Complement receptor 2–mediated targeting of complement inhibitors to sites of complement activation

Song, Hongbin; He, Chunqing; Knaak, Christian; Guthridge, Joel M.; Holers, V. Michael; Tomlinson, Stephen

doi:10.1172/jci17348

Cited by 98 publications

(91 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another exciting possibility is that alternative pathway complement inhibitors could be targeted to specific anatomic sites using Fab or singlechain variable fragments (80) or that linking inhibitors to the CR2 complement receptor could target them specifically to sites of complement activation (81). Such an approach may be advantageous to the dosing of such agents and reduce the side effect profile.…”

Section: Unanswered Questions and Future Directionsmentioning

confidence: 99%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

The Journal of Immunology

Self Cite

389

350

View full text Add to dashboard Cite

The complement system is increasingly recognized as important in the pathogenesis of tissue injury in vivo following immune, ischemic, or infectious insults. Within the complement system, three pathways are capable of initiating the processes that result in C3 activation: classical, alternative, and lectin. Although the roles that proinflammatory peptides and complexes generated during complement activation play in mediating disease processes have been studied extensively, the relative contributions of the three activating pathways is less well understood. Herein we examine recent evidence that the alternative complement pathway plays a key and, in most instances, obligate role in generating proinflammatory complement activation products in vivo. In addition, we discuss new concepts regarding the mechanisms by which the alternative pathway is activated in vivo, as recent clinical findings and experimental results have provided evidence that continuous active control of this pathway is necessary to prevent unintended targeting and injury to self tissues.

show abstract

Section: Unanswered Questions and Future Directionsmentioning

confidence: 99%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

The Journal of Immunology

Self Cite

389

350

View full text Add to dashboard Cite

show abstract

“…It will aid the development of a diagnostic immunoassay and allow speciation of the autoantibodies. This will allow rational therapy with anti-B cell therapy in those cases with high titers of circulating antibodies (115) and targeted application of complement inhibitors and regulators (55,113,133,146) in those cases with antibodies belonging to a complement-fixing subclass (IgG1 or IgG3).…”

Section: Implications For Human Mnmentioning

confidence: 99%

Experimental membranous nephropathy redux

Cybulsky

Quigg²,

Salant³

2005

American Journal of Physiology-Renal Physiology

115

133

View full text Add to dashboard Cite

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Active and passive Heymann nephritis (HN) in rats are valuable experimental models because their features so closely resemble human MN. In HN, subepithelial immune deposits form in situ as a result of circulating antibodies. Complement activation leads to assembly of C5b-9 on glomerular epithelial cell (GEC) plasma membranes and is essential for sublethal GEC injury and the onset of proteinuria. This review revisits HN and focuses on areas of substantial progress in recent years. The response of the GEC to sublethal C5b-9 attack is not simply due to disruption of the plasma membrane but is due to the activation of specific signaling pathways. These include activation of protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress proteins, proteinases, and others. Ultimately, these signals impact on cell metabolic pathways and the structure/function of lipids and key proteins in the cytoskeleton and slit-diaphragm. Some signals affect GEC adversely. Thus C5b-9 induces partial dissolution of the actin cytoskeleton. There is a decline in nephrin expression, reduction in F-actin-bound nephrin, and loss of slit-diaphragm integrity. Other signals, such as endoplasmic reticulum stress, may limit complement-induced injury, or promote recovery. The extent of complement activation and GEC injury is dependent, in part, on complement-regulatory proteins, which act at early or late steps within the complement cascade. Identification of key steps in complement activation, the cellular signaling pathways, and the targets will facilitate therapeutic intervention in reversing GEC injury in human MN.

show abstract

“…To investigate C3 and MAC deposition, frozen kidney sections were stained with anti-rat C3 or anti-rat C9 antiserum together with appropriate FITC-labeled secondary Abs as described (21). The binding of targeted complement inhibitors in the kidney was similarly analyzed using rabbit antiserum raised against K9/9 scFv.…”

Section: Immunofluorescence Microscopymentioning

confidence: 99%

Complement Inhibitors Targeted to the Proximal Tubule Prevent Injury in Experimental Nephrotic Syndrome and Demonstrate a Key Role for C5b-9

Imai

Song

et al. 2005

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

In glomerular diseases of diverse etiologies, dysfunction of the glomerular barrier to protein passage results in proteinuria, and proteinuria is considered an independent risk factor that plays a direct role in inflammation, interstitial fibrosis, and renal failure. The mechanism by which proteinuria leads to nephrotoxic injury is unclear, but a role for complement in mediating interstitial damage appears likely. We describe a strategy for Ag-specific targeting of complement inhibitors using a single chain Ab fragment and show that complement inhibitors targeted to the tubular epithelium protect against tubulointerstitial injury and renal dysfunction in a rat model of puromycin-induced nephrosis. The targeting of systemically administered complement inhibitors markedly enhanced their efficacy and obviated the need to systemically inhibit complement, thus reducing the risk of compromising host defense and immune homeostasis. Targeted inhibition of complement activation by Crry, and of membrane attack complex (MAC) formation by CD59 was equally therapeutic, demonstrating that the MAC plays a key role in proteinuria-induced tubulointerstitial injury. CD59 activity was dependent on its being targeted to the site of complement activation, and this is the first report of specific inhibition of the MAC in vivo after systemic administration of inhibitor. The data establish the MAC is a valid target for pharmaceutical intervention in proteinuric disorders and provide an approach to investigate the role of the MAC in complement-dependent disease under clinically relevant conditions.

show abstract

Complement receptor 2–mediated targeting of complement inhibitors to sites of complement activation

Cited by 98 publications

References 52 publications

The Central Role of the Alternative Complement Pathway in Human Disease

The Central Role of the Alternative Complement Pathway in Human Disease

Experimental membranous nephropathy redux

Complement Inhibitors Targeted to the Proximal Tubule Prevent Injury in Experimental Nephrotic Syndrome and Demonstrate a Key Role for C5b-9

Contact Info

Product

Resources

About