The low-throughput protein A adsorber: an immune modulatory device. Hypothesis for the mechanism of action in the treatment of rheumatoid arthritis

Brunner, Jürgen; Kern, Peter; Gaipl, Udo S.; Muñoz, Luis; Voll, Reinhard; Kalden, Joachim R.; Wiesenhutter, Craig W.; Herrmann, Martin

doi:10.1007/s10165-004-0366-6

Cited by 8 publications

(6 citation statements)

References 67 publications

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“…There has been longstanding controversy over the mechanism of action and unpredictable efficacy of the therapy for inflammatory and autoimmune diseases. Several hypotheses have been proposed, including removal of immunoglobulin and/or ICs, modification of small circulating ICs, and B cell depletion (40). A salient finding was that during each treatment, SPA could be proteolytically cleaved and enter the patient's circulation (41).…”

Section: Discussionmentioning

confidence: 99%

Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice

MacLellan¹,

Montgomery²,

Sugiyama³

et al. 2011

Arthritis & Rheumatism

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Objective Cells of the monocytic lineage play fundamental roles in the regulation of health, ranging from the initiation and resolution of inflammation to bone homeostasis. In rheumatoid arthritis (RA), the inflamed synovium exhibits characteristic infiltration of macrophages along with local osteoclast maturation, which, together, drive chronic inflammation and downstream articular destruction. The aim of this study was to explore an entirely novel route of immunoglobulin-mediated regulation, involving simultaneous suppression of the inflammatory and erosive processes in the synovium. Methods Using in vivo and in vitro studies of human cells and a murine model of RA, the ability of staphylococcal protein A (SPA) to interact with and modulate cells of the monocytic lineage was tested. In addition, the efficacy of SPA as a therapeutic agent was evaluated in murine collagen-induced arthritis (CIA). Results SPA showed a capacity to appropriate circulating IgG, by generating small immunoglobulin complexes that interacted with monocytes, macrophages, and preosteoclasts. Formation of these complexes resulted in Fcγ receptor type I–dependent polarization of macrophages to a regulatory phenotype, rendering them unresponsive to activators such as interferon-γ. The antiinflammatory complexes also had the capacity to directly inhibit differentiation of preosteoclasts into osteoclasts in humans. Moreover, administration of SPA in the early stages of disease substantially alleviated the clinical and histologic erosive features of CIA in mice. Conclusion These findings demonstrate the overarching utility of immunoglobulin complexes for the prevention and treatment of inflammatory diseases. The results shed light on the interface between immunoglobulin complex–mediated pathways, osteoclastogenesis, and associated pathologic processes. Thus, therapeutic agents designed to harness all of these properties may be an effective treatment for arthritis, by targeting both the innate inflammatory response and prodestructive pathways.

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Section: Discussionmentioning

confidence: 99%

Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice

MacLellan¹,

Montgomery²,

Sugiyama³

et al. 2011

Arthritis & Rheumatism

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“…A modification of auto‐antibodies and immune complexes by Prosorba column treatment has been suggested. Humoral and cellular changes observed in the course of the Prosorba ® treatment are supposed to result from conversion of small tissue penetrating non‐complement‐binding, proinflammatory IgG rheumatoid factor‐based immune complexes into the more readily phagocytosed intermediate‐sized, non‐tissue penetrating immune complexes that are opsonized with complement and which are rather short‐lived 40. Our results strongly suggest that complement activation was induced during Prosorba ® therapy.…”

Section: Discussionmentioning

confidence: 56%

MS characterization of apheresis samples from rheumatoid arthritis patients for the improvement of immunoadsorption therapy – a pilot study

Kienbaum

Koy

Montgomery

et al. 2009

Proteomics Clinical Apps

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Identification of proteins from apheresis samples was performed by both SDS-PAGE and 2-D gel separation of eluted proteins from staphylococcal protein A-based immunoadsorption columns (Prosorba(®) ) followed by MS peptide mass fingerprinting and MS/MS peptide sequencing on a MALDI QIT TOF mass spectrometer. MS/MS peptide sequencing was performed in conjunction with a micro reversed phase HPLC configured with an online MALDI plate-spotting device. Apheresis treatment had been performed in three patients with longstanding therapy refractory rheumatoid arthritis. 2-D gels displayed ca. 500 spots representing proteins that were eluted from the Prosorba(®) columns. From 54 gels, a total of 1256 protein spots had been picked and yielded in the identification of 56 non-redundant proteins without counting isoforms. Proteins from the eluates belong to five major groups comprising (i) immunoglobulins (IgG, IgA, IgM heavy and light chains; about 40% of the spots), (ii) proteins involved in coagulation, (iii) HDL/LDL-associated proteins, (iv) proteins from the complement system, and (v) acute phase proteins. MS analysis showed that the full-length C3 complement protein had been cleaved upon complement activation, presumably on the column, such that the anaphylatoxin C3a was produced and released during therapy. Our results are consistent with clinical observations on both patient responses to therapy and reported adverse events. For the first time, direct molecular information has become available to support mechanistic reasoning for the principle of function of staphylococcal protein A-based immunoadsorption therapy and for the explanation of adverse events. According to our results, removal and/or modulation of immune complexes together with complement activation can be regarded as the major events that are taking place during Prosorba(®) therapy. In order to avoid complement activation and induction of an inflammatory cascade, we suggest the prevention of C3a anaphylatoxin-related reactions during immunoadsorption therapy.

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“…Protein A also has therapeutic utility, but its toxicity and cost limit its use. Nonetheless, a protein A column from Cypress was approved by the U.S. FDA for the treatment of autoimmune diseases: immune thrombocytopenic purpura in 1987 and severe rheumatoid arthritis in 1999 . This treatment requires the use of protein A covalently linked to a silica matrix whereby the patient’s blood is passed through an external device in a manner similar to kidney dialysis (apheresis).…”

Section: Introductionmentioning

confidence: 99%

2,4,6-Trisubstituted Triazines as Protein A Mimetics for the Treatment of Autoimmune Diseases

et al. 2010

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A first-in-class series of low molecular weight trisubstituted triazines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure-activity relationship (SAR) demonstrates that the 1,3-phenylenediamine component was essential for robust activity. Twenty-two compounds, represented by lead molecule 34, displayed significant activity compared to protein A. These compounds may prove useful for the treatment of autoimmune disease.

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The low-throughput protein A adsorber: an immune modulatory device. Hypothesis for the mechanism of action in the treatment of rheumatoid arthritis

Cited by 8 publications

References 67 publications

Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice

Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice

MS characterization of apheresis samples from rheumatoid arthritis patients for the improvement of immunoadsorption therapy – a pilot study

2,4,6-Trisubstituted Triazines as Protein A Mimetics for the Treatment of Autoimmune Diseases

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