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Antisense Oligonucleotide-Based Therapy for HIV-1 Infection from Laboratory to Clinical Trials
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
As shown in Figure 7, serum complement CH50 concentrations decreased at a dose >≥10 mg/kg (infused over 10 min), beginning at 5 min from the start of infusion, and the C5a split products of complement increased, beginning within 2 min of infusion, at a dose of ≥5 mg/kg (infused over 10 min). The higher the dose, the earlier C5a appeared. At doses ≥2 mg/kg no changes were observed. Similarly, administration of 5, 10, or 20 mg/kg GEM®91 to monkeys by 10 min infusion induced prolongation of aPTT in dose-dependent manner (Figure 8).
Evaluation of the Immune System
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Moira Thomas, Elizabeth Drewe, Richard J. Powell
Deficiencies in the classical complement pathway typically present with early onset atypical or severe lupus-like illness or invasive bacterial infection with encapsulated organisms such as pneumococcus. Deficiencies in the alternate and terminal pathways predispose to meningococcal infection especially with unusual serotypes. The CH100 (or CH50) haemolytic complement test assesses activity of the classical and terminal complement pathways and the AP100 (or AP50) haemolytic complement test assesses activity of the alternate and terminal pathways. Thus the combination of these tests can identify the presence and likely location of any deficiency that can be followed up by measurement of the appropriate individual complement components. As haemolytic complement tests rely upon complement function, samples should be taken when patients are clinically stable and blood samples must be separated and frozen within a short time of venepuncture to avoid in vitro depletion of complement causing false positive results.
Rheumatology and Clinical Immunology
Published in John D Firth, Professor Ian Gilmore, MRCP Part 1 Self-Assessment, 2017
John D Firth, Professor Ian Gilmore
Meningococcal septicaemia can affect a normal host, but patients with a deficiency of a terminal complement component are particularly susceptible. This can most easily be detected by measuring the CH50 or CH100, which tests the ability of the complement in the patient’s serum to lyse erythrocytes by the classical complement pathway. If any complement component (C1-9) is missing, lysis will not occur.
Complement testing in the clinical laboratory
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Maria Alice V. Willrich, Karin M. P. Braun, Ann M. Moyer, David H. Jeffrey, Ashley Frazer-Abel
The differences between assay methodologies are wide, but all of them rely on the formation of the TCC, C5b-9, and measure its effect on the system, either by hemolysis (hemolytic assay), lysis of the contents of a liposome (liposome method), or by a neoepitope generated only after the formation of the C5b-9 (ELISA). As expected, the assays have different analytical measurable ranges as well as use different calibrators and cutoffs for normal and abnormal activity. A debate put this test into check when the FDA approved ravulizumab as it releases C5 at lower pH so that it can be internalized in the endosome and recycled as free ravulizumab. If the conditions of the CH50 assay also facilitate this dissociation, either through the acid buffer used in the assay or due to large dilutions in the testing, the level of measured inhibition by CH50 may underestimate the one in vivo, achieved in the patient. A discordance between drug concentration, clinical presentation, and CP function was recognized in a brief report that showed variation in how reliable different CH50 tests were in comparison to free C5 for monitoring ravulizumab [145]. As patients transition to ravulizumab from eculizumab, new tests should be evaluated to monitor ravulizumab therapy efficacy.
Complement system network in cell physiology and in human diseases
Published in International Reviews of Immunology, 2021
Roberta Romano, Giuliana Giardino, Emilia Cirillo, Rosaria Prencipe, Claudio Pignata
Overall, a normal AH50 with absent CH50 suggests an early classical pathway deficiency, involving a complement protein or a regulatory factor, while undetectable AH50 and normal CH50 activity imply a deficiency in one of the alternative pathway components; absent AH50 and CH50 suggest a late component deficiency. If clinical suspicion for complement deficiency is high, in spite of normal CH50 and AH50, a defect in lectin pathway may be ruled out measuring MBL. Once candidate proteins have been identified (Figure 2), single components should be tested in terms of both concentration and function since normal expression does not distinguish between a deficit of a protein due to an underlying gene mutation or to the presence of autoantibodies. The presence of autoantibodies appears to be likely when low levels of multiple components are detected [62]. Enzyme-Immuno-Assays, western blot, immunoprecipitation and nephelometry are techniques used to measure single component concentration [4,63]. The latter is routinely used to measure C3 and C4 plasma levels. Thereafter, serum tests may be used to assess the function: patient’s serum is mixed with complement depleted serum in order to evaluate hemolysis [63].
Revisiting the complement system in systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2020
Madhubala Sharma, Pandiarajan Vignesh, Karalanglin Tiewsoh, Amit Rawat
Defect in a complement component may affect the entire complement cascade. Complement activation by classical pathway is studied using sheep erythrocytes coated with rabbit antibodies. Functional assessment of alternative pathway can be performed using rabbit or guinea pig erythrocytes which are natural activators of human alternative pathway. Classical hemolytic assays can be performed using different methods – CH50 and AH50 the original hemolytic assays for classical and alternative pathways respectively were based on the titer of serum used for the lysis of 50% of specified cells. Defects in the classical complement pathway can be determined by 50% Hemolytic complement activity of serum. The main function of the complement system is to opsonize and lyse the target cells. Although we can quantify the individual complement components, it does not reveal the overall complement activity. CH50 is an assay through which we can screen the activity of classical pathway. This assay is sensitive for the detection of the quantity of every constituent of the classical pathway. It recognizes the ability of complement component of the classical pathway present in serum to lyse the sheep RBC coated with rabbit anti-sheep RBC Antibody (Hemolysin).