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A case of Sjögren's syndrome with the sicca complex is presented which was associated with persistently low or absent C4 levels, high levels of circulating immune complexes and abnormal reticuloendothelial clearance of damaged or IgG antibody sensitized autologous red blood cells (RBCs). Investigation of normal relatives of the patient revealed low C4 levels and abnormal reticuloendothelial clearance of damaged or sensitized RBCs, HLA, A, B, DR typing revealed a high incidence of the HLA B8, DR3 haplotype and of homozygous null alleles at the C4A locus in the family members. These results suggest that the C4 deficiency and the abnormal reticuloendothelial function in the patient was in part genetically determined and may have predisposed to the development of Sjögren's syndrome. These findings serve to emphasize the possible importance of abnormal macrophage function in the pathogenesis of Sjögren's syndrome and suggest that further investigation of these aspects may increase understanding of this disease. [ABSTRACT FROM AUTHOR]

A child with Fanconi's anaemia diagnosed at 7 years of age presented in adult life with lymphopenia, recurrent warts and Bowen's disease. The latter resulted in the development of multiple cutaneous squamous cell carcinomas which metastasized to the skeleton. Investigation of her immune function revealed selective defects in natural killer (NK) cell activity. Humoral immunity and several tests of cell-mediated responses were within normal or became normal after treatment with levamisole or transfer factor. Analysis of the defect in NK activity revealed that low levels could be induced in vitro by fibroblast interferon. Stimulation of blood lymphocytes from the patient with the interferon inducer poly (1)-poly (C) resulted in an increase in NK activity but incubation of her lymphocytes on tumour cells did not result in an increase in NK activity or the release of interferon. This contrasted with the marked increase in NK activity and interferon release observed when lymphocytes from normal controls were incubated on tumour cells. These findings suggested the absence of NK activity in this patient was secondary to a defect in interferon release from lymphocytes on exposure to tumour antigens. It is considered that these defects may have been an important predisposing factor in the development of malignancy in this patient and possibly other patients with Fanconi's anaemia. [ABSTRACT FROM AUTHOR]

The action of levamisole on immunoglobulin production was investigated in pokeweed mitogen-stimulated cultures of B and T cells. Immunoglobulin production was measured by nephelometric methods using specific antisera to IgA, IgG and IgM. Levamisole was shown to have no effect on B lymphocytes but pretreatment of T lymphocytes with levamisole resulted in an increase in immunoglobulin production which was maximal at 10-6 M. The latter increase appeared to be due to an effect on suppressor T cells in that pretreatment of T cells depleted of suppressor cells (by irradiation or removal of T cells with receptors with IgG) did not result in an increase in immunoglobulin production. Similar effects of levamisole were demonstrated against suppressor cells induced by concanavalin A in vitro and against spontaneous suppressor cell activity in vivo. The effect of levamisole and irradiation on suppressor cell activity against particular classes of immunoglobulin varied between individuals. Suppressor cell activity against IgA production alone was demonstrated in six of 17 subjects whereas in the remainder, suppressor cell activity was either not detected or inhibited production of all three immunoglobulin classes. The implications of this action of levamisole for its effects in vivo are unknown, but the results appear consistent with many of the observed effects of the drug. Selection of patients with diseases associated with high suppressor cell activity may lead to more effective use of the drug. [ABSTRACT FROM AUTHOR]

A number of previous studies have described antibodies in normal sera reactive to human leukaemia cells. In the course of studies on humoral immunity to acute myeloid leukaemia (AML) cells it was noticed that sera from normal subjects were cytotoxic in complement lysis and leucocyte dependent antibody (LDA) assays to blood leucocytes from patients with AML in remission. Investigation of these reactions in eleven patients with acute leukaemia in complete or partial remission revealed that reactivity occurred most frequently between sera from normal blood group O or B subjects and leucocytes from patients of blood group A (five patients). Leucocytes from blood group O patients were largely unreactive. Blood leucocytes from five of six patients in relapse did not react with normal sera. Subsequent studies revealed that the antigens were detected only on T lymphocytes. Reactivity could be removed by absorption on red cells of blood group A but not sheep or Ox red blood cells suggesting the antigens concerned were closely related to blood group A antigens. Some reactivity with antisera to the blood group H antigens was also evident in these studies. Gel filtration studies indicated that lymphocyte dependent antibody mediated cytotoxicity was mediated by IgG antibodies while complement dependent lysis was mainly mediated by IgM antibodies. The biological significance of these findings has yet to be determined hut these results suggest that reactivity with blood group antigens needs to he considered in in vitro cytotoxicity. [ABSTRACT FROM AUTHOR]

The underlying basis for hypogammaglobulinaemia in patients with chronic lymphatic leukaemia (CLL) was investigated by measurement of immunoglobulin produced in vitro in cultures of pokeweed mitogen-stimulated B and T lymphocytes. B and T cells were separated by sheep red blood cell rosette techniques and, by culture of these cells from CLL patients in various combinations with B or T cells from normal subjects, it was possible to measure independently the function of B lymphocytes and the helper or suppressor function of T lymphocytes. By these methods it was found that the B lymphocytes of six of eight patients failed to produce immunoglobulins in vitro. B lymphocytes from two patients appeared to produce immunoglobulins in vitro. T lymphocytes from five of the eight patients had low or undetectable helper T cell function and in six patients their T lymphocytes had excessive suppressor activity in comparison to T lymphocyte populations from normal subjects. Whether the primary abnormality in the CLL T cell populations was a deficiency of helper T cells or excess of suppressor T cells was uncertain from these studies. These results suggest that immunoglobulin production by B lymphocytes from most patients with CLL was abnormal but also that T cells from CLL patients may be abnormal in respect to their role in immunoglobulin production at an early stage of the disease. These findings may assist in understanding the pathogenesis of this disease and lead to new approaches in treatment. [ABSTRACT FROM AUTHOR]

The effector cells responsible for cytotoxic activity induced by phytohaemagglutinin, (PHA) pokeweed mitogen (PWM) and target cells complexed with lgG antibody has been investigated using cell separation techniques based on rosette Formation and separation through Hypaque-Ficoll mixtures. It was shown that PHA-induced cytotoxicity is predominantly a function of T cells and that Fc receptor-bearing cells are not involved to any major extent. Antibody-dependent killing is conversely a function of Fc receptor-bearing cells among which two subtypes can be distinguished. One of these has receptors for activated complement while the other bears receptors only and has no detectable receptors for complement. PWM appears to induce cytotoxicity in both T- and non-T-cell populations but the major cell type involved appears to be Fe receptor-bearing cells similar to those mediating antibody-dependent killing. It is concluded that PHA and antibody- dependent killing are the two most useful assays for discriminating between the cytotoxic activity of T and non-T cells in clinical studies. [ABSTRACT FROM AUTHOR]

We have previously shown that tumour cells may release soluble factors which inhibit the division of a variety of cells. These factors had marked immunosuppressive activity in vitro as shown by their ability to Inhibit lymphocyte mitogenic responses to lectins. allogeneic lymphocytes and pokeweed mitogen-induced immunoglobulin production. It was postulated that these factors may play an important role in determining the outcome of tumour host interactions in humans and be the source of immunosuppressive factors in the circulation of patients with cancer. In the present study, characterization of these mitogenic inhibitory factors released into the supernatants of cultured tumour cells was carried out by a number of sequential separation procedures involving affinity chromatography on wheat-germ lectin (WGL). gel filtration on PL-agarose and electrophoresis in polyacrylamide gels in the presence of sodium dodecyl sulphate (PAGE-SDS). The factors were identified throughout the separation procedure using inhibition of phytohaemagglutinin (PHA) stimulation of normal lymphocytes as an index of inhibitory function. By these techniques the inhibitory activity was shown to be associated with glycoproteins containing N-acetyl-β-D-glucosamine (NAcGlu) and having molecular weights (mol. wt) of approximately 140.000 and over 200,000 daltons. A further small mol. wt peak of 70,000 daltons was observed on PAGE-SDS. pi values of the fractions were 7.4 and 4.2. The activity was destroyed by heating, low pH and repeated freeze-thawing but was resistant to proteolytic enzymes, deoxyribonuclease, ribonuclease and neuraminidase. The active fractions were not associated with proteolytic activity and the inhibition of mitogenic responses was irreversible in nature. These results form the basis of studies to detect this factor in biological fluids and further evaluate its role in the tumour host relationship. [ABSTRACT FROM AUTHOR]

A number of previous reports have described the presence of factors which inhibit the response of lymphoid cells to phytohaemagglutinin. The present study describes an inhibitor of cell division synthesized and released directly from cultured tumour cells which appears to have similar immunosuppressive effects in vitro. This factor(s) was detected in a wide variety of cultured tumour cells and some cultures of normal foetal tissue. It inhibited the mitogenic response of lymphocytes to PHA and also the spontaneous cell division of a variety of cultured cells including the cells producing the factor. Pulse cytophotometry showed that cells were inhibited in the G1 phase. Production of the factor increased with time and was related to the number of cells in culture. Its synthesis was inhibited by cycloheximide. DNA and RNA synthesis was not required for its production. The factor appeared to have a high degree of biological activity m terms of the number of cultured cells required for production and in regard to the number of cells inhibited. The biological significance of this factor in vivo is unknown but in vitro it was shown to inhibit immunoglobulin and mitogen-induced responses which suggests it may play an important role in suppression of the immune response against tumour cells in the host. [ABSTRACT FROM AUTHOR]

Blood lymphocytes and rectal plasma cells have been studied in patients with ulcerative colitis taking part in a douhle-blind trial of treatment with azathioprine. Treatment for 1 year resulted in a modest fall in blood lymphocyte count, with little change in neutrophils or platelets. There was no major change in the proportions of circulating T and B lymphocytes, suggesting that the number of such cells per millilitre of blood fell in proportion to the change in lymphocyte count. The number of plasma cells in the rectal lamina propria was reduced to a mean less than half that of the control patient group. Blood K-cell cytotoxic activity fell at least 25-foId after 1 year's treatment. PHA-induced cytotoxicity was also reduced, but less consistently. Reduced K-cell activity is interpreted as reflecting depletion of effector cells from the circulation. The fall in lymphocyte count, K-cell activity and gut plasma cells was slow, indicating continuous inhibition of lymphopoiesis or differentiation throughout the trial period. Thus, azathioprine has some immunosuppressive effects which develop only after prolonged treatment. The clinical results of the trial did not show a major beneficial effect of azathioprine in the treatment of ulcerative colitis, nor were there clear correlations between the results of lymphocyte assays and clinical response in individual patients. [ABSTRACT FROM AUTHOR]

This report investigates functions and number of different lymphocyte types in patients with testicular and ovarian tumours before, during and following therapeutic irradiation. Irradiation causes loss of T cells, B cells and K cells at similar rates. The long term depletion of T cells, which is well recorded, is due to delayed and incomplete repopulation of a substantial proportion of this cell type. B cells and K cells, however, return to levels very close to normal by 6 and 3 months respectively after irradiation. Long-term depletion of T cells occurs even when the thymus is not irradiated. [ABSTRACT FROM AUTHOR]

Lymphoid sub populations in the blood and rectal mucosa were studied in six patients with ulcerative colitis or Cohn's disease who had been treated for over three year with azathioprine. Serial assays were performed to observe the changes occurring up to 12 weeks after treatment with azathioprine was stooped. While the patients were on the drug tow lymphoid populations showed marked depression. These were the plasma cells of the rectal lamina procris, and blood lymphocytes with cytotoxic activity against antibody-sensitized tared cells ('k' cells). After stopping azathioprine, both population showed a rapid rise to reach near normal levels by 12 weeks, Most of the recovery occurred within 3-5 weeks. There was no significant change in circulating immunogolblin-staining cells which could be attributed to the drug. Nor was azathioprine shown to have any effect on the mitotic response of lymphocytes to phytohaemagglutinin. Three patients, however, gave very low or erratic responses to PHA, which may have been related either to their disease or to steroid therapy, These results are discussed in relation to the mode of action of purine analogues as immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Antibodies which are to induce the killing of allogeneic myeloblasts by normal lymphoid cells have been found in a high proportion of patients with acute myeloid leukaemia. The cytotoxic mechanism induced by this antibody activity is shown to be highly effective in terms of the number of myeloblasts which can be killed by a given number of lymphoid cells and the antibody concentration needed to induce killing. Reasons for the in vivo failure of this cytotoxic mechanism, assuming that antibodies occur against autologous myeloblasts, are suggested by studies in which the cytotoxic lymphoid population has been monitored serially. Some patients are shown to have almost undetectable levels of cytotoxic effector cell activity. A further reason for the failure of this mechanism related to 'blocking activity' in the serum is being investigated. Preliminary results suggest that assay of this antibody activity against myeloblasts may also be of value in following the response to immunotherapy and in providing early warning of relapse. It is suggested that the demonstration of antibody-dependent lymphocyte activity against acute myeloid leukaemic cells provides an additional insight into this disease which may have important implications in management and therapy of acute myeloid leukaemia. [ABSTRACT FROM AUTHOR]