Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A vertebrate immune response is initiated by the presentation of foreign protein Ag to MHC class II-restricted T lymphocytes by specialized APC. Presentation of self-peptides in association with MHC class II molecules is also necessary for the induction of T cell tolerance. It is important to understand whether functionally divergent APC are responsible for delivering these distinct signals to class II-restricted T cells. Here we examine the ability of I-Ad surface molecules expressed in diverse cell types to stimulate I-Ad-restricted T cells. Recipients included J558L myeloma cells and EL4 lymphoma cells expressing barely detectable or undetectable levels of Ii chain mRNA. This allowed us to examine the influence of Ii expression on the presentation of intracellular Ag and thus test the hypothesis that Ii chain is necessary to prevent access of self-peptides to newly synthesized class II molecules. Ii chain expression did not restore the ability of transformants to process and present soluble protein Ag. A striking result was the finding that cells showing a defect in the exogenous class II presentation pathway were capable of functioning as stimulators when they expressed intracellular secreted but not signal-less V-CH3b Ag. Thus, so-called professional APC that can capture and process exogenous protein Ag may express a specialized set of proteins not required for the presentation of self-peptides.
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PMID:Formation of complexes between self-peptides and MHC class II molecules in cells defective for presentation of exogenous protein antigens. 131 96

Thirteen monoclonal antibodies designated as MFC-1 to MFC-13 were obtained from hybridoma cells cloned after the fusion of mouse myeloma cells with spleen cells of mice immunized with purified human protein C. Studies were made to determine where the antibodies bound to the molecule of protein C and whether they affected the biological actions of protein C. By using the immunoblotting technique, six of these antibodies were shown to bind to the light chain of protein C, and five to the heavy chain of protein C and also activated protein C. The remaining two antibodies bound to neither the light chain nor the heavy chain, though both antibodies bound to the intact protein C. Antibodies specific for the light chain did not bind to the gamma-carboxyglutamic acid-domain. Two of the antibodies specific for the heavy chain (MFC-13 and -1) inhibited the amidolytic activity of activated protein C. The MFC-13 also inhibited the activity of bovine activated protein C, but not that of human Factor IXa, Factor Xa, or thrombin. In addition to these two antibodies, another one for the heavy chain (MFC-10) and two antibodies for the light chain (MFC-9 and -11) inhibited the inactivation of Factor Va by human activated protein C. One of the antibodies which inhibited the enzyme activity (MFC-1) blocked the inhibition of activated protein C by protein C inhibitor. Another one for the heavy chain (MFC-5) inhibited the activation of protein C by thrombin regardless of the presence or absence of thrombomodulin. Based on these results, we have established the positions of some monoclonal antibody-binding sites on the protein C molecule.
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PMID:Monoclonal antibodies to human protein C: effects on the biological activity of activated protein C and the thrombin-catalyzed activation of protein C1. 258 38

Monoclonal antibody NL16, prepared with phosphorylcholine (PC)-binding myeloma protein C.BBPC3 (C3), identified an idiotope (C3-16 Id) that was present on T15 IdX+ myeloma proteins (MP) C3, T15, and H8, but not the T15 IdX- MP M167 and M603. The binding of C3 to NL16 is PC inhibitable, indicating that C3-16 Id is site associated. Inhibition studies with PC-specific hybridoma proteins (HP) demonstrated that the T15-type L chain VK22 and elements of the H chain were required for C3-16 Id expression. Studies of amino acid sequences of these PC-binding HP and MP showed that VK22+, T15 IdX+ HP, and MP that use the T15 D region (YYGSS) sequences were always C3-16 Id+. However, the reverse was not true, because all but one VK22+, T15 IdX+ HP with D region sequence changes were C3-16 Id-. This suggested that NL16 defined a specificity mainly determined by the D region of the H chain. A direct test of this hypothesis with heterologous heavy/light chain recombinant molecules obtained from C3-16 Id+ and C3-16 Id- HP of known sequence, showed that the D region was critical to idiotope expression. Additionally, an examination of the amino acid sequences of VK22+, T15 IdX- HP, HPCG14, and HPCM6 suggest that profound changes in the D region may also alter the expression of T15 IdX (an Id defined by a multispecific antiserum from A/He mice). The C3-16 Id+ was found in anti-PC serum of most Ig haplotype-inbred strains except for CBA/J, C3H, and PL, which are all of the Igh-Cj haplotype. Amino acid sequences of PC-binding CBA and PL HP showed marked changes in the D region from the T15 type, and this may account for the C3-16 Id- character of Igh-Cj strains.
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PMID:T15 D region germ line amino acid sequences distinguished by monoclonal anti-idiotope antibody. 396 16

To estimate the minimal structural requirements for cross-reaction of idiotypic determinants, we determined the capacity of monoclonal antibodies specific for the idiotype of the phosphorylcholine (PC)-binding myeloma protein TEPC-15 for cross-reactivities with the PC-binding, acute-phase protein C-reactive protein (CRP) and the hemagglutinin from the horseshoe crab Limulus polyphemus (limulin), which binds sialic acid and PC. Certain monoclonal antibodies (MAb) to the TEPC-15 idiotype showed strong cross-reactions with CRP and limulin when tested by enzyme-linked immunoadsorbent assays. The specificity of the cross-reactivities was confirmed by testing the binding of the reactive anti-TEPC-15 MAb to both CRP and limulin in the presence of p-nitrophenylphosphorylcholine (pNPPC), N-acetylneuraminic acid, and bovine submaxillary mucin. The binding of the MAb to both CRP and limulin was strongly decreased by pNPPC, partially decreased by free PC, and not affected by N-acetylneuraminic acid or bovine submaxillary mucin. Neither CRP nor limulin showed significant overall sequence homology to vertebrate immunoglobulins. However, CRP, limulin, and TEPC-15 variable region heavy chain (VH) shared short stretches of homology (8-10 amino acids) that mapped to a stretch comprised of the second complementarity determining region and third framework region of the TEPC-15 VH. These results might reflect either evolutionary convergence forced upon molecules of diverse evolutionary histories because of steric requirements of binding the same ligand, or a conservation of primitive combining site gene segments in evolution.
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PMID:Invertebrate recognition protein cross-reacts with an immunoglobulin idiotype. 620 May 68

It is known that immunoglobulins can be processed and that idiotypic peptides are presented on MHC class II molecules to T cells. It has also been demonstrated that T cells can recognize a complex of an Id-peptide/MHC molecule as a tumor-specific antigen on B lymphoma cells. However, plasmacytomas, an important type of B cell malignancies, most often lack class II molecules and are thus expected to be poor targets for Id-specific, CD4+ T cells. Nevertheless, we now demonstrate that cloned, MHC class II restricted T cells, specific for a lambda 2(315) idiotypic peptide, convey protection in vivo (Winn assay) against the class II molecule-negative MOPC315 (alpha, lambda 2(315)) plasmacytoma. T cells can also inhibit the growth of MOPC315 cells in vitro provided that MHC compatible (H-2d) splenocytes and extra lambda 2(315) are added. Based on these data we suggest that the myeloma protein secreted by MOPC315 cells attains such a high local concentration in vivo that it is processed and presented by neighboring host APC to the Id-specific T cells. Such activated T cells secrete lymphokines which may directly affect the growth of MOPC315 cells in the vicinity. Alternatively, lymphokines from activated T cells stimulate local host cells, like macrophages, to become tumoricidal.
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PMID:The role of idiotype-specific, CD4+ T cells in tumor resistance against major histocompatibility complex class II molecule negative plasmacytoma cells. 809 65

Investigation of recurrent venous thromboembolic events in a 46-year-old man with progressive IgG kappa (total serum IgG, 74.3 mg/ml) multiple myeloma revealed profound reductions in free protein S (PS) antigen (<0.l U/ml) and PS activity (0.33 U/ml). Total PS antigen, protein C, antithrombin III, and C4b-binding protein levels were within normal limits. The patient had no family history suggestive of a congenital PS deficiency and no history of thrombosis predating the diagnosis of his plasma cell dyscrasia. Patient IgG was isolated from serum using a protein A-sepharose affinity column and characterized. PS-dependent clotting assays (Staclot Protein S, Diagnostica Stago, Asnieres sur-Seine, France) performed on normal pooled plasma mixed with dilutions of patient IgG (0.0-33.0 mg/ml) revealed a dose-dependent neutralization of PS activity by 43%. Total and free PS antigen levels were measured using Laurell rocket electroimmunodiffusion (Assera-Plate Protein S, Diagnostica Stago), which revealed a similar dose-dependent reduction in free PS antigen but preserved normal total PS antigen. Free PS antigen was reduced by 77% to 0.23 U/ml using an IgG concentration (16.5 mg/ml) less than one-fourth of that of the patient at time of serum collection. Specific binding of the patient IgG to commercially available purified human PS was demonstrated by Western immunoblot analysis. Whereas acquired free PS deficiency has been previously reported in association with nephrotic syndrome, inflammatory bowel disease, HIV infection, and varicella infection, this is the first reported case of a hypercoagulable syndrome associated with acquired free PS deficiency and multiple myeloma.
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PMID:Acquired free protein S deficiency associated with multiple myeloma: a case report. 860 34

In this paper, the results of some recent studies on idiotype-specific T cells in human multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are discussed. By using different in vitro measurements such as 3H-thymidine incorporation and ELI-SPOT assay, idiotype-specific T cells have been demonstrated in most of MM and MGUS patients. Based on the cytokine-secretion profiles, idiotype-specific T cells were found to comprise both Th1 and Th2 cells. A Th1 type immunity was found preferentially in indolent disease and a Th2-like response predominated in advanced MM, suggesting a specific T-cell regulation of the tumor B-cell clone. The mode of T-cell recognition of id determinants on M-components has been studied. We found that idiotype-specific T cells recognized processed id determinants presented by MHC class II (HLA-DR) molecules on APC. B cells were much more efficient APC than monocytes. With the aim to induce or to amplify an idiotype-specific T-cell response, we have immunized MM patients with the autologous M-component precipitated in aluminum. Three out of the five patients showed an induction of specific cellular and humoral immunity. Nevertheless, the role for such immunity in controlling the tumor clone remains to be established.
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PMID:Idiotype-specific T cells in multiple myeloma: targets for an immunotherapeutic intervention? 886 33

We have investigated the possible interaction of paraprotein (pp) with anticoagulation mechanisms and fibrinolysis. Eighty four patients with monoclonal gammapathy (MG) were included to the study, 59 of them with multiple myeloma (MM). In 48.8% cases some defect was found. Decreased levels of antithrombin III (AT III) was observed in 13.3%, protein C (PC) in 18.3% and protein S (PS) in 13.5% of patients. Distribution between the free and the bound PS fraction remained normal. The most frequent abnormality found was the reduction of plasminogen (PLG) activity, which was observed in 35.1% and elevated levels of plasminogen activator inhibitor, detected in 42.3% of cases, respectively. Decreased plasminogen activator activity was observed in only one patient. The relationship between isotype and concentration of paraprotein and frequency of factor levels abnormalities was not found. The incidence of arterial and/or venous thrombosis was higher in patients with laboratory defect in comparison with the unaffected, however, the difference was not statistically significant. In contrast, the incidence of hemorrhagic complications was significantly lower in these patients (p < 0.01), although in most of them simultaneous defect of plasmatic coagulation and/or platelet functions was detected. We suggest, the interaction with both hemostatic and anticoagulation systems could result to "elimination" of inauspicious effect of pp on hemostasis. The impairment of anticoagulation systems and fibrinolysis is another type of paraprotein interference with hemostasis. It is also considered to be another pathogenetic mechanism of secondary deficiency of AT III, PC, PS and PLG.
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PMID:[Disorders of anticoagulation and fibrinolysis in monoclonal gammopathies--another mechanism of paraprotein interference with hemostasis]. 923 17

Thromboembolism is not uncommon in multiple myeloma (MM) patients on treatment, but its pathogenesis remains poorly understood. We report the results of a prospective randomized trial of 62 newly diagnosed MM patients tested at baseline for hypercoagulability and treated with intensive chemotherapy with or without thalidomide in a randomized fashion. During the induction phase, 12 patients (19%) developed evidence of deep venous thrombosis (DVT), which was significantly more common in the thalidomide arm (36%) than in the control group (3%) (P = 0.001). Fourteen patients (23%) were found to have a baseline-reduced response to activated protein C (APC) in the absence of factor V Leiden mutation. Using a Kaplan-Meier analysis, a significantly higher proportion of patients with APC resistance developed DVT (5/14 versus 7/38; P = 0.04) irrespective of thalidomide administration. The risk of DVT was highest (50%) in patients with APC resistance on thalidomide. None of the patients with normal APC response and not receiving thalidomide developed DVT. In conclusion, in this series, acquired APC resistance was present in almost one-quarter of newly diagnosed myeloma patients and significantly increased the risk of DVT.
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PMID:Activated protein C resistance in the absence of factor V Leiden mutation is a common finding in multiple myeloma and is associated with an increased risk of thrombotic complications. 1194 31

APC-80200 (Mylovenge) has been developed for the treatment of B-cell malignancies and is currently in phase II clinical trials as a therapeutic vaccine for patients with advanced multiple myeloma. This vaccine candidate appears to be of particular benefit in patients who have received high-dose chemotherapy to reduce tumor load following stem cell rescue. APC-80200 is also being tested in patients with amyloidosis.
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PMID:Technology evaluation: APC-80200, Dendreon. 1243 55


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