Biomedical subjects
Publications and source records attributed to E Klein.
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Courses of repeated delayed hypersensitivity challenge reactions at the sites of tumors have been shown to eradicate malignant and premalignant epidermal neoplasms. Local immunotherapy produces therapeutic responses in malignant and premalignant lesions before they are clinically detectable. This leads to a reduced incidence and prevention of tumors. Immunotherapeutic approaches are effective in controlling the early stages of mycosis fungoides and may aid in the management of the cutaneous manifestations in the late stages of the disease. Immunotherapeutic methods induce regressions of soft tissue lesions of a number of multifocal or metastatic malignant diseases with or without concurrent chemotherapy. Immunotherapeutic effects on tumors are similar with primary and recall antigens. Separated components of the cell-mediated immune system induce regressions of tumors following intralesional or perilesional administration, indicating common factors in host defenses against malignant diseases.
Alkaline phosphatase [orthophosphoricmonoester phosphohydrolase (alkaline pH optimum), EC 3.1.3.1] purified from a Burkitt lymphoma cell line (Daudi) and Moloney-virus-induced murine leukemia (YAC) showed unique catalytic properties in substrate specificity and inhibition by cysteamine-S-phosphate. It migrated on polyacrylamide gel electrophoresis in a single activity band. Alkaline phosphatase with similar properties was found in several human lymphoblastoid cell lines, in chronic lymphatic leukemic cells, in organs of leukemic mice, and in sera of patients with certain lymphoproliferative disorders.
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Topical application of a relatively low concentration of one or more agents to which the patient has previously been sensitized can mobilize cell-mediated immune systems at the site of neoplastic or premalignant lesions. Such treatment has proved to be effective against both primary and metastatic skin lesions. It is also suggested that dermatologic experience may provide a model for other cancer immunotherapies.
We examined the specificity of the lg "coating" on murine tumor cells grown in vivo. Cells were treated in vitro for release of cell-bound lg from ascites tumors. Such uncoated cells showed an increased expression of tumor-associated antigens and a parallel decrease in intensity of the lg coat, but displayed no changes in the expressions of other normal membrane antigens. This was shown by a complement-dependent cytotoxicity assay and radioimmunoassay. These changes were attenuated if the tumor originated from animals that had been irradiated before tumor inoculation. No alterations were found with corresponding cells propaged in vitro and submitted to the same treatments. Our findings and others suggest tumor-specific antibodies among the lg coats detected on tumor cells grown in vivo.
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A fraction with lymphokine properties was isolated from supernatant medium of the continuous cultured human lymphoblast cell line, 1788. Culture medium containing 2% human serum was used for cell growth in order to minimize antigenicity of supernatant fractions isolated from the medium. The culture medium was passed through an Amicon XM-100 membrane, concentrated over a PM-10 membrane, lyophilized, and reconstituted to a final concentration of approximately 40:1. Studies in vivo and in vitro showed that the active fraction contained skin reactive factor (when injected intradermally into guinea pigs and humans), lymphotoxin, migration inhibition factor, chemotactic factor, and macrophage activation factor. This same preparation, when injected intralesionally into cutaneous tumors, induced an inflammatory reaction followed by tumor regression. The fraction confined between membranes of pore size 10,000-100,000 daltons was active in promoting tumor regression, while the fraction less than 10,000 daltons was inactive. Patients with skin lesions from metastatic carcinoma of the breast and other malignancies were studied, and 16 out of 30 treated lesions were judged to have undergone either complete or greater than 50% regression. Of these, 8 were biopsied before and after lymphokine injection, and 6 out of 9 were negative for tumor cells. Additional studies in vitro with material fractionated on Sephadex G-200 indicated that the macrophage-activating component binds to alpha-2 macroglobulin in the culture medium.
Hemodynamic data were obtained within 15 hours of admission in 11 previously healthy patients (20 to 51 years of age, 7 men and 4 women) who had developed transient, reversible pulmonary edema without cardiac dilation in association with near-death from freshwater drowning (2 cases), pentobarbital overdose, heroin overdose (2 cases), smoke inhalation, chest trauma, sepsis (2 cases), pancreatitis, or prolonged abdominal surgery with suspected sepsis. Using a balloon-tipped flow-directed catheter, the pulmonary artery systolic/diastolic pressures (in mm Hg) were 25/12, 22/9, 31/11, 26/15, 20/10, 35/15, 40/15, 32/18, 20/10, 24/10, and 20/7; the corresponding pulmonary capillary wedge pressures (in mm Hg) were 8, 9, 6, 14, 6, 6, 15, 15, 10, 10, and 5, respectively. Plasma colloidal osmotic pressures measured in the latter 5 cases were 26, 18, 18, 18, and 15 mm Hg, respectively. In addition, the protein content of the alveolar fluid was 5.1, 3.4, 4.0, and 7.1 g per 100 ml in 4 patients. The concentration and distribution of the protein in plasma and alveolar fluid were very similar. These findings provide strong efidence that altered capillary permeability is responsible for the pulmonary edema.
Compared to peripheral blood lymphocytes the ability of human tonsil T cells and MLC blasts to bind sheep, human and horse erythrocytes was found to be increased. Tonsil and MLC T cells were able to bind sheep red blood cells without any cold incubation, i.e. they were 'early' rosettes, and higher percentage of human and horse erythrocyte rosettes were formed by these cells. Low doses of phytohaemagglutinin increased the proportion of rosettes between peripheral blood, tonsil, MLC cells and human and horse erythrocytes. PHA acted only on T cells, and not on B cells, lymphoblastoid B and other cell lines. On the ground of the stronger rosetting property of MLC blasts and tonsil cells, it is likely that the T cells responsible for binding of horse and human erythrocytes after PHA treatment are 'early' or 'active' rosetting cells.
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One of the antigens present in isotonic phosphate buffer extract of calf thymus nuclei against which antibodies are produced in collagen diseases, was shown not to attach to tanned sheep erythrocytes. It is, however, well exposed on slides coated with smears of ENA-extract and fixed with methanol-acetone. Reactions with the antigen can be demonstrated by the mixed haemadsorption technique. Preliminary results suggest that it may be a ribonucloprotein closely related to the 'soluble ribonucleoprotein" (sRNP) attachable to tanned erythrocytes. It may also have a similar relationship to clinical symptoms.
Human delayed hypersensitivity to living BCG organisms and/or Varidase was adoptively transferred to mice and assayed in mice by a radioisotope footpad assay (FPA). A mixture of the antigen and peripheral blood lymphocytes from patients (positive skin reactions to PPD and/or Varidase) or healthy volunteers was inoculated into the footpads of lethally X-irradiated mice. A positive footpad reaction was accompanied by an increased leakage of the radiolabelled serum protein from the blood stream into the intercellular space at the site of inoculation, and was measured by the 'foot-count ratio', or radioactivity in the test foot divided by radioactivity in the contralateral foot. The intensity of the footpad reaction correlated directly with the skin test response of the human lymphocyte donors.
Cell-mediated immune challenge reactions to a number of antigens at tumor sites resulted in regressions of various types of benign, premalignant, and malignant lesions in man. Regressions varied from partial to complete and lasted from several months to more than 10 years. Increased levels of cell-mediated immunocompetence were attained by several means, including reduction of tumor burden, immunopotentiation, or transfer of immunity. Antitumor activities of immune challenge reactions are selective for tumor cells and appear to be independent of the nature of the antigens used or the type of neoplasm. Combinations of immunotherapy with other treatment modalities resulted in augmentation of antitumor effects. Preliminary studies indicate that cellular and noncellular mediators of delayed hypersensitivity induce antitumor activities that may be significant in the regressions of neoplasms induced by cell-mediated immune challenge reactions. Since cell-mediated immune reactions are frequent occurrences, they may be a factor in apparently spontaneous regressions of neoplasms.
Lymphocyte blastogenesis induced by autologous tumor biopsy cells, by allogeneic lymphocytes and by PHA, was performed in the presence of autologous or allogeneic serum collected from normal blood donors. In 13 of the 15 cases lymphocyte stimulation by autologous tumor cells was inhibited in the presence of autologous serum. In contrast, autologous serum somewhat enhanced the blastogenic effect of PHA and allogeneic lymphocytes.
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