbs defined each tumour by the particular pattern of antigens harboured. It is striking that most of the antigens were present in the normal thymus and that only two tumours had additional antigenicities. Additionally, quantitative variations were observed in the levels of expression of these antigens.

Animals↗

Effect of lymphoma grafts on natural killer cell activity in AKR and C57BL/6 mice.

The natural killer (NK) cell activity of spleen suspensions was measured in AKR and C57BL/6 mice grafted either with isogeneic thymic or nonthymic lymphomas. The transplanted cells originated from lymphoid tumors (B, T, or null) which developed either spontaneously (AKR) or after radiation exposure or after injection of retroviruses (C57BL/6). The NK response was significantly enhanced in AKR and C57BL/6 mice grafted with nonthymic and with some thymic lymphoma lines maintained by in vivo passages. The increase of NK activity which took place during the first 5 days after grafting was concomitant with a hyperplasia of the spleen red pulp. Cells from invaded spleens presented a suppressive effect on NK activity. Most primary AKR thymomas and 4 out of 8 tested thymic lymphomas maintained by in vivo passage in C57BL/6 mice were not inducers. In vitro passaged lymphomas, whether AKR or C57BL/6, displayed variable capacity of stimulation which did not match those of the same in vivo maintained lines. It was found that the capacity of most cultured cells to stimulate NK activity correlated positively with the reverse transcriptase concentration of the corresponding culture media.

Animals↗

Response to ConA and PHA of host and donor thymic cells in radiation bone marrow chimeras.

The response of thymic cells to ConA and PHA was followed during 49 days in 9 Gy-irradiated C3H mice reconstituted with (C3H X AKR)F1 BM. Thymic suspension were fractionated firstly according to their capacity to bind PNA, and secondly by their Thy-1 surface antigen: Thy-1.1 antiserum was used either to lyse doner-derived cells or to separate them from host cells by panning. From days 14 to 25, when the donor-derived elements expand rapidly, the PNA- fraction remains stable and equal to 6%, suggesting that PNA+ and PNA- cell populations develop independently of each other. On the contrary, the PNA- fraction which initially represents 6% of the surviving cells rises up to 12% after day 20 and remains at this level in the long-lived host population until the end of the experiment (49 days). The response to ConA returns to normal as early as 15 days after X-rays in the PNA- fraction, whereas the response to PHA is still impaired at the end of the experiment. In both cases host cells express a higher level of responsiveness to mitogens than donor cells.

Agglutination↗

Protective effect of bone marrow and spleen suspensions on radiation-induced leukemogenesis in C57BL/6 mice.

The present experiments are an attempt to precise the type and localization of the cells involved in the protective effect of hemopoietic suspensions against the radiation-induced thymic lymphosarcoma (TLS) of C57BL/6 mice. Inocula containing variable numbers of BM or spleen CFUs from 60-day-old and 360-day-old donors were tested. According to their origin, the suspensions differed with respect to the CFU replication rate, the CFU ability to differentiate towards the T lineage and the content of the suspensions in thymic precursors. Two levels of inhibition were observed: BM suspensions from 60-day-old donors containing 1,500 CFUs had the best protective effect: 14.5% of TLS; 1,500 CFUs from 360-day-old donors were slightly but not significantly less efficient (28.5%). The second level of inhibition (36-46% of TLS) was obtained with all the following inocula: a) 1,200 and 300 spleen CFUs or 300 and 95 BM CFUs from 60-day-old donors, b) 1,500 spleen CFUs from aged donors. Seventy-six spleen CFUs from 60-day-old donors, 120 BM or 175 spleen CFUs from aged donors had no effect. These results suggest that in addition to the high replication rate of the BM CFUs as compared with spleen CFUs, cells endowed with an optimal protective effect are present in BM suspensions and are either absent or present in very small amount in spleen suspensions. These cells which induce an early repopulation of the thymus might correspond to thymic precursors.

Animals↗

[Changes in the serum protein profile during radiotherapy of the upper respiratory and digestive tracts].

Patients with a cancer of the upper airways or upper gastro-intestinal tract present a state of malnutrition as a result of the disease itself and, more importantly, as a result of its localisation. Loco-regional radiotherapy often leads to an aggravation of this state. The protein profile, consisting of nine serum proteins, was determined each week in 54 patients with cancer of the upper respirato-gastro-intestinal tract receiving radiotherapy. During the course of radiotherapy, the already altered nutritional state of these patients deteriorated further, as shown by a regular and significant downturn in the weight curve. The weekly monitoring of the protein profile showed a gradual and significant decrease in the levels of nutritional proteins (prealbumin, retinol binding protein, transferrin) and immunoglobulins (IgM, IgA) and a small variation in the levels of inflammatory proteins (haptoglobin, orosomucoid, C3 complement fraction, alpha 1-antitrypsin). The protein profile, established on the basis of carefully selected proteins, can provide useful information in the monitoring of a patient's nutritional state.

Adult↗

Distribution of terminal deoxynucleotidyl transferase activity between peaks I and II in host and donor thymic cells of bone-marrow-restored mice after X-irradiation.

The terminal deoxynucleotidyl transferase (TdT) activity and its distribution between peaks I and II after chromatographic elution were studied on days 15 and 17 after X-irradiation, in host- and donor-derived thymic cells of lethally irradiated (9 Gy) mice restored with BM cells. It was found that the population derived from the surviving host thymocytes differed markedly from the donor-derived population. The cells of host origin has a low TdT activity especially in peak II and the ratio peak I/peak II remained close to 1 instead of 0.1 in controls. These alterations reflect a reduced replication rate and possibly a modification of the cellular metabolic activity (phosphorylation-dephosphorylation). In contrast, the donor-derived elements displayed a very high TdT activity related to their elevated rate of replication, and the ratio peak I/peak II which was close to 1 on day 15 returned rapidly to normal. The impaired replication ability and the metabolic alteration of the host cells might be attributed either to a specific property of the radiation-resistant thymocytes or to residual cellular injury or to a combination of both.

Animals↗

Terminal deoxynucleotidyl transferase activity in the regenerating thymus of x-irradiated mice.

The distribution of terminal deoxynucleotidyl transferase (TdT) enzyme activity (EU per 10 8 cells) between peaks I and II was followed for a period of 42 days in regenerating thymus of lethally irradiated (9 Gy) C3H mice restored with 10 6 (C3H x AKR) F1 bone marrow cells. The detection of Thy-1.1 and Thy-1.2 surface antigens allowed for the discrimination between host and donor cells, and the main subpopulations of thymic cells were characterized by their sensitivity to H-2 k antiserum and to dexamethazone. Two peaks of TdT activity could be detected on phosphocellulose chromatographic separation. The distribution of TdT activity between these two peaks was followed during the two periods of thymic endo- and exoregeneration. Peak I TdT activity was closely correlated with the variation in the percentage of high H-2 population. Peak II activity was mostly related to low H-2 cells. The per cell content of both peak I and peak II activities exceeded the norm in rapidly expanding populations. Finally between days 10 and 14 the TdT activity of the endoregenerating population was apparently not different from that of the exoregenerating population between days 14 and 22.

Animals↗

Influence of serum thymic factor (FTS) on radiation-induced leukaemogenesis in thymectomized AKR mice.

The influence of serum thymic factor (FTS) on extrathymic leukaemogenesis induced in thymectomized AKR mice by fractionated sub-lethal irradiation was studied. Thirty-day-old thymectomized mice were submitted to four doses at weekly intervals (1.75 Gy) and thereafter treated with FTS (1 ng) for 9 days. Two groups were restored with either bone marrow or spleen cells prior to FTS treatment. In another group mice were treated with FTS (12 ng) for 1 month after thymectomy and prior to irradiation. Results indicated that primarily irradiation and FTS, and, to a lesser extent, restoration and age of the mice at the time of their first radiation exposure influenced leukaemogenesis. Irradiation increased the spontaneous low incidence of extrathymic leukaemia (5%) up to 50%. Although nothing is yet known about the expression of endogenous retroviruses in thymectomized AKR mice, the possible expression of leukaemogenic recombinants, either identical to or different from mink-cell-focus-inducing viruses (MCF), might explain this enhancing effect of radiation on leukaemogenesis. Mice developed two types of leukaemias: "null" leukaemias whose cells bore no detectable theta antigen or surface immunoglobulin, and B leukaemias. Among the null leukaemias, two kinds could be distinguished: "early" ones which were observed before 450 days, and in which BM and spleen were similarly involved, and "late" ones which displayed the same characteristics as B leukaemias, i.e. delayed appearance (after 450 days) and splenic origin. Although FTS did not modify the overall frequency of leukaemias, it increased significantly the incidence of the "early" null ones. It had no effect on the frequency or the latency of late null and B leukaemias. Any population of theta-negative T cells sensitive to FTS could be an acceptable candidate for "early" null leukaemogenesis. The origin of "late" null leukaemias remains an open question.

Age Factors↗