Abnormal regulation in the production of IL2 in Hodgkin's disease

Patients with active Hodgkin's disease demonstrate a significant depression of cellular immunity. The present study, performed with lymphocytes from 16 untreated patients with active Hodgkin's disease and 13 healthy control volunteers, demonstrate an equivalent IL 2 production in vitro in both groups. Our results, however, demonstrate an abnormal regulation of IL 2 production in patients. A negative control of IL 2 production involving monocytes producing PGE 2 able to induce radiosensitive suppressor T lymphocytes, has been identified previously with cells from healthy donors. In the present study we demonstrate that this negative control is hyper functioning with cells from Hodgkin's disease patients.     

Reversal of cell surface abnormalities of T lymphocytes in hodgkin's disease after in vitro incubation in fetal sera.

The capacity of periphal blood lymphocytes from patients with untreated Hodgkin's disease to form E rosettes with sheep erythrocytes and to respond in vitro to PHA stimulation were found to be profoundly impaired. In 49% of the patients, the percentage of E rosette-forming cells (E-RFC) was more than two standard deviations below the mean for normal donors. Overnight incubation of the peripheral blood lymhocytes from these patients in culture media containing 20% fetal calf serum was followed by restoration of the percentage of E-RFC up to normal levels. Similar results have been observed after incubation in fetal human serum, but not in adult human AB serum or adult bovine serum. Incubation of peripheral blood lymphocytes from untreated patients in20% fetal calf serum also resulted in a remarkable restoration of their capacity to respond normally to PHA. Possible mechanisms involved in these reversible cell surface and in vitro lymphocyte function abnormalities in Hodgkin's disease are discussed.     

Potentiation of the defective monocyte chemotaxis in Hodgkin's disease by in vitro tuftsin treatment

In vitro pre-incubation of monocytes derived from patients with Hodgkin's disease with tuftsin (50 micrograms/ml) significantly restored the deficient chemotactic responsiveness of these cells to the complement-derived factor C5a, as demonstrated by a monocyte migration assay based on the Boyden technique. Potentiation of the chemotactic responsiveness of monocytes was most significant after elective splenectomy. The results indicate that the specific receptors required for tuftsin activities may be available on the monocyte membranes in Hodgkin's disease. Since tuftsin is a natural, non-immunogenic tetrapeptide that can also be produced synthetically, it may provide a new therapeutic approach in Hodgkin's disease to at least partial restoration of the defective cellular immunity.     

Infraclavicular chest wall tumors in Hodgkin's disease

In six of 91 cases of Hodgkin's disease observed over a three-year period, a tumor mass filling the infraclavicular hollow was noted. It was on the left side in all instances. Although in four cases it was the only superficial manifestation of Hodgkin's disease for a long period, in all cases there were ultimately other areas of involvement. The lesion did not occur in any of 81 cases of lymphosarcoma observed concurrently.     

L-Asparaginase in Treatment of Acute Leukaemia and Lymphosarcoma

L-Asparaginase was used to treat 40 patients with acute leukaemia or lymphosarcoma. Fifteen with acute lymphoblastic leukaemia either untreated or in relapse after previous therapy were given “Squibb,” “Bayer,” or “Porton” L-asparaginase. Five of these patients had complete remission of their disease, and four had good partial remission. Eleven patients with acute myeloid leukaemia were treated for a short period with L-asparaginase alone. None of them went into remission though a pronounced fall in the numbers of circulating white cells was seen. Six patients with lymphosarcoma received L-asparaginase, two of them having good partial remissions.The toxic side-effects of the L-asparaginase from the three sources seemed to vary, and L-asparaginase from Erwinia carotovora appeared to be antigenically different from the enzyme produced by Escherichia coli.The way in which leukaemic cells become resistant to the action of the enzyme requires further investigation. To overcome this resistance asparaginase should be used in combination with other drugs in the treatment of acute leukaemia.     

Cap formation on lymphocytes from patients with leukemic diseases induced by four different lectins.

When ficoll purified peripheral blood lymphocytes were treated with fluorescein conjugated lectins from lentils (LCH), castor beans (RCA) and phaseolus coccineus beans (L-and E-PHA) for 15 min and the percentages of the cap forming cells were examined, the values of leukemic lymphocytes were reduced compared to the values obtained with normal lymphocytes. The reduction was more than half in patients with acute and chronic myelogenous leukemia and immunoblastoma, it was only one quarter in patients with chronic lymphocytic leukemia, Hodgkin's disease and lymphosarcoma. The lowest number of cap forming cells was found in lymphoblasts of established lymphoblastoid cell lines. The four different lectins showed nearly the same capacity in the induction of caps. After successive binding, the different lectins showed cocapping on the lymphocyte surface.     

Impaired T- and B-cell functions in patients with Hodgkin's disease

Summary The mitogenic response of T-cell subsets, the production of interleukin-1 (Il-1) and interleukin-2 (Il-2) and in vitro immunoglobulin production was investigated in patients with Hodgkin's disease (HD). The mitogenic response of mononuclear cells (MNC) and the OKT4⁺ and OKT8⁺ subsets was greatly reduced in advanced disease stages and could only partially be restored with exogeneous Il-2. In untreated patients with HD — except those with highly advanced disease — the OKT4⁺ lymphocytes showed normal response to phytohemagglutinin in contrast to the MNC suggesting inhibiting agents or cells within the MNC. These findings corresponded to reduced Il-2 synthesis of MNC, whereas isolated OKT4⁺ — cells produced normal or elevated amounts of Il-2. MNC or monocytes produced normal or even higher amounts of lipopolysaccharide-induced Il-1 than controls. The results do not confirm a defect in this component of the interleukin system in HD. The immunological impairment was not limited to the T-cell system but involved B-cell activation and differentiation as well. The pokeweed mitogen-induced IgM, IgG and IgG production was highly suppressed in untreated HD, whereas the MNC of previously treated patients produced subnormal amounts of immunoglobulin in vitro. It is not yet clear whether this defect is T-cell-mediated or primarily a B-cell deficiency.     

Comparison of the effectiveness of metoclopramide and dexamethasone in the prevention of cytostatic-induced vomiting

Efficiency of anti-emetic properties of metoclopramide and dexamethasone was compared. Both drugs were administered to 22 patients with newly diagnosed untreated previously Hodgkin's disease during ABVD therapy. Number of vomiting episodes, nausea intensity and everyday patients' activity on the day of cytostatics administration were evaluated. Metoclopramide prevented vomiting in 55% of patients while dexamethasone in 65%. This difference was statistically insignificant. Patients' everyday activity was statistically significantly more frequently normal in patients receiving dexamethasone in comparison with placebo and decreased in patients receiving metoclopramide. Therefore, patients preferred dexamethasone.     

Bronchoalveolar lavage in the assessment of pulmonary Hodgkin's disease

Abnormal chest radiographs in patients with Hodgkin's disease are occasionally due to pulmonary Hodgkin's disease. The fluids recovered from bronchoalveolar lavages (BALs) from 50 patients prior to autologous bone marrow transplantation for advanced Hodgkin's disease were examined. Abnormal chest roentgenograms were present in 24 patients (48%); 4 (17%) of these had Reed-Sternberg cells or their mononucleated variants in the lavage fluid and an alveolar lymphocytosis averaging 31.4% (normal: 11.5%). The lymphocytes were small and monotonous. Of the 20 patients with abnormal chest roentgenograms but no Reed-Sternberg cells in the lavage fluid, the lymphocyte count was 10.88%, with only 3 patients exceeding 17%. Two patients with normal chest roentgenograms had Reed-Sternberg-like cells in their lavage fluids and averaged 23% lymphocytes in their lavage differential count. Eosinophils averaged 1% or less of the lavage differential and were not predictive of pulmonary Hodgkin's disease. This experience suggests that pulmonary Hodgkin's disease can be diagnosed by BAL. Reed-Sternberg cells and their mononucleated variants can be recognized by their characteristic cytomorphologic features, although care must be taken not to misinterpret reactive binucleated macrophages as neoplastic cells. In patients with Hodgkin's disease, Reed-Sternberg cells should be sought when an alveolar lymphocytosis is present.     

Hypothyroidism in Hodgkin's disease patients

PURPOSE: Study of thyroid function in Hodgkin's disease patients in complete remission. PATIENTS AND METHODS: We examined the thyroid function of 160 Hodgkin's disease patients in complete remission for at least one year, and determined the values of supersensitive thyroid stimulating hormone (sTSH), free T4 (fT4), free T3 (fT3) hormones. RESULTS: Normal values were observed in 117 patients, subclinical change (only elevated sTSH) in 28 patients, clinical hypothyroidism in 14 patients (also low fT4 and/or fT3), hyperthyroidism (Basedow's disease) in one patient. Hypothyroidism was one and a half times more frequent in females than in males. The normal and low thyroid function group did not differ from each other in mean age, histological subtypes, disease stage, general symptoms, and whether lymphangiography was performed. Hypothyroidism was more frequent in patients who had undergone mantle or neck radiotherapy. The onset of thyroid gland underfunction was more pronounced from six years after neck radiotherapy. The thyroid disease could be controlled using a daily dose of 25-225 mg levothyroxin. CONCLUSIONS: During the care of Hodgkin's disease patients routine examination of the thyroid function is important for the early recognition and prevention of treatment related late complications. On the other hand in treatment planning phase more attention should be paid to thyroid gland protection when neck radiotherapy is used.     

Is first salvage chemotherapy the last-line chemotherapy in children with Hodgkin's disease? A tentative answer based on long observation of two patients

In 82 children affected with Hodgkin's disease, in whom a complete remission was obtained, the first relapses occurred in 13 patients, their outcome was a follows: one child died of relapse and in 12 others second complete remissions were achieved. They were durable in 10 children (median, 65.5 months). Two remaining children had further relapses, their treatment consisted of four successive salvage chemotherapies. Both patients are now in their fifth complete remission. The third-line chemotherapy was already introduced 78+ months and 39+ months ago respectively. We believe that it is not possible to determine exactly the end-stage of Hodgkin's disease in those children and adolescents who have failed the first-line salvage chemotherapy.     

Immunoglobulin synthesis after HLA-identical marrow grafting. V. The role of peripheral blood monocytes in the regulation of in vitro immunoglobulin secretion stimulated by pokeweed mitogen

The ability of purified monocytes to regulate in vitro immunoglobulin (Ig) production was examined in 12 patients after HLA-identical marrow grafting. Five patients were studied less than 3 mo after grafting and seven more than 1 yr after grafting. One of the former had acute graft-vs-host disease and five of the latter had chronic graft-vs-host disease. Ficoll-Hypaque-separated peripheral blood mononuclear cells from patients, normal marrow donors, or healthy unrelated individuals were separated into T and non-T cells by sheep erythrocyte rosetting. Highly enriched monocyte and B cell subpopulations were obtained by placing the non-T cells over discontinuous Percoll gradients. Co-cultures of patient or normal monocyte populations with either normal or patient T and B cells with pokeweed mitogen were performed. A hemolytic plaque assay was used to assess Ig secretion after 6 days of culture. Co-culture of T and non-T cells from 10 of 12 patients failed to produce Ig. Monocyte-enriched fractions from all patients provided normal accessory cell functions when co-cultured with normal T and B cells. Two of five patients with chronic graft-vs-host disease had monocytes that suppressed Ig synthesis at high ratios of monocytes to normal T and B cells. Normal monocyte-enriched fractions did not restore Ig production to T and B cells of patients whose T and non-T cells failed to produce Ig. These data indicate that the observed defects in pokeweed mitogen-driven Ig secretion after marrow grafting are due primarily to defective T and B cell functions and that the monocyte accessory function is intact in most patients studied.     

Decreased monocyte antibody-dependent cell-mediated toxicity in stage I–II malignant melanoma

Summary Lymphocyte and monocyte antibody-dependent cell-mediated cytotoxicity (ADCC) against human red blood cells was examined in 28 stage-I-II malignant melanoma patients. Eighteen were studied at various time intervals after receiving SC Corynebacterium parvum (C. parvum); 10 were untreated. Fifteen normal age-matched controls were also studied. Monocyte ADCC was significantly decreased in untreated patients compared with controls (P<0.005) and was significantly increased above controls and untreated patients in individuals treated with C. parvum (P<0.008). No significant differences in lymphocyte ADCC were seen. Optimal enhancement of monocyte ADCC by C. parvum occurred from 2 weeks to 1 month after treatment. Significant decreases in ADCC to baseline levels occurred in patients studied from 3 to 6 months beyond treatment.     

In vitro study of bone marrow from leukemia patients and patients without hematologic disease

The bone-marrow of 26 patients not affected with hematological diseases and 10 patients with untreated leukemia was investigated according to Dexter in long-term cultures. Survival time and cell content of those long-term cultures started with normal bone marrow were not influenced significantly, if reinoculation was made with autologeneic or allogeneic bone marrow. Even without repeated inoculation, leukemic cells grew for a longer time in long-term cultures than normal bone marrow cells. As far as the outcome of the disease is concerned, no conclusion can be drawn from the duration of cultivating leukemic cells growth.     

Splenic monocyte-macrophage dependent suppression of autologous granulocyte-progenitors growth in Hodgkin's disease

The studies described compare the effect of spleen cell suspensions from 11 patients with Hodgkin's disease (HD) and 5 healthy subjects on the clonal growth of autologous marrow granulopoietic progenitors in diffusion chamber culture (CFU-G/D). Adherent monocyte/macrophage fraction of splenocytes from HD suppresses the proliferation of autologous CFU-G/D. This inhibition was mediated by an indomethacin-sensitive humoral factor(s). Non-adherent lymphoid cells stimulated myeloid colony formation. Dose response curves demonstrated a markedly increased inhibitory-activity production already by low numbers of splenic monocytes/macrophages from HD whereas a comparable counts of monocytes/macrophages from the spleens of healthy subjects stimulated the CFU-G/D growth. These results may suggest a possible activation of splenic monocytes/macrophages with an enhanced prostaglandin-mediated suppressor activity release for local granulocytopoiesis in the spleens of patients with HD.     

DNA synthesis by jejunal mucosa in responsive and non-responsive coeliac disease.

DNA synthesis by jejunal biopsy specimen from patients with coeliac disease and from controls was measured by an organ culture technique. The rate of synthesis in the mucosa of patients with untreated coeliac disease was almost eight times that in normal mucosa. Patients whose jejunal mucosa remained flat despite prolonged gluten withdrawal showed a rate of DNA synthesis significantly lower than that of the untreated patients, while those whose jejunal mucosa had responded to gluten withdrawal showed a rate similar to that of normal subjects. Impaired enterocyte production in nonresponsive coeliac disease may be responsible for the failure to regenerate villi after gluten withdrawal.     

Monocyte antibody-dependent cellular cytotoxicity in cancer patients

Summary Antibody-dependent cellular cytotoxicity (ADCC) mediated by peripheral blood monocytes was determined in 120 patients who had gastrointestinal tract (GIT), lung and breast cancer, melanoma, or Hodgkin's and non-Hodgkin's lymphoma. Results were expressed in terms of maximum cytotoxicity and cytotoxicity at E : T=1 : 10 and were compared with the results obtained in 63 normal subjects. There was a significant decrease in maximal cytotoxicity for both the GIT cancer and the melanoma patient groups, but not for any of the other groups. These differences were not confirmed when results were expressed at low effector: target cell ratios, e.g., cytotoxicity at E : T=1 : 10. The relationship between monocyte ADCC and disease extent was examined in those groups with sufficient numbers. Monocyte ADCC was higher in patients with GIT cancer of limited extent than in patients with extensive GIT cancer and in the control group.     

Cytodiagnosis of Hodgkin's disease in sputum specimens

In patients with histologically proven Hodgkin's disease, knowledge of the extent of involvement of lymph nodes and other organs has proven valuable in the determination of treatment and prognosis. One of the most common sites of involvement outside the hematopoietic system has been shown to be the lung parenchyma; in this study, six patients with a tissue-proven diagnosis of Hogdkin's disease and positive cytologic findings in the sputum were reviewed. Three cell types not found in normal sputum specimens were identified in these patients and were correlated with the histologic patterns of the tumors as seen in lung biopsies. Our results suggest the usefulness of sputum examination as an adjunctive or possibly a substitute diagnostic procedure in the evaluation of patients with Hodgkin's disease and possible lung involvement. They also suggest that in some cases the cytologic diagnosis can be quite specific in the identification of neoplastic cells as consistent with a diagnosis of Hodgkin's disease.     

Redox and activation status of monocytes from human immunodeficiency virus-infected patients: relationship with viral load

Monocytes are precursors of tissue macrophages, which are major targets of human immunodeficiency virus type 1 (HIV-1) infection. Although few blood monocytes are infected, their resulting activation could play a key role in the pathogenesis of HIV disease by modulating their transendothelial migration and inducing the production of reactive oxygen species (ROS). ROS participate in chronic inflammation, HIV replication, and the apoptosis of immune system cells seen in HIV-infected subjects. Published data on monocyte activation are controversial, possibly because most studies have involved monocytes isolated from their blood environment by various procedures that may alter cell responses. We therefore used flow cytometry to study, in whole blood, the activation and redox status of monocytes from HIV-infected patients at different stages of the disease. We studied the expression of adhesion molecules, actin polymerization, and cellular levels of H2O2, Bcl-2, and thioredoxin. Basal H2O2 production correlated with viral load and was further enhanced by bacterial N-formyl peptides and endotoxin. The enhanced H2O2 production by monocytes from asymptomatic untreated patients with CD4(+) cell counts above 500/microliter was associated with a decrease in the levels of Bcl-2 and thioredoxin. In contrast, in patients with AIDS, Bcl-2 levels returned to normal and thioredoxin levels were higher than in healthy controls. Restoration of these antioxidant and antiapoptotic molecules might explain, at least in part, why monocyte numbers remain relatively stable throughout the disease. Alterations of adhesion molecule expression and increased actin polymerization could play a role in transendothelial migration of these activated monocytes.