Suramin as an anticomplementary agent in xenotransplantation.
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Animals↗
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Clustering of integral membrane proteins of the human erythrocyte membrane stimulates autologous IgG binding, complement deposition, and phagocytosis.
Damaged or old erythrocytes are cleared rapidly from circulation. Because several common biochemical lesions can induce the clustering of integral membrane proteins, we have proposed that formation of microscopic protein aggregates in the membrane might constitute a cell surface marker that promotes removal of the defective/senescent cells. We demonstrate here that treatments that cluster integral membrane proteins in erythrocytes (1 mM ZnCl2, 1 mM acridine orange, and 0.35 microM melittin) induce autologous IgG binding, complement fixation, and phagocytosis by human monocytes in vitro. Removal of the clustering agents prior to incubation in autologous serum or cross-linking of cell surface proteins before addition of clustering agents prohibited the above response, while cross-linking after treatment with the clustering agents preserved the response even if the clustering agents were later removed. Furthermore, subsequent reversal of the chemical cross-link maintaining the clustered distribution also reversed the induction of IgG binding, complement deposition, and phagocytosis. Finally, by deleting or inactivating different steps in the phagocytosis pathway, the chronology of steps was shown to be: (i) integral protein clustering, (ii) IgG binding, (iii) complement deposition, and (iv) phagocytosis.
Acridine Orange↗
Abrogation of baboon natural xenoantibody to pig splenocytes by DL-penicillamine.
Natural xenoantibodies are believed to be IgM in nature and are known to play a critical role in the hyperacute rejection of distantly related xenografts. The purpose of this study was to determine whether the reducing agent DL-penicillamine could inactivate baboon natural xenoantibodies to pig splenocytes. Pooled baboon serum was treated with varying concentrations of DL-penicillamine over different lengths of time and a complement-mediated cytotoxicity assay was used to determine the reactivity of baboon natural xenoantibodies to pig splenocytes. A whole-cell ELISA assay was used to assess the binding of both IgG and IgM xenoantibodies to pig splenocytes. In addition, DL-penicillamine-treated serum was dialyzed to assess its potential clinical application. These in vitro experiments indicate that both IgM and IgG baboon natural xenoantibodies bind to pig splenocytes, but only IgM xenoantibody is cytotoxic. The binding of baboon natural IgM xenoantibody can be eliminated, and the cytotoxicity of IgM xenoantibody markedly reduced by DL-penicillamine treatment despite continued binding of IgG xenoantibody to pig splenocytes. In addition, DL-penicillamine can be dialyzed, suggesting that it may be an efficacious clinical treatment, the toxicity of which can be regulated with hemodialysis.
Animals↗
Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis.
The complement system is an important mediator of the acute inflammatory response, and an effective inhibitor would suppress tissue damage in many autoimmune and inflammatory diseases. Such an inhibitor might be found among the endogenous regulatory proteins of complement that block the enzymes that activate C3 and C5. Of these proteins, complement receptor type 1 (CR1; CD35) has the most inhibitory potential, but its restriction to a few cell types limits its function in vivo. This limitation was overcome by the recombinant, soluble human CR1, sCR1, which lacks the transmembrane and cytoplasmic domains. The sCR1 bivalently bound dimeric forms of its ligands, C3b and methylamine-treated C4 (C4-ma), and promoted their inactivation by factor I. In nanomolar concentrations, sCR1 blocked complement activation in human serum by the two pathways. The sCR1 had complement inhibitory and anti-inflammatory activities in a rat model of reperfusion injury of ischemic myocardium, reducing myocardial infarction size by 44 percent. These findings identify sCR1 as a potential agent for the suppression of complement-dependent tissue injury in autoimmune and inflammatory diseases.
Animals↗
Antibody-complement-mediated cytotoxicity is enhanced by ribosome-inactivating proteins.
The antibody-mediated cytotoxicity of complement can be increased by the ribosome-inactivating proteins gelonin and PAP-S. Treatment of human lymphoid cells that express CALLA with an anti-CALLA monoclonal antibody, J5, and then with rabbit complement, leaves about 6% of the cells alive. The same treatment in the presence of a sublethal concentration of gelonin or PAP-S leaves only about 0.02 and 0.3% of the cells alive respectively. This synergistic effect has potential implications for the in vitro elimination of malignant cells or of immunocompetent cells from bone marrow before its transplantation.
Antibody-Dependent Cell Cytotoxicity↗
Epstein Barr virus binding induces internalization of the C3d receptor: a novel immunotoxin delivery system.
Epstein Barr virus (EBV) infection of human B lymphocytes is initiated by selective binding of the virus to the C3d receptor (EBV/C3d receptor) on the cell surface and results in polyclonal proliferation of infected cells. In these studies we examined the fate of the EBV/C3d receptor during viral infection by using an immunotoxin made from a monoclonal antibody (HB5) reactive with the receptor and the potent toxin, gelonin. Binding of the HB5-gelonin conjugate to the EBV/C3d receptor before EBV infection (at concentrations as low as 10(-11) M) significantly inhibited the subsequent polyclonal proliferation of virus-infected B lymphocytes. HB5 antibody and gelonin alone did not inhibit proliferation. Because internalization of gelonin-antibody conjugates is required to cause cytotoxicity, these results indicate that infection of B lymphocytes with EBV selectively induced endocytosis of the EBV/C3d receptor with concomitant internalization of the immunotoxin. Proliferation of B lymphocytes that were activated by prior infection with EBV, or activated by cross-linking of their surface immunoglobulin molecules, was not inhibited by the antibody-toxin conjugate even at concentrations as high as 10(-7) M. Also, the growth of B lymphoblastoid cell lines cultured in the presence or absence of infectious EBV was not inhibited by HB5-gelonin. Thus, our results suggest that the EBV/C3d receptor is internalized only during the infection of normal B lymphocytes by EBV, with co-internalization of immunotoxin, and indicate that internalization of the EBV/C3d receptor-immunotoxin complex does not occur simply as a consequence of activation and proliferation of B lymphocytes. The use of a ligand to induce endocytosis of its receptor offers a new strategy for the selective delivery of immunotoxins to cells and may be more generally applicable.
Adult↗
Influence of augmented Hageman factor (Factor XII) titers on the cryoactivation of plasma prorenin in women using oral contraceptive agents.
Prolonged cold storage of plasma may induce the conversion of plasma prorenin (inactive renin) to renin. This phenomenon is exaggerated in oral contraceptive (OC) users; the titer of Hageman factor (HF, Factor XII) in OC users is higher than in nonusers. The present study relates these observations. The increment in plasma renin activity (PRA) during cold storage, as measured by generation of angiotensin I, correlated strongly with the initial plasma titer of HF. Increasing the HF titer of nonusers to that observed in OC users by addition of purified HF increased cold-induced PRA at least twofold, while reducing the plasma HF titer of OC users correspondingly decreased cold-induced PRA. Thus, in OC users, the enhanced conversion of plasma prorenin to renin during cold storage reflects the elevated plasma titer of HF.
Angiotensin I↗
Defective regulation of chemotaxis in cirrhosis.
The presence of a severe leukotactic defect in cirrhotic patients has been confirmed. This defect is due to the presence of abnormally high levels of the chemotactic factor inactivator (CFI) in serums of patients with hepatic cirrhosis. This inactivator inhibits each of three different chemotactic factors tested and does so in an irreversible manner. As would be predicted by these results, generation of chemotactic activity in cirrhotic serums by a complement-activating agent is markedly impaired. Physicochemical features of CFI in cirrhotic serum differ slightly from that found in normal human serum. These results indicate the nature of the chemotactic defect in cirrhotic patients and may explain the increased susceptibility of these patients to bacterial infections and some of their reported defected in expression of cellular immunity.
Aminopeptidases↗
Levels of total haemolytic complement activity in paired dairy cow-newborn calf sera.
Total haemolytic complement (CH50) activities of sera obtained from newborn dairy calves and their corresponding dams were compared. The differences between the mean maternal and neonatal CH50 concentrations were significant (P less than or equal 0.001). The concentration of CH50 units/ml in sera from 16 calves was 52.0 +/- 21.4, whereas, for the cows it was 195.8 +/- 24.0. The ratio of cow: calf serum CH50 values averaged 4.24 with a range from 1.77 to 8.00. A positive rank correlation of 0.479 (P less than 0.05) was found between the CH50 titres in calves and their dams. Anticomplementary substances were not detected in calf sera. The possible relationships betweeen deficient CH50 levels in newborn calves and their susceptibility to infectious agents is discussed.
Age Factors↗
B30-MDP, a synthetic muramyl dipeptide derivative for tumour vaccination to enhance antitumour immunity and antimetastatic effect in mice.
The effect of a muramyl dipeptide derivative (B30-MDP) on the augmentation of antitumour immunity against highly metastatic L5178Y-ML25 mouse lymphoma cells was examined in CDF1 (Balb/c x DBA/2) mice. Mice immunized with a mixture of X-irradiated tumour cells (10(3)) and B30-MDP (100 micrograms) on 7 days prior to challenge by viable tumour cells displayed a significant decrease in metastasis towards the target organs, liver and spleen, compared with that of untreated mice. Immunization of mice with the mixture on day 5 or 7 after tumour challenge, when the level of glutamic-pyruvic transaminase (GPT) and glutamic-oxaloacetic transaminase (GOT) in sera of mice inoculated with viable tumour cells was observed to be normal, caused less metastasis than immunization with X-irradiated tumour cells alone. Sensitization with X-irradiated tumour cells admixed with B30-MDP induced almost two times higher cytotoxicity of spleen cells against L5178Y-ML25 lymphoma cells than sensitization with X-irradiated tumour cells without B30-MDP. In contrast, cytotoxic activity of spleen cells against another target, L1210 lymphoma cells derived from BDF1 mice, was not observed by immunization with X-irradiated L5178Y-ML25 cells with or without B30-MDP. Specific lysis by splenic cells of the immunized mice against L5178Y-ML25 cells decreased to the normal level when T cells were deleted from the immunized spleen cells by the treatment of rabbit anti-mouse Thy1.2 antibody and rabbit complement. These results indicate that B30-MDP is able to augment a specific tumour immunity due to the enhancement of cytotoxicity mediated by T lymphocytes, and is useful as an immunopotentiating agent for active immunization of inactivated tumour cells.
Acetylmuramyl-Alanyl-Isoglutamine↗
[Bacterial penicillin-binding proteins as specific targets of beta-lactam-antibiotics and as factors of resistance to antibiotics (author's transl)].
Bacteria contain several isofunctional, beta-lactam sensitive membrane enzymes engaged in the synthesis of cell wall peptidoglycan (peptidoglycan-DD-carboxypeptidases, -transpeptidases, -endopeptidases) as members of sets of even more numerous membrane proteins with specific, high binding-affinity for beta-lactam antibiotics (penicillin-binding proteins, PBPs). Effective inhibition of bacterial growth by beta-lactam antibiotics requires simultaneous inactivation of the essential functions of several PBPs by formation of stable enzyme-antibiotic complexes. Failure to achieve permanent inactivation of all essential targets by a given beta-lactam appears to be another cause of bacterial beta-lactam resistance, in addition to known resistance mechanisms based on action of beta-lactamases and on screening off targets from antibiotic by a penetration barrier. Different groups of beta-lactam antibiotics vary characteristically in their affinity for specific essential PBPs. Combined application of two beta-lactams which complement each other in the inactivation to essential targets is a possibility to overcome resistance of single antibiotics.
Anti-Bacterial Agents↗
RAD4 gene of Saccharomyces cerevisiae: molecular cloning and partial characterization of a gene that is inactivated in Escherichia coli.
In contrast to other Saccharomyces cerevisiae RAD genes involved in nucleotide excision repair of DNA, the RAD4 gene could not be isolated by screening a yeast genomic library for recombinant plasmids which complement the UV sensitivity of rad4 mutants (Pure et al., J. Mol. Biol. 183:31-42, 1985). We therefore attempted to walk to RAD4 from the neighboring SPT2 gene and obtained an integrating derivative of a plasmid isolated by Roeder et al. (Mol. Cell. Biol. 5:1543-1553, 1985) which contains a 4-kilobase fragment of yeast DNA including a mutant allele of SPT2. When integrated into several different rad4 mutant strains, this plasmid (pR169) complements UV sensitivity at a frequency of approximately 10%. However, a centromeric plasmid containing rescued sequences which include flanking yeast DNA no longer complements the phenotype of rad4 mutants. Complementing activity was restored by in vivo repair of a defined gap in the centromeric plasmid. The repaired plasmid fully complements the UV sensitivity of all rad4 mutants tested when isolated directly from yeast cells, but when this plasmid is propagated in Escherichia coli complementing activity is lost. We have mapped the physical location of the RAD4 gene by insertional mutagenesis and by transcript mapping. The gene is approximately 2.3 kilobases in size and is located immediately upstream of the SPT2 gene. Both genes are transcribed in the same direction. RAD4 is not an essential gene, and no increased transcription of this gene is observed in cells exposed to the DNA-damaging agent 4-nitroquinoline-1-oxide. The site of inactivation of RAD4 in a particular plasmid propagated in E. coli was localized to a 100-base-pair region by gene disruption and gap repair experiments. In addition, we have identified the approximate locations of the chromosomal rad4-2, rad4-3, and rad4-4 mutations.
Alleles↗
Complement-fixation test for rotavirus detection: comparison and analysis of different methods to reduce anti-complementary activity of some specimens.
The complement-fixation test may be used to detect rotaviral antigens directly in clinical specimens. However, a certain number of specimens tested for human rotaviruses by the complement-fixation test show an anti-complementary activity. By comparing eight techniques we analysed this anti-complementary activity and identified the best method for its reduction. Pretreatment of clarified supernatant of stool suspensions by some methods resulted in a reduction of anti-complementary activity, without reducing the sensitivity of the method. Clarified supernatants of 8/36 (22.2%) specimens were anti-complementary; this anti-complementary activity was best removed by absorption with fetal calf serum or calf albumin. Such treatment offers practical means of increasing the specificity of complement-fixation test. Some observations suggest that the anti-complementary activity of stool suspensions may be frequently due to presence of one or more chelating agents that may be in faecal specimens.
Absorption↗
Cloning and characterization of the umu operon responsible for inducible mutagenesis in Escherichia coli.
In Escherichia coli, radiation and chemically inducible mutagenesis requires a functional umuC gene product. The umuC mutants are defective in mutagenesis and slightly sensitive to DNA damaging agents. A chromosomal fragment that complemented the umuC mutations for UV mutability and UV resistance was cloned into miniF vector plasmid pMF3 by a shotgun method. A restriction map of the hybrid plasmid was constructed. Further subcloning, Tn1000 insertion inactivation, and complementation tests revealed that there are two genes, umuD and umuC in the former umuC region. The gene products of umuD and umuC were identified by the maxicell method to be proteins with Mr of 18 000 and 46 000, respectively. The two genes comprise an operon, and the transcriptional direction is from umuD to umuC. A plasmid carrying an umuC'-lac'Z gene fusion was constructed in vitro to study the regulation of the umu operon. It was shown that the umu operon is inducible by UV and chemical mutagens, and is regulated by the recA and lexA genes.
Bacterial Proteins↗
Effect of metrizamide, a nonionic radiographic contrast agent, on human serum complement. Comparison with ionic contrast media.
The nonionic radiographic contrast material (RCM) metrizamide causes consumption of total complement activity in normal human serum (NHS) in vitro in the absence and to a lesser extent also in the presence of EDTA. The depression of titers of total complement is related to an inactivating effect of metrizamide on component C2. Furthermore, metrizamide induces activation of the alternative pathway as evidenced by the appearance of C3 and factor B cleavage products in NHS, dependent on the presence of divalent cations. Alternative pathway activation is probably mediated by an antagonizing effect of metrizamide on the inactivation of C3b. Unlike ionic RCM, the nonionic substance metrizamide does not lead to cleavage of the internal thiolester bond present in native C3 and C4, at concentrations that produce potent consumption of C3 activity in NHS.
Complement Activation↗
Hereditary angioedema controlled with danazol. Report of a case.
Hereditary angioedema is a condition which should be approached with caution and concern for the patient. The fact that the disease can be fatal cannot be overemphasized. The routine medical history should include questions aimed at identifying these patients. If the angioedema patient is to be treated, provisions must be made for maintenance of an adequate airway. This should include intubation if deemed necessary, and the practitioner should be prepared for a tracheostomy. Close observation following extubation is indicated. A case report in which the patient was controlled with danazol, a synthetic androgen, has been presented. The primary advantage of this drug is a decrease in the various side effects which have been associated with other therapeutic agents used previously in the treatment of hereditary angioedema.
Adult↗
Epsilon-amino-caproic acid in the treatment of Osler's hereditary angioneurotic edema.
This clinical entity described for the first time by Osler in 1888 presented a great therapeutic problem during many decades because of its severity. Landerman and later on Donaldson and Evans established the pathogenic mechanisms of this disease finding a deficiency in the inhibitor of the first activated component of complement, an alpha 2 aminoglycoprotein, to be the mechanism responsible of the same. More concretely, alterations in the plasmin, kinin and kallikrein systems are those that will lead to a change in vascular permeability with resultant tissue alterations. Four cases of hereditary angioneurotic edema are studied in female patients aged between 15 and 50 years and with family history consistent with angioneurotic familiar edema in which there were six cases of death due to edema of the glottis. Once the diagnosis had been made the patients were subjected to treatment with EACA at doses of 2.5 gm every 6 hours. The determinations of complement were similar in the four cases, with marked decreases in C4 and C1 inhibitor with a decrease in total complement in three cases. Regarding secondary effects, vomiting was found only in one cases, which as the dose was reduced did not necessitate termination of treatment. In summary, considering the results obtained in the cases above, we believe that due to its good tolerance and moderate cost, epsilon-amino-caproic acid at the abovementioned dosage is an excellent pharmacological agent in the treatment of Osler's hereditary angioneurotic edema.
Adolescent↗
Clinical safety of intravenous immune globulin and freedom from transmission of viral disease.
Although rare, side-effects have been associated with the administration of iv immune globulins (IVIG). While the clinical presentation may be similar, several different mechanisms account for these adverse reactions. There are those effects in the hypogammaglobulinaemic patient which are probably due to antigen-antibody interaction (so-called inflammatory reactions), those due to spontaneous activation of the complement system (possibly caused by IgG aggregates), those due to true hypersensitivity (for example, hypersensitivity to IgA), and those due to possible contaminants or even stabilizers or preservatives which might have been used. The incidence and nature of clinical side-effects seen in 37 patients who were treated with a native IVIG is shown. In addition, data are provided which support the absence of transmission of human immune deficiency virus in idiopathic thrombocytopenia (ITP) patients, and the agents of non-A, non-B hepatitis in 41 immune-deficient patients having periods of follow-up ranging up to 18 months. Finally, evidence of the inactivation of human immunodeficiency virus during the manufacturing procedure is provided.
Antibodies, Viral↗