Defective handling of mycobacteria.
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Biomedical subjects
Publications and source records attributed to B Petrini.
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The blood lymphocyte population was studied in 23 breast cancer patients treated with adjuvant tamoxifen for 1.5-2 years, and in an equal number of control patients. The size and cellular composition of the blood lymphocyte population, as assessed by monoclonal antibodies directed against various subsets, did not differ between the two patient groups. However, lymphocytes from the tamoxifen-treated patients exhibited a significantly lower NK activity against K562 cells. In contrast, the proliferative response of lymphocytes to ConA was significantly higher. These results indicate that tamoxifen may modulate the immune system.
The blood lymphocyte population was examined in 34 patients who were treated with 131I for toxic or atoxic nodular goitre. One to three doses of 300-550 MBq of 131I were administered at 1-week intervals. Lymphocyte counts were found to be significantly reduced at both 1 and 6 weeks after treatment. This decrease was accompanied by a changed composition of the lymphocyte subpopulations. The frequency of lymphocytes expressing membrane receptors for C'3 (EAC-rosette forming cells) was significantly reduced at 1 and 6 weeks following 131I administration. At 6 weeks there was a small but statistically significant increase of the frequency of T cells as identified by Leu 1 monoclonal antibodies. This was essentially due to an increased proportion of helper/inducer T cells as identified by Leu 3 monoclonals. 131I treatment also decreased the capacity of lymphocytes to secrete immunoglobulins (Ig) when stimulated with pokeweed mitogen (PWM). The greatest effect was observed for IgM. Secretion of IgG and IgA were less reduced. Mitogenic stimulations of lymphocytes with phytohemagglutinin (PHA) and concanavalin A were not significantly changed. It is concluded that these findings, with the exception of mitogen reactivity, are largely similar to those occurring following external radiation therapy for cancer. It is suggested that blood lymphocytes passing through the continuously irradiated gland are damaged mainly by beta-rays. The effect of 32P treatment on the blood lymphocyte population was examined in 16 patients with polycythemia vera. Before treatment the lymphocyte counts were within the normal range but the expression of certain membrane structures, as identified by monoclonal antibodies against total T cells (Leu 1 and 4), helper/inducer (Leu 3) and suppressor/cytotoxic T cells (Leu 2), were slightly decreased. Moreover, mitogenic responses of the lymphocytes to PHA and PWM-induced Ig secretion were impaired. Following a single oral dose of 32P (150-305 MBq), which normalized the production of erythrocytes and/or platelets, the blood lymphocyte counts were reduced by approximately 40 per cent 12 weeks after treatment. Examination of subsets demonstrated that the proportion of B-cells, as identified by B1 monoclonal antibodies, was decreased by the highest relative extent. On the other hand, lymphocytes expressing the above-mentioned T cell markers were somewhat increased. 32P treatment markedly increased PHA reactivity but it further reduced PWM-induced Ig secretion. The latter observation was in agreement with the finding that serum concentrations of Ig were reduced after treatment.
The effects of 9-deoxy-delta 9-prostaglandin D2 (PGJ2) and 9-deoxy-delta 9-delta 12-prostaglandin D2 (delta 12PGJ2), which are metabolites of PGD2, on lymphocyte and monocyte reactions were studied in vitro. Expression of various phenotypic markers of lymphocyte subsets, as detected by monoclonal antibodies, was not affected by overnight incubation in 3 x 10(-5) M PGJ2. Phytohemagglutinin stimulation and natural killer activity of lymphocytes was reduced by PGJ2 and delta 12 PGJ2. Monocyte reactivity to 12-o-tetradecanoylphorbol-13-acetate, as assessed by chemiluminescence, was stimulated by preincubation of the cells for 1 h in 3 x 10(-5) M PGJ2 or delta 12 PGJ2. Such an augmentation was not exerted by PGD2.
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The blood lymphocyte population was examined in 34 patients who were treated with 131I for toxic or atoxic nodular goiter. The patients received one to three doses of 300-550 MBq of 131I administered at 1 week intervals. Lymphocyte counts were significantly reduced both 1 and 6 weeks after treatment. This reduction was accompanied by a changed composition of the lymphocyte population. The frequency of lymphocytes expressing membrane receptors for C'3 (EAC-rosette forming) was significantly reduced 1 and 6 weeks after 131I-administration. At 6 weeks there was a slight but statistically significant increase of the frequency of T-cells as identified by Leu 1 monoclonal antibodies. This was largely caused by an increased proportion of helper/induced T-cells as identified by Leu 3a monoclonals. 131I-treatment also reduced the capacity of lymphocytes to secrete immunoglobulins (Ig) upon PWM-stimulation. The most pronounced effect was observed for IgM. Secretion of IgG and IgA were less reduced. Mitogenic stimulations of lymphocytes with PHA and ConA were not significantly changed. We conclude that these changes observed, with the exception of mitogen reactivity, are essentially similar to those occurring after external radiation therapy for cancer. We speculate that blood lymphocytes passing through the continuously irradiated gland are damaged mainly by emitted beta-particles.
The influence of 32P treatment on the blood lymphocyte population was examined in 16 patients with polycythaemia vera who had not previously been treated with cytotoxic drugs or irradiation. Before treatment the lymphocyte counts were within the normal range but the expression of certain membrane structures, as detected by monoclonal antibodies directed against total T cells (CD 3 and 5), helper/inducer (CD 4) and suppressor/cytotoxic T cells (CD 8), were slightly reduced. In addition, mitogenic responses of the lymphocytes to PHA and PWM-induced Ig secretion were severely impaired. Following a single oral dose of 32P (150-305 MBq), which was shown to normalize the production of erythrocytes and/or platelets, the blood lymphocyte counts were reduced by approximately 40% 12 wk after treatment. Subset analysis showed that the proportion of B cells, as identified by monoclonal antibodies (CD 20), was reduced to the highest relative extent. On the other hand, lymphocytes expressing the above T cell markers were somewhat increased. 32P treatment sharply increased PHA reactivity but it further reduced PWM-induced Ig secretion. The latter observation was in line with the finding that serum concentrations of Ig were reduced following treatment.
The effect of some prostaglandins (PGs) and leukotrienes (LTs) on lymphocytes and monocytes was tested in vitro. Overnight incubation with PGD2 reduces the expression of Leu-2 antigen (suppressor/cytotoxic phenotype) and of Fc receptors for IgG. PGA2, PGD2 and to a lesser extent PGE2 inhibit PHA reactivity of lymphocytes. LTB4 does not have any inhibitory activity. Preincubation of lymphocytes with PGD2 and PGE2 decreases their NK activity. LTB4, but not the PGs tested, stimulates monocyte metabolism as assessed by chemiluminescence.
The incidence of symptoms generally associated with infectious disease was assessed by a questionnaire sent out to 519 disease-free breast cancer patients 7 to 12 years after primary treatment. All patients were treated in the context of a randomized trial where pre- and postoperative radiation (45 Gy) was evaluated versus surgery only. The results indicate a significantly higher morbidity among patients treated with preoperative irradiation compared with those irradiated postoperative (p less than 0.05). This increased morbidity mainly seemed to be caused by symptoms usually associated with respiratory tract infection (p less than 0.05). Although statistically not significant the preoperatively irradiated patients also had a higher morbidity than those treated with surgery alone. There was no difference between postoperatively irradiated patients and patients treated with surgery only. A significantly higher integral dose (absorbed energy within the body) of the pre- compared with the postoperative group (p less than 0.025) is associated with the differences in morbidity between the two irradiated groups. An explanation for the increased morbidity seems to be that the volume of lung tissue, encompassed within the full-dose target volume, is the crucial factor. This volume was considerable in the preoperatively treated patients but kept at a minimum in the postoperative group.
The prognostic relevance of phytohemagglutinin (PHA) and purified protein derivative (PPD) lymphocyte reactivity at diagnosis and after radiotherapy was evaluated in breast cancer patients. The patients were followed up to 13 years and the prognostic value expressed as ratios between observed number of deaths and "estimated" number of deaths under the null hypothesis. There was no significant association between the initial PHA and PPD reactivity and the survival of the patients. On the other hand, mortality up to 8 years after radiotherapy was significantly higher for patients with low PHA and PPD reactivity at completion of treatment. Furthermore, patients who had higher than average PPD reactivity 6 to 10 months after radiotherapy, seemed to have a higher survival rate. The prognostic relevance of postirradiation lymphocyte reactivity was only to some extent explained by clinical stage.
Seventeen patients with advanced, noncurable gastrointestinal cancer with symptoms of anorexia and malnutrition were treated with controlled enteral or total parenteral nutrition over a 3-week period. Eleven patients received enteral and six parenteral nutrition. The nutrition was given with 30-40 kcal/kg b.w. daily. No anticancer treatment was given. Before and after the treatment period, the patients were assessed regarding their nutritional, immunological, and performance status. None of the studied nutritional parameters changed significantly over the 3-week period and there was no clear indication of an improved lymphocyte reactivity. There was a tendency toward improvement in performance status for the patients on enteral nutrition, while the reverse seemed to be true for the parenteral group. It is concluded that nutritional support may halt the progressive malnutrition often seen in patients with cancer and serve as a palliative treatment in selected patients.
The reduction of mitogen responses of blood lymphocytes which occur after radiation therapy for breast cancer, known to be largely due to inhibitory monocytes, can partly be reverted by indomethacin which is an inhibitor of prostaglandin (PG) synthesis. This may indicate that PG-synthesis by blood monocytes is increased after irradiation or that PG-sensitivity of the lymphocyte population is increased. To test the latter possibility the sensitivity of the PHA-response of blood lymphocytes to varying concentrations of PGE2 and PGD2 was examined in 15 patients with breast cancer before and up to 6 months after local radiation therapy (46 Gy). The results showed that the sensitivity of the PHA-response was not significantly changed after treatment suggesting that the immunosuppression observed after irradiation is partly due to an increased production of PGs rather than an increased PG-sensitivity of lymphocytes.
The long-term effect of local irradiation for breast cancer on the blood lymphocyte population was examined in 149 women who had been disease-free for 5-6 and 10-11 years. The patients were included in a clinical trial aiming at determining the value of pre- and post-operative irradiation (45 Gy) compared to surgery only. It was observed that the relative mitogen responses of lymphocytes to phytohaemagglutinin (PHA) and Concanavalin (Con A) and in a mixed lymphocyte culture (MLC) were significantly lower in irradiated compared to unirradiated patients at least a decade after treatment. The prolonged reductions of mitogen responses after irradiation could partly be due to an increased proportion of lymphocytes which may express suppressor function since the Con A-inducible suppressor activity of lymphocytes was significantly higher in irradiated compared to unirradiated patients.
Blood lymphocyte counts and various lymphocyte subsets, as defined by rosette tests, were examined in breast cancer patients and correlated to the extent of tumor disease and prognosis. One hundred sixty-six patients tested before or shortly after surgery were included. It was observed that the frequency of E-rosette-forming lymphocytes correlated to the development of distant metastases (P = 0.007) and survival (P = 0.022). A high frequency of E-rosette-forming cells was associated with a poor prognosis. The well-known prognostic value of clinical tumor stage and axillary lymph node involvement was also confirmed. A possible relation between the tumor disease and other immune variables was indicated by the finding that the frequency of EAC-rosette-forming lymphocytes (mainly B-cells) was reduced in patients with relatively large primary tumors. This relation was most pronounced in patients without axillary node involvement (P less than 0.01). In addition, it was observed that the blood lymphocyte counts were significantly higher in patients with three or more tumor-involved axillary nodes than in those with zero to two (P less than 0.005). Our results seem to stand in contrast to the generally held view that low lymphocyte counts and a low proportion of E-rosette-forming cells in the blood are associated with a large tumor burden and a poor prognosis.
Currently, the most probable theory of tumor surveillance is neither the existence of any tumor-specific, antigen-dependent, T-cell-mediated cytotoxic effect that could eliminate spontaneous tumors in man and that could be used for some kind of vaccination against tumors, nor the complete absence of any surveillance or defense systems against tumors. What is probable is the cooperation of a number of antigen-independent, relatively weakly cytotoxic or possibly only cytostatic humoral and cellular effects, including nutritional immunity, tumor necrosis factor, certain cytokines, and the cytotoxic effects mediated by macrophages, NK cells, NK-like cells, and certain stimulated T-cells. One question remaining to be solved is why these antigen-independent effects do not attack normal cells. A number of plausible hypotheses are discussed. The hypothetical surveillance system is modulated both by traditional cancer treatment and by attempts at immunomodulation. Radiotherapy reduced the T-helper cell function for almost a decade, but not those of macrophages or NK cells. T-cell changes have no prognostic implication, supporting, perhaps, the suggestion of a major role for macrophages and NK cells. Cyclic adjuvant chemotherapy reduces the peripheral lymphocyte population and several lymphocyte functions but not NK activity. Most of the parameters were normalized some years following treatment, but NK activity remained elevated and Th/Ts cell ratio was still decreased. This might possibly be taken to support the surveillance role of NK cells. Bestatin increases the frequency of lymphocytes forming rosettes with sheep red blood cells (but not their mitogenic responses), enhances NK activity, and augments the phagocytic capacity of granulocytes and monocytes (but not their cytotoxic activity). Improved survival with Bestatin treatment following chemotherapy has been observed in patients with melanoma Stages 1b and II and in patients with acute nonlymphatic leukemia, where BCG also seems active, although possibly only in patient groups with less than 49% complete remissions.
Local radiation therapy for breast cancer depletes the blood of various subsets of lymphocytes. Previous studies showed that the recovery is still incomplete at 30 months. To further elucidate the recovery we examined blood lymphocyte counts of 138 disease-free women and various lymphocyte subsets in 102 of these patients. These patients, 5-6 and 10-11 years earlier, had entered a clinical trial in which preoperative irradiation (45 Gy) was evaluated against postoperative irradiation (45 Gy) or surgery only. Patients who had undergone surgery only served as controls. Total lymphocyte counts of the irradiated patients were still significantly reduced 10-11 years after treatment. This reduction was mainly attributable to a subnormal level of T-cells as determined by the monoclonal antibody Leu-1 and the ability to form rosettes with sheep erythrocytes, whereas the number of non-T cells, expressing C'3 receptors, did not differ significantly from the controls. Within the T-cell population a subset with helper/inducer phenotypes, detected by Leu-3a antibodies, was significantly reduced even 10-11 years after irradiation. T-cells with suppressor/cytotoxic phenotypes, stainable with Leu-2a antibodies, however, had already recovered 5-6 years after irradiation. The duration of the radiation induced reductions of different lymphocyte subsets may be related to the physiological turn-over of the cells or a changed distribution of cells in the body.