Manipulation of the Complement System for Benefit in Sepsis

There is evidence in sepsis, both in rodents and in humans, that activation of the complement system results in excessive production of C5a, which triggers a series of events leading to septic shock, multiorgan failure, and lethality. In rodents following cecal ligation and puncture (CLP), which induces polymicrobial sepsis, in vivo blockade of C5a using neutralizing antibodies dramatically improved survival, reduced apoptosis of lymphoid cells, and attenuated the ensuing coagulopathy. Based on these data, it seems reasonable to consider therapeutic blockade of C5a in humans entering into sepsis and septic shock. Strategies for the development of such an antibody for use in humans are presented.

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Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Cells ◽

10.3390/cells10081844 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1844

Author(s):

Maria Luísa da Silveira Hahmeyer ◽

José Eduardo da Silva-Santos

Keyword(s):

Septic Shock ◽

Actin Polymerization ◽

Current Knowledge ◽

Cecal Ligation ◽

Experimental Models ◽

Rho Proteins ◽

Growing Cell ◽

Sepsis And Septic Shock

Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with elevated mortality rates. Rho proteins can interact with a considerable number of targets, directly affecting cellular contractility, actin filament assembly and growing, cell motility and migration, cytoskeleton rearrangement, and actin polymerization, physiological functions that are intensively impaired during inflammatory conditions, such as the one that occurs in sepsis. In the last few decades, Rho proteins and their downstream pathways have been investigated in sepsis-associated experimental models. The most frequently used experimental design included the exposure to bacterial lipopolysaccharide (LPS), in both in vitro and in vivo approaches, but experiments using the cecal ligation and puncture (CLP) model of sepsis have also been performed. The findings described in this review indicate that Rho proteins, mainly RhoA and Rac1, are associated with the development of crucial sepsis-associated dysfunction in different systems and cells, including the endothelium, vessels, and heart. Notably, the data found in the literature suggest that either the inhibition or activation of Rho proteins and associated pathways might be desirable in sepsis and septic shock, accordingly with the cellular system evaluated. This review included the main findings, relevance, and limitations of the current knowledge connecting Rho proteins and sepsis-associated experimental models.

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Role of C5 Activation Products in Sepsis

The Scientific World JOURNAL ◽

10.1100/tsw.2010.216 ◽

2010 ◽

Vol 10 ◽

pp. 2395-2402 ◽

Cited By ~ 18

Author(s):

Peter A. Ward

Keyword(s):

Multiorgan Failure ◽

Cecal Ligation ◽

Membrane Attack Complex ◽

Lymphoid Cells ◽

Immune Functions ◽

Human Sepsis ◽

Activation Products ◽

C5a Anaphylatoxin

Complement activation products are known to be generated in the setting of both experimental and human sepsis. C5 activation products (C5a anaphylatoxin and the membrane attack complex [MAC] C5b-9) are generated during sepsis following infusion of endotoxin, or after cecal ligation and puncture (CLP), which produces polymicrobial sepsis. C5a reacts with its receptors C5aR and C5L2 in a manner that creates the “cytokine storm”, and is associated with development of multiorgan failure (MOF). A number of other complications arising from the interaction of C5a with its receptors include apoptosis of lymphoid cells, loss of innate immune functions of neutrophils (PMNs, polymorphonuclear leukocytes), cardiomyopathy, disseminated intravascular coagulation, and complications associated with MOF. Neutralization of C5ain vivoor absence/blockade of C5a receptors greatly reduces the adverse events in the setting of sepsis, markedly attenuates MOF, and greatly improves survival. Regarding the possible role of C5b-9 in sepsis, the literature is conflicting. Some studies suggest that C5b-9 is protective, while other studies suggest the contrary. Clearly, in human sepsis, C5a and its receptors may be logical targets for interception.

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NEW ASPECTS OF SEPSIS AND SEPTIC SHOCK PATHOGENESIS IN CHILDREN. THE COMPLEMENT SYSTEM AS TARGET FOR AN EFFECTIVE THERAPY

Russian Journal of Infection and Immunity ◽

10.15789/2220-7619-2018-1-19-24 ◽

2018 ◽

Vol 8 (1) ◽

pp. 19-24

Author(s):

A. P. Prodeus ◽

M. V. Ustinova ◽

A. A. Korsunskiy ◽

A. G. Goncharov

Keyword(s):

Septic Shock ◽

Complement System ◽

Effective Therapy ◽

Sepsis And Septic Shock ◽

The Complement System

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Fc-Independent Protection from SARS-CoV-2 Infection by Recombinant Human Monoclonal Antibodies

Antibodies ◽

10.3390/antib10040045 ◽

2021 ◽

Vol 10 (4) ◽

pp. 45

Author(s):

Tal Noy-Porat ◽

Avishay Edri ◽

Ron Alcalay ◽

Efi Makdasi ◽

David Gur ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Complement System ◽

Neutralizing Antibodies ◽

Human Monoclonal Antibodies ◽

Antibody Treatment ◽

Future Design ◽

The Complement System

The use of passively-administered neutralizing antibodies is a promising approach for the prevention and treatment of SARS-CoV-2 infection. Antibody-mediated protection may involve immune system recruitment through Fc-dependent activation of effector cells and the complement system. However, the role of Fc-mediated functions in the efficacious in-vivo neutralization of SARS-CoV-2 is not yet clear, and it is of high importance to delineate the role this process plays in antibody-mediated protection. Toward this aim, we have chosen two highly potent SARS-CoV-2 neutralizing human monoclonal antibodies, MD65 and BLN1 that target distinct domains of the spike (RBD and NTD, respectively). The Fc of these antibodies was engineered to include the triple mutation N297G/S298G/T299A that eliminates glycosylation and the binding to FcγR and to the complement system activator C1q. As expected, the virus neutralization activity (in-vitro) of the engineered antibodies was retained. To study the role of Fc-mediated functions, the protective activity of these antibodies was tested against lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice, when treatment was initiated either before or two days post-exposure. Antibody treatment with both Fc-variants similarly rescued the mice from death reduced viral load and prevented signs of morbidity. Taken together, this work provides important insight regarding the contribution of Fc-effector functions in MD65 and BLN1 antibody-mediated protection, which should aid in the future design of effective antibody-based therapies.

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Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells

Gene Therapy ◽

10.1038/s41434-021-00239-9 ◽

2021 ◽

Author(s):

Anna K. Dreismann ◽

Michelle E. McClements ◽

Alun R. Barnard ◽

Elise Orhan ◽

Jane P. Hughes ◽

...

Keyword(s):

Complement System ◽

Functional Expression ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Complement Factor ◽

Factor I ◽

Complement Factor I ◽

Age Related ◽

The Complement System

AbstractDry age-related macular degeneration (AMD) is characterised by loss of central vision and currently has no approved medical treatment. Dysregulation of the complement system is thought to play an important role in disease pathology and supplementation of Complement Factor I (CFI), a key regulator of the complement system, has the potential to provide a treatment option for AMD. In this study, we demonstrate the generation of AAV constructs carrying the human CFI sequence and expression of CFI in cell lines and in the retina of C57BL/6 J mice. Four codon optimised constructs were compared to the most common human CFI sequence. All constructs expressed CFI protein; however, most codon optimised sequences resulted in significantly reduced CFI secretion compared to the non-optimised CFI sequence. In vivo expression analysis showed that CFI was predominantly expressed in the RPE and photoreceptors. Secreted protein in vitreous humour was demonstrated to be functionally active. The findings presented here have led to the formulation of an AAV-vectored gene therapy product currently being tested in a first-in-human clinical trial in subjects with geographic atrophy secondary to dry AMD (NCT03846193).

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Interaction with complement proteins and dendritic cells implicates LCCL domain-containing proteins (CCps) of malaria parasites in immunomodulation

Biochemical Journal ◽

10.1042/bcj20180494 ◽

2018 ◽

Vol 475 (21) ◽

pp. 3311-3314 ◽

Cited By ~ 1

Author(s):

Puran Singh Sijwali

Keyword(s):

Dendritic Cells ◽

Complement System ◽

Protein Complexes ◽

Immune Defense ◽

Malaria Parasites ◽

Classical Complement Pathway ◽

Soluble Immune Complexes ◽

Multimeric Protein ◽

The Complement System

The evasion of host immune defense is critical for pathogens to invade, establish infection and perpetuate in the host. The complement system is one of the first lines of innate immune defense in humans that destroys pathogens in the blood circulation. Activation of the complement system through direct encounter with pathogens or some other agents leads to osmolysis of pathogens, clearance of soluble immune complexes and recruitment of lymphocytes at the site of activation. Although malaria parasites are not exposed to the complement system owing to their intracellular development for most part of their life cycle in the human host, the extracellular stages must face the complement system of human or mosquito or both. In a recent issue of the Biochemical Journal, Sharma et al. reported that Plasmodiumfalciparum LCCL domain-containing protein 1 (PfCCp1) inhibited activation of the classical complement pathway and down-regulated effector responses of dendritic cells, which implicate PfCCp1 and related proteins in immunomodulation of the host that likely benefits the parasite. PfCCp1 belongs to a multi-domain protein family that exists as multimeric protein complexes. It needs to be investigated whether PfCCp1 or its multimeric protein complexes have an immunomodulatory effect in vivo and on the mosquito complement system

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Anti-GD2 IgA kills tumors by neutrophils without antibody-associated pain in the preclinical treatment of high-risk neuroblastoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003163 ◽

2021 ◽

Vol 9 (10) ◽

pp. e003163

Author(s):

Mitchell Evers ◽

Marjolein Stip ◽

Kaylee Keller ◽

Hanneke Willemen ◽

Maaike Nederend ◽

...

Keyword(s):

High Risk ◽

Sensory Neurons ◽

Complement System ◽

Severe Pain ◽

Neuroblastoma Cells ◽

Antibody Therapy ◽

Preclinical Treatment ◽

The Complement System

BackgroundThe addition of monoclonal antibody therapy against GD2 to the treatment of high-risk neuroblastoma led to improved responses in patients. Nevertheless, administration of GD2 antibodies against neuroblastoma is associated with therapy-limiting neuropathic pain. This severe pain is evoked at least partially through complement activation on GD2-expressing sensory neurons.MethodsTo reduce pain while maintaining antitumor activity, we have reformatted the approved GD2 antibody ch14.18 into the IgA1 isotype. This novel reformatted IgA is unable to activate the complement system but efficiently activates leukocytes through the FcαRI (CD89).ResultsIgA GD2 did not activate the complement system in vitro nor induced pain in mice. Importantly, neutrophil-mediated killing of neuroblastoma cells is enhanced with IgA in comparison to IgG, resulting in efficient tumoricidal capacity of the antibody in vitro and in vivo.ConclusionsOur results indicate that employing IgA GD2 as a novel isotype has two major benefits: it halts antibody-induced excruciating pain and improves neutrophil-mediated lysis of neuroblastoma. Thus, we postulate that patients with high-risk neuroblastoma would strongly benefit from IgA GD2 therapy.

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Sepsis

10.2310/fm.1147 ◽

2020 ◽

Author(s):

Steven P LaRosa ◽

Steven M. Opal

Keyword(s):

Intensive Care Unit ◽

Septic Shock ◽

Severe Sepsis ◽

Intensive Care ◽

Organ Dysfunction ◽

Fluid Resuscitation ◽

Multiorgan Failure ◽

Sepsis Management ◽

The Past ◽

Sepsis And Septic Shock

Sepsis, along with the multiorgan failure that often accompanies this condition, is a leading cause of mortality in the intensive care unit. Although modest improvements in the prognosis have been made over the past two decades and promising new therapies continue to be investigated, innovations in the management of septic shock are still required. This chapter discusses the definitions, epidemiology, and pathogenesis (including microbial factors, host-derived mediators, and organ dysfunction) relating to sepsis. Management of severe sepsis and septic shock is also described. This review contains 5 figures, 11 tables, and 99 references. Keywords:Organ dysfunction, sepsis, septic shock, infection, bacteremia, fluid resuscitation, vasopressor

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