T helper/suppressor ratios in chemotherapy and radiotherapy.
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Biomedical subjects
Publications and source records attributed to B Petrini.
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PWM-induced in vitro Ig synthesis was measured in cell cultures containing B lymphocytes from healthy controls and T lymphocytes collected from breast cancer patients before and after radiotherapy, respectively. The amounts of IgG and IgM did not differ between these two types of cultures. Lymphoid cell suspensions containing 3-5% monocytes were irradiated with 13 Gy and co-cultured with non-irradiated B lymphocytes. The PWM induced production of IgG and IgM in these cultures was decreased as compared to non-irradiated controls.
Local radiation therapy may severely deplete the recirculating pool of lymphocytes as manifested by a reduction of blood lymphocyte counts. There is considerable controversy, however, concerning the changes of the distributions of subsets of blood lymphocytes during the acute and late phases after irradiation. This report provides evidence that radiation therapy directed to different anatomic sites may change the distribution of subsets of blood lymphocytes in different ways. For instance, during the acute phase after radiation therapy for breast cancer there is a more extensive reduction of the proportion of lymphocytes with receptors for C3 than that of lymphocytes with receptors for sheep erythrocytes (characteristics of B- and T-cells respectively). Such a difference, however, was not observed in groups of patients receiving pelvic irradiation. The controversy in the literature concerning the distribution of lymphocyte subsets after irradiation may thus in part be due to the fact that the patients examined have received radiation therapy to different body regions.
The capacity of the blood lymphocyte population to spontaneously lyse K562 and Chang cells In vitro was examined in women who received local radiation therapy (45.0 Gy) for breast cancer. It was observed that cytotoxicity, on a cell-for-cell basis, was significantly reduced against K562 cells at completion of irradiation. This was followed by a recovery to the pretreatment level within 3-4 months and remained relatively constant for approximately 2 yr. The pattern of these changes were reasonably similar to that of the frequency of lymphocytes expressing Fc-receptors for IgG. In contrast, the relative cytotoxicity against Chang cells was unchanged at completion of irradiation. At 3-4 months, however, the relative cytotoxicity was increased above the pretreatment level and remained elevated for at least 2 yr. The results indicate that different effector cells are involved in the spontaneous destruction of K562 and Chang cells.
T helper and T suppressor lymphocyte subpopulations were examined before and after postoperative adjuvant radiation therapy for breast cancer. Absolute numbers of all T cell subsets were reduced by 70-80%. The proportion of IgG-Fc receptor-bearing T cells (Tg cells) was significantly reduced and that of IgM-Fc receptor-bearing T cells (Tm cells) significantly increased at completion of local radiation therapy with 45 Gy (4500 rad). Proportions of T suppressor (Ts) and T helper (Th) cells determined by monoclonal antibodies were not changed by radiation therapy. The overlapping between Tg and Ts subpopulations was 20-30% as examined by double labelling.
Radiation treatment of breast cancer patients (45.0 Gy) profoundly affected the peripheral blood lymphocytes. The number of these cells was markedly reduced with non-T-cells being more extensively depleted than T-cells immediately after radiation. The long-lasting lymphopenia, on the other hand, was mainly due to reduced number of T-cells. Antigen and mitogen stimulability, MLC reactivity, pokeweed (PWM)-induced immunoglobulin (Ig) production in vitro, and different cytotoxic functions decreased. Depletion of lymphocytes largely restored the radiation-depressed lymphocyte reactivity. The effects of in vitro exposure of blood lymphocytes to x-rays were similar to those seen after radiotherapy. Non-T-cells and T-cells with Fc-receptors for IgG were relatively radiosensitive. This latter observation agreed well with demonstrated increase of PWM-induced Ig synthesis after in vitro exposure to x-rays. T-suppressor cells defined by monoclonal antibodies were, however, radioresistant. The cytotoxic functions were reduced. No correlations were found between the pretreatment immunological status or the extent of radiation-induced immunological suppression, respectively, and prognosis.
Concanavalin a (Con A)-induced and Con A-inducible human suppressor lymphocytes were examined for their radiosensitivity (16 Gy). It was observed that X-ray exposure of Con A-induced suppressor cells abolished some of the suppressive activity. Exposure of lymphocyte preparations did not prevent the subsequent induction by Con A of suppressor cells capable of inhibiting mitogen responses of lymphocytes. The relative size of the Con A-inducible suppressor population in the blood was not changed in breast cancer patients after local radiation therapy.
The influence on the blood lymphocyte population of two types of postoperative adjuvant chemotherapy regimes given to patients with large breast tumors or involved axillary lymph nodes have been examined. Cyclic treatment with a combination of chlorambucil, methotrexate and 5-fluorouracil was more myelotoxic and required more extensive dose reductions than treatment with cyclophosphamide, methotrexate and 5-fluorouracil with the dosage used. Both treatments reduced the size of the blood lymphocyte population and changed its cellular composition, as defined by rosette tests, to approximately the same extent. Response of the lymphocytes to specific and non-specific mitogens were also affected to approximately the same extent. A comparison of the clinical value between the two treatments has not yet been performed.
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A group of 17 patients, having undergone modified radical mastectomy for breast cancer, received 12 cycles of chemotherapy with methotrexate, 5-fluorouracil, and chlorambucil during 17 months. The number of circulating T and non T lymphocytes, as defined by E, EAC, and ME rosette formation, were reduced during treatment. The Non-T lymphocytes, however, were reduced to the highest relative extent. Relative phytohemagglutinin and mixed lymphocyte culture responses of the cells decreased, whereas purified protein derivative responses were unchanged. Serum concentrations of IgM were reduced, but IgA and IgG concentrations were unchanged or slightly increased. Antibody titres to morbilli and herpes simplex were not changed, whereas the antibody activity against cytomegalovirus (CMV) increased in several seropositive patients. None of these patients, however, developed signs of a CMV infection.
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Purified staphylococcal alpha-, gamma-, and delta-toxin were shown to cause activation of lymphoid cells from adult human donors and of cord cells in vitro as measured by [14C]thymidine incorporation after 7 days of incubation. T cell-enriched and T cell-depleted lymphocyte suspensions were activated in a similar fashion. Beta-toxin, on the other hand, exerted no valid stimulation of the various lymphocyte preparations. The lymphocyte-activating properties of alpha- and gamma-toxin were shown to be independent of their hemolytic capacity. The results probably reflect unspecific mitogen effects, but a component of specific reactivity cannot be excluded. We suggest that the unspecific triggering of lymphocytes in vitro is caused by surface-active properties of the toxins.
T lymphocytes with Fc receptors for IgM (Tm cells) or IgG (Tg cells), known under certain conditions to exert help or suppression, and T-helper and T-suppressor cells, defined by fluorescein-isothiocyanate-conjugated monoclonal antibodies, were determined in 7 patients with chronic dermatophytosis. There appeared to be a relation between severity of the disease and decreased proportion of Tm cells with concomitant increase of Tg cells. However, only in 1 severe case there was also a shift of T-helper and T-suppressor cells as defined by monoclonal antibodies.
Blood lymphocyte reactivity to purified protein derivative of tuberculin (PPD) and phytohaemagglutinin (PHA) was examined in 62 patients with breast carcinoma who received postoperative adjuvant radiation therapy or cyclic chemotherapy with chlorambucil, methotrexate and 5-fluorouracil. Both treatments impaired the immunologic reactivity of blood lymphocytes as measured by PPD and PHA stimulation in vitro. Radiation therapy seemed to cause more profound and protracted suppression of the PPD response than chemotherapy.
Peripheral lymphocyte subpopulations were examined in 37 women with breast carcinoma who were postoperatively randomized to adjuvant local radiation therapy or cyclic treatment with 5-Fluorouracil, Methotrexate and Chlorambucil. Both T and non-T lymphocyte counts were reduced but the latter subpopulation was reduced to the highest relative extent in both groups of patients. Following radiation therapy the non-T cells repopulated more rapidly than the T cells, whereas the repopulation seemed to be the reverse in patients treated with chemotherapy.
T-lymphocyte subpopulations, PWM stimulated in vitro Ig production by mononuclear cells, and spontaneous cell-mediated cytotoxicity (SCMC) were determined in patients with Mycosis fungoides (MF) as well as in sex- and age-matched normal controls. We were able to confirm our earlier findings of a significantly higher frequency of T-lymphocytes with Fc-receptors for IgG (Tg cells) and a proportion of T lymphocytes with Fe receptors for IgM (Tm cells) not significantly differing from normal controls. As defined by monoclonal antibodies, the proportion of T-helper cells (Leu3A) was significantly lower, whereas the T-suppressors cells (Leu2A) were in the range of normal controls. The PWM stimulated and spontaneous Ig synthesis in vitro was lower in MF patients whereas there was no difference in the SCMC activity, in comparison with normal controls. The lower frequency of T-helper cells in the peripheral blood may be explained by their migration to the skin.
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