CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment

Interactions between the malignant plasma cells of multiple myeloma and stromal cells within the bone marrow microenvironment are essential for myeloma cell survival, mirroring the same dependence of normal bone marrow-resident long-lived plasma cells on specific marrow niches. These interactions directly transduce prosurvival signals to the myeloma cells and also induce niche production of supportive soluble factors. However, despite their central importance, the specific molecular and cellular components involved remain poorly characterized. We now report that the prototypic T cell costimulatory receptor CD28 is overexpressed on myeloma cells during disease progression and in the poor-prognosis subgroups and plays a previously unrecognized role as a two-way molecular bridge to support myeloid stromal cells in the microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell directly transduces a prosurvival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal dendritic cell to produce the prosurvival cytokine IL-6 (involving novel cross-talk with the Notch pathway) and the immunosuppressive enzyme IDO. These findings identify CD28 and CD80/CD86 as important molecular components of the interaction between myeloma cells and the bone marrow microenvironment, point to similar interaction for normal plasma cells, and suggest novel therapeutic strategies to target malignant and pathogenic (e.g., in allergy and autoimmunity) plasma cells.     

The mechanism of action of the immunosuppressive drug FK-506

The novel immunosuppressive drug FK-506 inhibits the induction of lymphocyte proliferation in vitro by mitogenic combinations of phorbol esters and calcium ionophores. Early events inducible by phorbol esters alone are unaffected, while changes induced by calcium ionophores alone are completely suppressed by as little as 0.1 nM FK-506. The event in lymphocyte activation inhibited by FK-506 is completed early in the response. Its completion requires the provision of a Ca2+ signal and concurrent activation of protein kinase C and is accelerated as a function of the strength of protein kinase C activation.     

Quantitative and qualitative differences between benign and malignant mesothelial cells in pleural fluid

Quantitative as well as qualitative cellular parameters were investigated in 20 cases of reactive mesothelial proliferations and 40 cases of primary pleural mesotheliomas. The two groups showed statistically significant differences in the nuclear areas, cytoplasmic areas and standard deviations. In the mesotheliomas, the mean nuclear area and the mean cytoplasmic area were larger than in the reactive proliferations. Nine cases could not be properly classified with these quantitative parameters alone. Qualitative analysis revealed highly characteristic features in the mesotheliomas. Morula formation as well as irregular and coarse reticular chromatin patterns were strongly indicative of mesothelioma. The location and shape of the nucleus and the type and amount of cytoplasmic vacuolization gave additional information for distinguishing between the two groups.     

Implementation of a molecular epidemiology approach to human pleural malignant mesothelioma

The carcinogenic effect of asbestos has been reported in the literature since 40 years, and early studies describing the epidemic occurrence of malignant mesothelioma (MM) in asbestos workers, have become a paradigm of occupational cancer research. Research on MM was abandoned for many years since MM was considered as an asbestos-related disease, interesting only from a perspective of disease control and preventive policies. The introduction of new biological endpoints in the epidemiological studies has boosted research in the field, providing new tools for the study of emerging priority in cancer research and in public health. This approach, known as molecular epidemiology has a great potential in the study of MM, contributing to the understanding of susceptibility factors, to the evaluation of cancer risk in people occupationally or environmentally exposed to carcinogens, and to the enhancement of diagnosis and therapy. A comprehensive approach based on the use of banks of biological samples is presented and its advantages discussed here. The application of innovative endpoints, such as oncoproteins in biologic fluids, genetic polimorphisms, or gene function is discussed, and relevant literature reviewed.     

Resistance of ascitic fluid immunosuppressive factor DNA to pancreatic deoxyribonuclease]

It was found that incubation of Ehrlich tumour ascitic fluid with pancreatic DNAse does not result in a destruction of 5S DNA in the immunodepressive factor. After phenol deproteination of the ascitic fluid the resistance of this nucleic factor to DNAse is lost. It is possible that the native nucleic factor is represented by DNP and contains a protein component. During polyacrylamide gel electrophoresis the mobility of the nucleic factor labelled with [3H]-thymidine and isolated after chromatography on hydroxyapatite is found to be nearly the same as that for transferine.     

Staphylococcal L-asparaginase: antilymphoma and immunosuppressive action.

Staphylococcal L-asparaginase inhibits blastic transformation of human lymphocytes and growth of mice leukemia lymphoblasts L5178Y-R. The enzyme is removed from blood stream of DBA/2 mice very rapidly.     

Studies on the mechanism of action of dinitramine: effect on soybean root plasma membrane

The effect of dinitramine, a selective herbicide, on the plasma membrane of the soybean (Glycine max L.) root was studied. Used as marker systems to observe the herbicide effect were two plasma-membrane-specific enzymes, pH 6.5 ATPase and glucan synthetase.     

Characterization of an immunosuppressive factor from malignant ascites that resembles a factor induced in vitro by carcinoembryonic antigen

Oncodevelopmental antigens may cause immunologic suppression in the host through release of suppressor molecules from the host's own immunoregulatory cells. This concept has been difficult to study until recently when carcinoembryonic antigen was shown to induce the release of such molecules from normal circulating human mononuclear cells in vitro. However, the amount of the suppressor moiety generated was too small to adequately characterize, and its presence in vivo, i.e., in the cancer-bearing host, was unknown. Therefore, we sought to isolate and characterize a similar or identical macromolecule from ascites having an elevated CEA level in patients with cancer. A single malignant ascites, when precipitated at 0 to 35% ammonium sulfate saturation, was the source of suppressive factor for purposes of isolation and standardization. Suppression was quantitated by reduction of [3H]thymidine incorporation by phytohemagglutinin-stimulated normal human peripheral blood mononuclear cells. Sephadex G-200 chromatography revealed probable aggregation of the factor in isotonic buffers; aggregation was reduced in the presence of 8 M urea. Purification was achieved by precipitation with 5% trichloroacetic acid (TCA). The suppressor factor remained soluble in TCA and demonstrated a 95-fold increase in specific activity. Analytical sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated a single protein band of 50,000 daltons. Ascites from three additional cancer patients gave identical results. Physicochemical characterization of the suppressor moiety revealed stability at 70 degrees C for 30 min and at pH 2 and pH 10 for 24 hr. Delipidation by chloroform-methanol extraction, proteolytic enzyme digestion, and protamine sulfate precipitation did not affect activity, suggesting that lipid, simple peptides, and nucleic acids were not crucial. However, periodate oxidation irreversibly destroyed suppressor activity, suggesting the importance of carbohydrate to the molecule and offering one explanation for protease resistance. Similarities in m.w. (50,000 daltons), isoelectric point (pI = 3.4), physical properties (heat and acid stability and resistance to proteases), and immunologic activity of this factor with that released from lymphocytes after in vitro exposure to carcinoembryonic antigen indicates they may be identical. Our results suggest that early aberrant events induced in the immunoregulatory network by tumor-associated antigens may be relevant and may lead to better understanding of immunosuppression in the cancer-bearing host.