Intravenous Immunoglobulin Preparations Research Articles

THE POTENTIAL OF HUMAN PLASMA AND HUMAN BLOOD PRODUCTS FOR IMMUNE PROTECTION

Intravenous Immunoglobulin (IVIg) were used for the first time at the late seventies for treatment of patient with primary and secondary immunodeficiencies. Тhe first observations opened a wide field for basic and clinical research leading to a rapidly expanding use of IVIg for the treatment of patients with multiple diseases. The immunoglobulin preparations contain large amount of intact form of IgG molecules with comparable values of subclasses as in native plasma. Тhose properties account for the normal half-life of injected immunoglobulin of three weeks, and its ability to react normal with the complement components and with the specific Fcγ-receptors on the surface of phagocytes and lymphocytes. IVIg is produced from plasma pules from several thousand donors, which leads to wide spectre of variable regions of IgG molecules in the product. Some of the antibodies in the product can recognize bacterial, virus and fungal antigens are essential in replacement therapy in patients with antibody deficiency. А good understanding of the molecular and cellular basis of the immunoregulatory actions of intravenous immunoglobulin preparations is important for optimizing their use in inflammatory diseases for conducting new clinical observations.

Severe Gastrointestinal Complications After IVIG Infusion in Newborns: A Two-Center Study and Literature Review

Background: There are several studies regarding perforations after intravenous immunoglobulin (IVIG) infusion; however, the risk factors are not defined yet. Objectives: The present study aimed to investigate gastrointestinal complications in newborns regarding the reported immunoglobulin A (IgA) levels in IVIG preparations. Methods: This retrospective chart review was conducted on term newborns who received IVIG therapy in two centers in Istanbul. The study included patients with IVIG-associated gastrointestinal bleedings, necrotizing enterocolitis (NEC), and intra-abdominal perforations without any underlying diseases and recorded demographic data (gestational age, birth weight, and gender) and the IgA levels in the IVIG preparations. Infants born below 35 gestational weeks were excluded as they were more likely to have NEC. Results: A total of 71 patients received IVIG therapy, and 15.5% (n = 11) developed major gastrointestinal system (GIS) complications. A total of 36 patients were born ≥ 35 gestational weeks, and gastrointestinal perforation or bleeding occurred in 22.2% (n = 8) of these patients. Two patients died before surgery due to aggressive disease progression. None of these patients had any gastrointestinal symptoms before IVIG therapy or any predisposing factors for gastrointestinal perforation. All patients were on spontaneous breathing and enteral feeding without intolerance. The IgA level content of the IVIG preparations was related to the major GIS complications with strong evidence, and the safe threshold resulted in 14 mg/dL in receiver operating characteristic (ROC) analysis in the present study group. Conclusions: Higher IgA levels in IVIG preparations might be a risk factor for gastrointestinal perforation and bleeding in term newborns. Clinicians should be aware of this potential complication when using IVIG therapy in term newborns and closely monitor for signs and symptoms of major gastrointestinal complications.

Autoantibody profiles in intravenous immunoglobulin preparations: A possible cause of mistaken autoimmunity diagnosis.

Intravenous immunoglobulins (IVIgs) derived from the pooled plasma of thousands of donors contain numerous types of IgG molecules, including autoantibodies commonly used to diagnose autoimmunity. While these autoantibodies can cause misinterpretation of serological tests for IVIg recipients, their profiles in IVIg preparations are not fully understood. Using binding-capability based immune assays, we measured 18 varieties of clinically relevant autoantibodies in domestic blood donor-derived IVIg products. In addition, we analyzed an IVIg product from a US brand to evaluate the influence of regional and racial differences. Based on the determined autoantibody titers, pharmacokinetics of passively acquired autoantibodies and their possible detection period in serum were estimated. Anti-thyroglobulin (Tg), anti-thyroidperoxidase (TPO), and anti-Sjögren's-syndrome-related antigen A (SS-A) antibodies were present in considerable amounts in IVIg products. Notably, these three autoantibodies can be detected in IVIg recipients' sera for up to 3 months after infusion. To the best of our knowledge, this is the first study that analyzed multiple autoantibody profiles in both pooled plasma and IVIg products and that further evaluated their potential influences on diagnosis of autoimmunity. Clinicians should keep in mind that IVIgs contain several autoantibodies and that their infusion can produce false-positive serology results. To establish an accurate diagnosis, serological tests must be carefully interpreted and clinical symptoms should be more purposefully considered if patients are receiving IVIg therapy.

Review of available therapies for the treatment of pediatric COVID-19-associated polyarticular inflammatory syndrome

Recently, there have been an increasing number of reports from around the world describing children and adolescents with multisystemic inflammatory conditions associated with COVID-19. The clinical features of these pediatric cases are both similar to and different from other well-described inflammatory syndromes, including Kawasaki disease. Symptoms appear to develop after infection, rather than in the acute phase of COVID-19. Regarding the clinical spectrum, much remains unknown.
 The new disease entity challenges specialists around the world in developing universal management protocols. In the fight for the health and lives of patients, treatment according to standard protocols for Kawasaki disease has been used. However, further clinical trials are required to prove the effectiveness and safety of these treatments. There are reports of successful therapy using intravenous immunoglobulin preparations and steroid therapy. Biologic, antiviral, antibiotic, antiplatelet and anticoagulant therapies are also used. The described pediatric disease can be associated with hemodynamic failure, so treatment should take place in a hospital setting, under the watchful eye of a multidisciplinary team.

Cation exchange chromatography removes FXIa from a 10% intravenous immunoglobulin preparation

Cation exchange chromatography removes FXIa from a 10% intravenous immunoglobulin preparation

Safety of Intravenous Immunoglobulin Replacement Therapy in a Group of Patients with Primary Immune Deficiency

Background Intravenous immunoglobulin (IVIG) has been used as antibody replacement therapy in primary immunodeficiency diseases for more than 50 years. Most routinely, IVIG is used in patients with predominantly antibody deficiency and combined immunodeficiency. Aim To evaluate the safety of regular intravenous immunoglobulin (IVIG) among patients with primary immunodeficiency diseases who receive IVIG as a replacement treatment. Methods Our study included 40 patients with primary immunodeficiency following up regularly in the Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, These patients were followed up for one year in order to evaluate the incidence of occurrence of adverse reactions among the patients who received IVIG monthly, Once patients with adverse reactions have been identified, the following data were taken and reviewed : a specific type of adverse reaction to IVIG; the time interval between onset of adverse reaction and beginning of IVIG infusion; IVIG preparation, dose and infusion rate; medical management done during side effects . Statistics were used to analyze and interpret the data. Results This study included 40 PID patients. They were 31 males (77.5%) and 9 females 22.5% with a male to female ratio of 3.4:1. At time of enrolment in the study, the median age was 73.5 months (14 – 218 months). In our studied population the median age of symptoms onset was 23 months (1 – 187 months), and age at diagnosis was 25 months (2-192 months). This made the diagnostic lag to have a median of 9 months (0-56 months). From our studied population only one patient (2.5%) out of the study groups developed anaphylaxis and was shifted to another brand. Conclusion IVIG is a safe drug for patients with primary antibody deficiency with minimal reported side effects.

Safety and Tolerability of Intravenous Immunoglobulin in Chronic Inflammatory Demyelinating Polyneuropathy: Results of the ProCID Study.

The ProCID study evaluated the efficacy and safety of three doses of a 10% liquid intravenous immunoglobulin (IVIg) preparation (panzyga®) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This report describes the safety findings. Patients were randomised to receive a 2.0 g/kg induction dose followed by maintenance doses of either 0.5, 1.0 or 2.0 g/kg IVIg every 3 weeks over 24 weeks. All 142 enrolled patients were included in the safety analyses. In total, 286 treatment-emergent adverse events (TEAEs) were reported in 89 patients, of which 173 (60.5%) were considered treatment-related. Most TEAEs were of mild severity. Eleven serious TEAEs were reported in 6 patients. Two serious TEAEs in one patient (headache and vomiting) were considered related to treatment, which resolved without study discontinuation. No treatment-related thrombotic events, haemolytic transfusion reactions or deaths occurred. One patient discontinued the study due to a TEAE (allergic dermatitis) probably related to IVIg. Headache was the only dose-dependent TEAE, with incidences ranging from 2.9 to 23.7%, the incidence of all other TEAEs was similar across treatment groups. Most TEAEs were associated with the induction dose infusion, and the rate of TEAEs decreased thereafter. The median (IQR) daily IVIg dose was 78 (64-90) g, and 94.4% of patients tolerated the maximal infusion rate of 0.12 ml/kg/min without pre-medication. Infusions of 10% IVIg at doses up to 2.0 g/kg with high infusion rates were safe and well tolerated in patients with CIDP. EudraCT 2015-005443-14, NCT02638207.

SARS-CoV-2 spike antibody concentration in gamma globulin products from high-prevalence COVID-19 countries are transmitted to X-linked agammaglobulinemia patients.

Patients with X-linked agammaglobulinemia (XLA) are characterized by humoral impairment and are routinely treated with intravenous immunoglobulin (IVIG). In this study, we aimed to investigate the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in IVIG preparations harvested globally and evaluate the transfer of SARS-CoV-2 antibodies to the XLA patient. A single-center, prospective cohort study was conducted in the period of November 2020 to November 2022. Clinical and laboratory data, specifically, SARS-CoV-2 spike IgG levels from the serum of 115 IVIG preparations given to 5 XLA patient were collected. Concurrently, SARS-CoV-2 spike IgG levels from the serum of the 5 XLA was collected monthly. Five XLA patients were evaluated within the study period. All were treated monthly with commercial IVIG preparations. A total of 115 IVIG treatments were given over the study period. The origin country and the date of IVIG harvesting was obtained for 111 (96%) of the treatments. Fifty-four IVIG preparations (49%) were harvested during the COVID-19 pandemic of which 76% were positive (>50AU/mL) for SARS-CoV-2 spike antibodies which were subsequently transmitted to the XLA patients in an approximate 10-fold reduction. SARS-CoV2 spike IgG was first detected in IVIG batches that completed their harvest date by September 2021. Positive products were harvested from origin countries with a documented prevalence over 2,000 per 100,000 population. As the prevalence of COVID-19 infections rises, detection of SARS-CoV-2 spike IgG in commercial IVIG products increases and is then transmitted to the patient. Future studies are needed to investigate the neutralizing capabilities of SARS-CoV-2 IgG and whether titer levels in IVIG remain consistent as the incidence of infection and vaccination rates in the population changes.

Cross-Reactivity of Antibodies in Intravenous Immunoglobulin Preparation for Protection against SARS-CoV-2.

Severe cases of COVID-19 continue to put pressure on medical operations by prolonging hospitalization, occupying intensive care beds, and forcing medical personnel to undergo harsh labor. The eradication of SARS-CoV-2 through vaccine development has yet to be achieved, mainly due to the appearance of multiple mutant-incorporating strains. The present study explored the utility of human intravenous immunoglobulin (IVIG) preparations in suppressing the aggravation of any COVID-19 infection using a SARS-CoV-2 pseudovirus assay. Our study revealed the existence of IgG antibodies in human IVIG preparations, which recognized the spike protein of SARS-CoV-2. Remarkably, the pretreatment of ACE2/TMPRSS2-expressing host cells (HEK293T cells) with IVIG preparations (10 mg/mL) inhibited approximately 40% entry of SARS-CoV-2 pseudovirus even at extremely low concentrations of IgG (0.16-1.25 mg/mL). In contrast, the antibody-dependent enhancement of viral entry was confirmed when SARS-CoV-2 pseudovirus was treated with some products at an IgG concentration of 10 mg/mL. Our data suggest that IVIG may contribute to therapy for COVID-19, including for cases caused by SARS-CoV-2 variants, since IVIG binds not only to the spike proteins of the virus, but also to human ACE2/TMPRSS2. An even better preventive effect can be expected with blood collected after the start of the COVID-19 pandemic.

Intravenous immunoglobulin preparations attenuate lysolecithin-induced peripheral demyelination in mice and comprise anti-large myelin protein zero antibody.

Intravenous immunoglobulin (IVIg) has been used to treat inflammatory demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, and multifocal motor neuropathy. Despite studies demonstrating the clinical effectiveness of IVIg, the mechanisms underlying its effects remain to be elucidated in detail. Herein, we examined the effects of IVIg on lysolecithin-induced demyelination of the sciatic nerve in a mouse model. Mice -administered with IVIg 1 and 3 days post-injection (dpi) of lysolecithin -exhibited a significantly decreased demyelination area at 7 dpi. Immunoblotting analysis using two different preparations revealed that IVIg reacted with a 36-kDa membrane glycoprotein in the sciatic nerve. Subsequent analyses of peptide absorption identified the protein as a myelin protein in the peripheral nervous system (PNS) known as large myelin protein zero (L-MPZ). Moreover, injected IVIg penetrated the demyelinating lesion, leading to deposition on L-MPZ in the myelin debris. These results indicate that IVIg may modulate PNS demyelination, possibly by binding to L-MPZ on myelin debris.

Selective Measurement Of Activated Contact Activation Factor XII In The Matrix Of Intravenous Immunoglobulin

Activated factor XII (FXIIa) has been identified as a possible impurity in intravenous immunoglobulin preparations. Chromogenic peptide substrates are used for measuring FXIIa. Absolute selectivity, however, can be hardly obtained in such direct chromogenic assays due to the similar cleavage preferences of related proteases including kallikrein (KK) and activated factor XI (FXIa). Our highly selective method for the FXIIa measurement combines the binding of FXIIa to its solid phase-immobilized, specific inhibitor corn trypsin inhibitor (CTI) followed by immunological detection of the resulting complex via immunological detection of the protease.

Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage.

Autoimmune neuropathy associated with antibodies against pan-neurofascin is a new subtype of nodo-paranodopathy. It is relevant because it is associated with high morbidity and mortality. Affected patients often require intensive care unit treatment for several months, and data on the reversibility and long-term prognosis are limited. The pathogenicity including IgG subclass-associated mechanisms has not been unravelled, nor directly compared to anti-neurofascin-155 IgG4-related pathology. Understanding the underlying pathology might have a direct impact on treatment of these severely affected patients. By a multicentre combined prospective and retrospective approach, we provide clinical data of a large cohort of patients with anti-neurofascin-associated neuropathy (n = 18) including longitudinal titre and neurofilament light chain assessment via Ella® and relate clinical data to in vitro pathogenicity studies of anti-neurofascin antibodies. We assessed antibody binding characteristics and the pathogenic effects of anti-pan-neurofascin versus neurofascin-155 antibodies on living myelinating dorsal root ganglia co-cultures. Additionally, we analysed the IgG subclass profile and the complement binding capacity and effector functions considering the effects of intravenous immunoglobulin preparations via enzyme-linked immunosorbent and cell-based assays. In contrast to chronic neurofascin-155 IgG4-associated neuropathy, anti-pan-neurofascin-associated disease presented with a high morbidity and mortality, but as a monophasic and potentially reversible disorder. During follow-up, antibodies were no longer detectable in 8 of 11 patients. Anti-pan-neurofascin had direct access to the nodes of Ranvier in myelinating cultures titre-dependently, most probably inducing this severe phenotype. Antibody preincubation led to impaired paranode formation, destruction of paranodal architecture and alterations on paranodal myelin and sensory neurons in the cultures, with more severe effects than neurofascin-155 antibodies. Besides IgG4, subclass IgG3 was detected and associated with complement binding and cytotoxic effects in vitro. As a possible correlate of axonal damage in vivo, we detected highly increased serum neurofilament light chain levels (sNF-L), correlating to serum C3a. Still, sNF-L was not identified as a marker for poor prognosis, but rather as an intra- and interindividual marker for acuteness, severity and course, with a strong decrease during recovery. Our data provide evidence that anti-pan-neurofascin antibodies directly attack the node and induce severe and acute, but potentially reversible, nodo-paranodal pathology, possibly involving complement-mediated mechanisms. Screening for autoantibodies thus is crucial to identify this subset of patients who benefit from early antibody-depleting therapy. Titre and sNF-L might serve as valuable follow-up parameters. The prospect of a favourable outcome has high relevance for physicians, patients and relatives during months of critical care.

Antibody response after COVID-19 vaccination in intravenous immunoglobulin-treated immune neuropathies.

BackgroundThis study assessed the prevalence of anti‐SARS‐CoV‐2 antibodies in therapeutic immunoglobulin and their impact on serological response to COVID‐19 mRNA vaccine in patients with intravenous immunoglobulin (IVIg)‐treated chronic immune neuropathies.MethodsForty‐six samples of different brands or lots of IVIg or subcutaneous IgG (SCIg) were analyzed for anti‐SARS‐CoV‐2 IgG using ELISA and chemiluminescent microparticle immunoassay (CMIA). Blood sera from 16 patients with immune neuropathies were prospectively analyzed for anti‐SARS‐CoV‐2 IgA, IgG, and IgM before and one week after IVIg infusion subsequent to consecutive COVID‐19 mRNA vaccine doses and after 12 weeks. These were compared to 42 healthy subjects.ResultsTwenty‐four (52%) therapeutic immunoglobulin samples contained anti‐SARS‐CoV‐2 IgG. All patients with immune neuropathies (mean age 65 ± 16 years, 25 % female) were positive for anti‐SARS‐CoV‐2 IgG after COVID‐19 vaccination. Anti‐SARS‐CoV‐2 IgA titers significantly decreased 12‐14 weeks after vaccination (p=0.02), IgG titers remained stable (p=0.2). IVIg did not significantly reduce intra‐individual anti‐SARS‐CoV‐2 IgA/IgG serum titers in immune neuropathies (p=0.69). IVIg‐derived anti‐SARS‐CoV‐2 IgG did not alter serum anti‐SARS‐CoV‐2 IgG decrease after IVIg administration (p=0.67).ConclusionsOur study indicates that IVIg does not impair the antibody response to COVID‐19 mRNA vaccine in a short‐term observation, when administered a minimum of two weeks after each vaccine dose. The infusion of current IVIg preparations that contain anti‐SARS‐CoV‐2 IgG does not significantly alter serum anti‐SARS‐CoV‐2 IgG titers.

Passive immunization against COVID-19 by anti-SARS-CoV-2 spike IgG in commercially available immunoglobulin preparations in severe antibody deficiency

Passive immunization against COVID-19 by anti-SARS-CoV-2 spike IgG in commercially available immunoglobulin preparations in severe antibody deficiency

Low- versus high-concentration intravenous immunoglobulin for children with Kawasaki disease in the acute phase.

Few studies have compared the effects of low-concentration (5%) and high-concentration (10%) intravenous immunoglobulin (IVIG) preparations for patients with Kawasaki disease (KD) in the acute phase. The purpose of this study was to compare outcomes between low- and high-concentration IVIG preparations in children with KD, using a national inpatient database in Japan. We used the Diagnostic Procedure Combination database to identify patients with KD treated with IVIG from April 2012 to March 2020. We identified those receiving high- and low-concentration IVIG preparations as an initial treatment. The outcomes included the proportions of patients with coronary artery abnormalities (CAAs) and IVIG resistance, length of stay, and medical costs. Propensity score-matched analyses were conducted to compare the outcomes between the 2 groups. Instrumental variable analyses were performed to confirm the results. We identified 48046 patients with KD and created 4:1 propensity score-matched pairs between the low- and high-concentration IVIG groups. There was a significant difference in the percentage with IVIG resistance between the 2 groups (20.6% vs 24.1%; risk difference, 3.5% [95% confidence interval, 2.3-4.7]; P<.001). However, there was no significant difference in CAAs (1.6% vs 1.6%; risk difference, 0.013% [95% confidence interval, -0.34 to 0.37]; P=.953). The instrumental variable analyses showed similar results. The proportion of CAAs did not differ significantly between those receiving low- and high-concentration IVIG. To confirm the results of this study, prospective studies adjusting for duration of IVIG administration and duration of observation are needed.

Polyvalent Immunoglobulin Preparations Inhibit Pneumolysin-Induced Platelet Destruction.

Platelets play an important role in the development and progression of respiratory distress. Functional platelets are known to seal inflammatory endothelial gaps and loss of platelet function has been shown to result in loss of integrity of pulmonary vessels. This leads to fluid accumulation in the pulmonary interstitium, eventually resulting in respiratory distress. Streptococcus pneumoniae is one of the major pathogens causing community-acquired pneumonia. Previously, we have shown that its major toxin pneumolysin forms pores in platelet membranes and renders them nonfunctional. In vitro, this process was inhibited by polyvalent intravenous immunoglobulins (IVIGs). In this study, we compared the efficacy of a standard IVIG preparation (IVIG, 98% immunoglobulin G [IgG]; Privigen, CSL Behring, United States) and an IgM/IgA-enriched immunoglobulin preparation (21% IgA, 23% IgM, 56% IgG; trimodulin, Biotest AG, Germany) to inhibit pneumolysin-induced platelet destruction. Platelet destruction and functionality were assessed by flow cytometry, intracellular calcium release, aggregometry, platelet viability, transwell, and flow chamber assays. Overall, both immunoglobulin preparations efficiently inhibited pneumolysin-induced platelet destruction. The capacity to antagonize pneumolysin mainly depended on the final IgG content. As both polyvalent immunoglobulin preparations efficiently prevent pneumolysin-induced platelet destruction and maintain platelet function in vitro, they represent promising candidates for clinical studies on supportive treatment of pneumococcal pneumonia to reduce progression of respiratory distress.

Регистр пациентов с первичными иммунодефицитными состояниями в Иркутской области

In this paper, the main epidemiological indicators of primary immunodeficiency disorders (PIDDs) in the Irkutsk region based on analysis of data from 66 patients registered in the PIDDs database from 2010 to November 2021 were studied. The prevalence of primary immunodeficiencies in the Irkutsk region totals 2.75:100,000 of the population. The cohort of living patients is dominated by children (74%). A total of 22 nosological forms were verified in the registry of primary immunodeficiencies. Molecular genetic diagnosis was confirmed in 26% of the patients. Hematopoietic cell transplantation was performed in 21.2% of the patients. Intravenous immunoglobulin preparations are received by 19.7% of patients. The main purpose of the registry is to systematise patients with primary immunodeficiencies, provide them with the necessary treatment in a timely manner and improve their quality of life.

Modelling the concentration of anti-SARS-CoV-2 immunoglobulin G in intravenous immunoglobulin product batches.

Plasma-derived intravenous immunoglobulin (IVIg) products contain a dynamic spectrum of immunoglobulin (Ig) G reactivities reflective of the donor population from which they are derived. We sought to model the concentration of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG which could be expected in future plasma pool and final-product batches of CSL Behring's immunoglobulin product Privigen. Data was extracted from accessible databases, including the incidence of coronavirus disease 2019 and SARS-CoV-2 vaccination status, antibody titre in convalescent and vaccinated groups and antibody half-life. Together, these parameters were used to create an integrated mathematical model that could be used to predict anti-SARS-CoV-2 antibody levels in future IVIg preparations. We predict that anti-SARS-CoV-2 IgG concentration will peak in batches produced in mid-October 2021, containing levels in the vicinity of 190-fold that of the mean convalescent (unvaccinated) plasma concentration. An elevated concentration (approximately 35-fold convalescent plasma) is anticipated to be retained in batches produced well into 2022. Measurement of several Privigen batches using the Phadia™ EliA™ SARS-CoV-2-Sp1 IgG binding assay confirmed the early phase of this model. The work presented in this paper may have important implications for physicians and patients who use Privigen for indicated diseases.

Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

Hypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

Immunomodulation: Immunoglobulin Preparations Suppress Hyperinflammation in a COVID-19 Model via FcγRIIA and FcαRI.

The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and “cytokine storm”. The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response.