Background and Indications for Protein A-Based Extracorporeal Immunoadsorption

Background and Indications for Protein A-BasedExtracorporeal Immunoadsorption

*Goran Matic, †Thomas Bosch, and ‡Wolfgang Ramlow

*Labor Muller, Rostock; †Nephrology Division, Klinikum Grosshadern, University of Munich, Munich; and‡Dialysegemeinschaft Nord e.V., Rostock, Germany

Abstract: Protein A (SPA), a major cell wall componentof Staphylococcus aureus, has occupied numerous investi-gators from its discovery in the late fifties. Its availabilityand avid binding to human immunoglobulins have led toextensive usage for diagnostic and research purposes. To-day, SPA-based extracorporeal immunoadsorption relieson two rather different systems, namely, SPA-silica (Pro-sorba), and SPA-Sepharose (Immunosorba). Both systemsare approved by the Food and Drug Administration forthe core indications of rheumatoid arthritis and idiopathicthrombocytopenic purpura (SPA-silica) or hemophiliawith inhibitors (SPA-Sepharose). Off label indications in-

clude immune disorders with a conceivable connection be-tween autoantibody titers and disease activity, like formsof glomerulonephritis, systemic lupus erythematodes, my-asthenia, and the Guillain-Barre syndrome as well as al-loantibody formation in the context of e.g., transplanta-tion. This review summarizes historical developments andimportant properties of SPA. Indications for extra-corporeal therapy are discussed on the basis of availableinformation and personal experience. Key Words: Apher-esis—Plasmapheresis—Prosorba—Immunosorba—Immunomodulation—Plasma exchange—Protein A-immunoadsorption.

Protein A (SPA) from Staphylococcus aureus be-longs to the most thoroughly investigated bacterialvirulence factors. It is now well established that SpAis a potent biological response modifier showingmultiple immunocyte-stimulating and cytokine-inducing effects besides its well known ability to bindto immunoglobulins (1–7). Due to its properties invitro, when chemically crosslinked to agarose beads(Sepharose), it has been a popular means for extrac-tion of immunoglobulins.

STRUCTURE

More than 40 years ago, the Danish ScientistKlaus Jensen studied a cell wall component of staph-ylococci which could be found in the majority of S.aureus isolates. He named it Antigen A and demon-strated, as a first interpretation, antibodies against itin all human sera examined (8). Later investigationsshowed that Antigen A was a protein, and the namewas changed to Protein A. Also, the discovered pro-

tein reacted with the constant rather than with thecomplementary regions of antibodies, and therefore,the reactivity of sera had not indicated immunization(9,10). SpA was found to bind more than one immu-noglobulin demonstrating that it contained two ormore identical or similar structures (11). It is knowntoday that the intact protein is a single polypeptidechain with a cell wall binding structure and five do-mains each approximately 7 kd named C, B, A, D,and E starting from the cell wall (Fig. 1) (5,7,12). Theapparent molecular weight ranges from 27 kd whenremoved enzymatically from the cell wall to 42 kdwhen produced by secreting bacteria. The SPA genewas sequenced and cloned which confirmed the pe-riodicity of the gene product (5,12).

BUNDLED VERSATILITY

Details of the molecular interaction of SPA withimmunoglobulin are fairly well understood, and theconventional binding site on the Fc� fragment in-volving residues in the CH2-CH3 elbow region ofIgG 1, 2, and 4, and IgG 3 bearing the Gm3(s+)allotype has been well characterized (6,7,13,14).

Received June 2001.Address correspondence and reprint requests to Dr. Wolfgang

Ramlow, Dialysegemeinschaft Nord e.V., Nobelstr. 53, 18059Rostock, Germany. E-mail: [email protected]

Therapeutic Apheresis5(5):394–403, Blackwell Science, Inc.©2001 International Society for Apheresis

394

An alternative binding site exists on the Fab do-mains of a proportion of immunoglobulins encodedby the variable region heavy chain (VH) clan IIIgene family (6,13,14). This V region framework sur-face has been highly conserved during the evolutionof the adaptive immune system. Binding sites weretracked down to the framework regions 1 and 2 andthe complementarity determining region 2 (14).

SPA is known as B-cell superantigen due to itsability to stimulate 30–60% of the peripheral B-cellpopulation that carry V(H) III encoded immuno-globulins as receptors on their cell surface (1,2). Thefunction of these receptors mediating specific inter-action with prospective antigens is bypassed, andthey are crosslinked outside their complementaritydetermining regions leading to an intracellular signalthat may be comparable to the one that is generatedby true antigen contact (6). Interestingly, SPA bind-ing to VH III regions largely competes with the hu-man sialoprotein pFv that is involved in gut-associated immunity (3). It also shares its B-cellsuperantigen characteristics with staphylococcal en-terotoxin B and protein L (a coat protein of Pepto-streptococcus magnus) (3).

Despite the well-acknowledged Fc-mediated in-teraction with IgG, the VH III mediated cell inter-actions may be more important concerning the im-munomodulatory potence of SPA. SPA fragmentsdevoid of Fc-binding activity induce clonal deletionof VH III carrying B lymphocytes that is directlydependent on the avidity and affinity of the SPApreparation used (2). Also, interaction of SPA abro-gated of its IgG Fc-binding activity with VH III en-coded immunoglobulin M (IgM) leads to comple-ment activation and subsequent generation ofbiologically highly active complement split productsfollowed by an Arthus-like reaction (3). On theother hand, a minimized tryptic fragment of SPAretaining the Fc-binding property induced immuno-cyte proliferation and evoked a Th1-type immune

response in mice (15). Recently discovered, SPAconfers interaction of S. aureus with soluble and im-mobilized von Willebrand factor (16).

CONTAMINATION OF SPA PREPARATIONS

Typically, SPA has been isolated from S. aureuscultures by proteolytic cleavage from the bacterialcell wall. Culture supernatant from strains secretingSPA has also been employed (17). Thus, dependingon strains, culture conditions, and purification pro-cedures, SPA preparations have been contaminatedto varying degrees (17). Notably, heat-inactivatedand formaldehyde-fixed whole bacteria have alsobeen utilized in experimental settings (17).

It is difficult to resolve whether and which of thenumerous findings that had been linked to SPA wererather attributable to contaminants. For example,some SPA preparations contained traceableamounts of enterotoxins known as T-cell superanti-gens (18–20). These observations have to be consid-ered in the case of direct application of SPA as wellas for plasma adsorption. It was demonstrated byseveral investigators that leaching of substances oc-curs upon plasma perfusion over immobilized SPA(21–25). With the use of recombinant SPA or highlypurified SPA fragments, contamination seems lesslikely (2,3,26).

THERAPY OF MALIGNANCIES

In 1978, a tumoricidal effect was presented in apatient with colon carcinoma after plasma perfusionover heat inactivated and formaldehyde-fixed S. au-reus Cowan I immobilized in a microporous filtra-tion system (27). The therapeutic success was attrib-uted to the predominant cell wall constituent SPA,and the finding stimulated first encouraging trials ofcancer therapy in animals and in humans. Tumornecrosis was often seen as well as remissions in ma-lignancies resistant to conventional treatment(17,28–33). Studies focused on canine and humanbreast adenocarcinoma, human colon carcinoma,and malignancies induced by the exogenous felineleukemia retroviruses (28,30). Results were astonish-ing especially in feline leukemia virus infection withcomplete virus elimination and remission of virus-induced malignancies after direct treatment withsoluble SPA or plasma perfusion over immobilizedSPA (34,35).

Unfortunately, the plasma treatment proceduresand the SPA preparations were extremely heterog-enous and rendered the interpretation of the resultsmore difficult (17,30,31). For plasma perfusion, SPAwas immobilized to collodion charcoal, agarose

FIG. 1. Schematic representation is shown of cell wall-bound pro-tein A and its periodicity (adapted from [1]).

PROTEIN A-BASED IMMUNOADSORPTION 395

Ther Apher, Vol. 5, No. 5, 2001

beads, a cellulose zetachrome matrix, polyacryl-amide coated glass beads, or silica (17,28,30,31). Insome cases, whole inactivated bacteria were incu-bated with autologous plasma followed by centrifu-gation. Processed plasma volumes had ranged fromonly a few milliliters to the total calculated plasmavolume, and the extracorporeal circulation com-prised a regular continuous-flow plasma separationfollowed by adsorption, or plasma was perfused off-line over immobilized SPA (17,28,30,31).

The modes of action were controversely discussed,and elimination of circulating immune complexes aswell as immune stimulation by bacterial toxins wereconsidered (28,30). Finally, the first enthusiasmcould not be supported by further controlled clinicaltrials, and SPA-based cancer therapy has not gainedwide acceptance (28,31). However, two of the prod-ucts introduced at that time entered successful clini-cal trials outside oncology.

CLINICAL APPLICATION

One protein, two systemsThe widely available current systems are based

on SPA coupled to agarose beads (Sepharose)(Immunosorba, Fresenius Hemocare, St. Wendel,Saarland, Germany) or to silica (Prosorba, FreseniusHemocare, Redmont, CA, U.S.A.). A major featureof the Immunosorba system is its almost unlimitedadsorption capacity (36–41). Two columns are in-stalled in parallel, one is perfused with plasma whilethe other is regenerated, leading to the theoreticalpossibility of treating an unlimited plasma volume(Figs. 2 and 3). The columns are preserved in be-tween the therapeutic sessions and can be good, de-spite recognizable aging, for more than 20 extracor-poreal sessions (data from Rostock). Regenerationof columns during on-line plasma perfusion requirestechnical equipment with added safety features toassure no harmful regeneration fluid is infused andloss of plasma is kept minimal. The concept includesa built-in plasma detector and a pH-electrode in thecircuit from the columns back to the patient. Theyare adjustable by the operator, help to limit plasmaloss, and add to the safety of the system (39).

In practice, within the course of a session, effi-ciency declines with increasing processed plasmavolume because of rapid elimination of intravascularimmunoglobulins and consecutive gradient forma-tion between the extravascular and the plasma com-partment. Every column switch leads to some plasmadilution and a certain amount of plasma proteins arelost (39). Despite these considerations, in clinical

situations (like hemophilia with factor VII inhibi-tors), where rapid and close to total (auto)antibodyremoval is desirable, Immunosorba treatment seemsto be clearly advantageous over plasma exchange(37,38,42).

Contrary to the double column system,Prosorba is configured for the treatment of maxi-mally 2,000 ml of plasma, and the columns are dis-posed after each session (Figs. 2 and 3) (43,44). On-line plasma separation is achieved by a continuousflow centrifuge, and treatment duration usuallydoes not exceed 2 h (43). Somewhat intriguing,the side effects of Prosorba are different from Im-munosorba, and with Prosorba, neither the pro-cessed plasma volume nor the length of intervals be-tween sessions permits substantial removal ofimmunoglobulins or circulating immune complexes(39,44–51). Prosorba therapy is therefore often la-beled as immunomodulation, and the mode of actionis not yet clearly understood (52–54). On the otherhand, while the antibody eliminating capacity of Im-munosorba seems to underline its mode of action,our investigations suggest that intracytoplasmicType I and Type II T-cell cytokine production can bealtered upon immunoadsorption with double column

FIG. 2. Shown is a flow chart of the Prosorba (A) and the Im-munosorba (B) systems. On-line column regeneration with Im-munosorba requires added safety features.

G. MATIC ET AL.396


systems. Thus to date, an unknown immunomodula-tory pathway may also be operative with Immuno-sorba (55).

Rheumatoid arthritisRheumatoid arthritis belongs to the autoimmune

diseases with the highest prevalence rates, and pa-tients with high process activity resistant to conven-tional medication pose a heavy economic burden,besides suffering from a crippling disorder. Althougha number of novelties, e.g., tumor necrosis factoralpha inhibitors, will further reduce the number ofpatients not responding to therapeutic intervention,there is a demand for effective strategies with a well-balanced rate of side effects (43,56,57).

The Prosorba system was recently approved by

the Food and Drug Administration (FDA) in theUnited States for the treatment of rheumatoid ar-thritis resistant to conventional therapy with disease-modifying antirheumatic drugs including methotrex-ate. The decision was based on a pilot study and aunique prospective, controlled, and double-blindedclinical study which fulfilled the American Collegeof Rheumatology (ACR) 20 criteria and was close toACR 50 (43,56,57). The clinical application outsidestudy protocols will further show where to place Pro-sorba among existing therapies.

At Rostock, the first rheumatoid arthritis patiententered Immunosorba immunoadsorption in 1994.The 19 patients that have been treated since thenall represent desperate, drug resistant casesof rheumatoid arthritis. The achieved responsesare similar to the treatment arms within theProsorba trials, but the results are uncontrolled andretrospectively derived.

Idiopathic thrombocytopenic purpuraIdiopathic thrombocytopenic purpura (ITP) is the

most common of the immune-mediated cytopenias.Clinical diagnosis is based on the triad of decreasednumbers of circulating platelets, normal to increasedbone marrow megakaryocytes, and absence ofagents or disease known to induce thrombocytope-nia (58). Autoantibodies against platelet surfacemembrane glycoproteins can be typically demon-strated. Standard therapy with corticosteroids orsplenectomy produces a permanent remission in upto 80%, but chances decrease with the increasing ageof the patients (58). Acute thrombopenic situationsare mostly managed by high doses of intravenouslyadministered immunoglobulin (IVIG).

Prosorba was approved by the FDA for treatmentof ITP not responding to conventional therapy (58).The major analysis in this respect cites 72 treatedpatients with platelet counts below 50,000 �l (44).Eighteen patients responded to Prosorba therapywith platelet counts >100,000 and 15 with counts be-tween 50,000 and 100,000 �l (44). The mode of ac-tion has been discussed, and the treatment has yet tofind widespread application (52). A clear positionamong the available therapies has not been estab-lished, but Prosorba remains an interesting alterna-tive (58).

Immunosorba treatment has also been applied indifficult ITP cases (36). At the Rostock center, 1patient with malignant ITP (platelet counts withouttherapeutic intervention <1,000 �l) had been suc-cessfully treated with 2 extracorporeal antibodyeliminating sessions per week for more than 2 years.At the beginning, splenectomy had been omitted be-

FIG. 3. Shown is an illustration of the IgG-elimination capa-bilities of Immunosorba (A), Prosorba (B), and Immusorba (C)(also known as TR 350, an adsorber based on tryptophanecoupled to polyvinyl ethanol, Asahi Medical Co. Ltd., Tokyo,Japan). Datas from 1 patient who has been consecutively treatedat Rostock with each of the systems within a time frame of 4 years.Processed plasma volumes per session were up to 9 I (A), 1.25 I(B), and 2 I (C). X-axis indicates day of treatment within a seriesof homologous sessions.



cause of severe heart insufficiency. After two yearsof extracorporeal therapy, it was initiated during anepisode of elevated platelet counts induced by acombination therapy including apheresis, IVIG, andcytotoxic drugs. The life threatening situation wasresolved, and the patient was acceptably stabilizedwith weekly IVIG at platelet counts >10,000 �l (59).

HemophiliaHereditary hemophilia is a bleeding disorder with

clinical consequences depending on the residual ac-tivity of the deficient coagulation factors VIII (TypeA) or IX (Type B) (42,60,61). Factor concentratesare substituted prophylactically or on demand atbleedings. Substitution becomes difficult when pa-tients develop (allo)antibodies with neutralizing ac-tivity against the coagulation factors, known as in-hibitors (42,62). Low inhibitor titers can beovercome by relatively higher doses of factor con-centrate, a procedure that is limited, and its successdepends on the inhibitor titer. Because the inhibitorsare immunoglobulins, they can be readily eliminatedby extracorporeal SPA-based immunoadsorption(42,62).

As a consequence of missing alternativetherapies and life-saving clinical application,Immunosorba was approved for the treatment of he-mophiliacs with inhibitors by the FDA (62–65).Moreover, hemophilia represents the only indicationin which the unpleasant discussion about cost effi-ciency results in a clear advantage for immunoad-sorption versus excess administration of factor con-centrates.

One further step beyond management of theacutely bleeding patient is tolerance induction. Ac-cording to published treatment protocols from Mal-moe, Sweden, extracorporeal elimination of inhibi-tors followed by the administration of the cytotoxicdrug cyclophosphamide leads to longer lasting sup-pression of the corresponding B-cell clones inroughly half of the cases (36,64).

Acquired hemophilia is a rare disease of autoim-mune origin. Clinically, it resembles the hereditaryform with potentially life-threatening bleedingcomplications, and autoantibodies with inhibitoractivity can be eliminated regularly by intensiveImmunosorba treatment (65,66).

Glomerulonephritis and vasculitisVarious forms of vasculitic disorders, often pre-

senting with disease related antineutrophil cytoplas-mic antibodies or Goodpasture’s syndrome, havebeen natural targets in a number of clinical studieswith Immunosorba because of the conceivable con-nection between autoantibody titers and activity of

the disease. Most of the recruited patients were in acritical condition often presenting with rapidly pro-gressive glomerulonephritis close to, or on, dialysis(41,67–72).

A recently published controlled and prospectiveSwedish study randomized Immunosorba andplasma exchange (72). The multicenter study couldnot confirm a difference in the outcome betweenImmunosorba therapy and plasma exchange in cres-centic rapidly progressive glomerulonephritis and inGoodpasture’s syndrome. It is important to note,however, that more patients came off dialysis whentreated with Immunosorba. Complex in detail, theresults of the Swedish study are not surprising, re-membering that the beneficial clinical effects ofplasma exchange added to standard drug regimesonly appeared in a meta-analysis of studies that bythemselves could not prove a positive effect ofplasma exchange (69,72). Our own limited data sup-port the beneficial effects of Immunosorba treat-ment early in the course of Wegener’s granulomato-sis (70).

In Goodpasture’s syndrome, an imminent prob-lem in the management of the disease is the earlyestablishment of the diagnosis that has to be fol-lowed by an immediate elimination of the anti-collagen Type IV autoantibody. The considerationthat Immunosorba has some technical advantagesover plasma exchange may be of minor relevance(69,70). One has to keep in mind that the antibody-mediated damage at the glomerulus is irreversiblyestablished in the course of the disease, and quickantibody removal can only be achieved by extracor-poreal circulation.

An interesting, yet unresolved indication forImmunosorba therapy is focal segmental glomerulo-sclerosis. In these patients, proteinuria is probablyreduced by the elimination of a factor that is capableof increasing glomerular permeability to albuminand seems to be associated to immunoglobulins(67,68,73,74). Immunosorba treatment has also beenshown to reduce proteinuria in a number of (auto-immune) disease entities accompanied by changes inglomerular integrity; however, data is not sufficientfor substantial recommendations (68,70,71).

Thrombotic thrombocytopenic purpura/hemolyticuremic syndrome

The variable presentation, unpredictable clinicalcourse, and clinical responsiveness to agents with ob-scure mechanisms of action suggest that the syn-drome of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) represents

G. MATIC ET AL.398


a common reaction to a variety of provocative agents(75). The recent discovery of a defective metallopro-teinase that cleaves Willebrand factor multimerssheds more light onto this disease entity and fits wellinto the concept of the established therapy regimenapplying plasma exchange against fresh frozen orcryodepleted plasma (76–78). Despite several publi-cations suggesting either Prosorba or Immunosorbaas possible options, considering the establishedtherapeutic efficiency of plasma exchange, an appli-cation of extracorporeal immunoadsorption in thesetting of TTP/HUS is problematic outside of clinicalstudies (75,79–82). However, in TTP/HUS formspresenting with e.g., autoantibodies against endothe-lial cells, SPA-based immunoadsorption might bewell applicable. Presently, a conservative approachsuggests only TTP/HUS patients not responding toplasma exchange or plasma infusion should betreated by SPA-based immunoadsorption (80,83).

Systemic lupus erythematodesSystemic lupus erythematodes is a model disease

for disturbances of the immune system accompaniedby intravascular complement consumption. It was of-ten cited as a typical disorder mediated by circulatingimmune complexes (CIC), and a favorable role forplasmapheresis had been expected (41). Solubilizedimmune complexes ideally diffuse away from theirsite of formation, bind to erythrocytes, and are trans-ported to the mononuclear phagocyte system in theliver or spleen where they are taken up by cleavageof their receptor (CR1/CD35). As long as the systemis in equilibrium, deposition of CIC in tissues fol-lowed by destructive inflammatory reaction does nottake place (41). However, as soon as one of the com-ponents fails, e.g., complement factor levels or num-bers of CR1 decrease, the function of the mono-nuclear phagocyte system is impaired, or simply toomany CIC are formed, spill-over takes place, andunbound CIC precipitate in target tissues, e.g., leadto glomerulonephritis (41).

SPA binds very avidly to immunoglobulins thatare clustered within CIC (84). Treating large plasmavolumes, the Immunosorba system allows for com-plete elimination of CIC within a few extracorporealsessions possibly ameliorating the inflammatory pro-cess (41,85,86). The activity-related antibodiesagainst double-stranded DNA are also reduced tonormal. Unfortunately, from the clinical studies thathave been as yet conducted, one cannot clearly con-clude at which stage of the disease and how oftenImmunosorba treatment should be applied(41,68,69,71,72,85,86). Considering the literature,our experience, personal communications, the seri-

ous threat to the patient, and the minor side effectsof the extracorporeal treatment, lupus nephritisnot responding to cytotoxic medication is an overtindication for Immunosorba treatment (41,71,85,86).

As a general recommendation derived from thework of Braun et al. and personal assessment, im-munoadsorption should be conducted very aggres-sively in terms of treated plasma volume and fre-quency. It may be individually supported bycytotoxic or immunosuppressive drugs and should befollowed by prophylactic intravenous immunoglobu-lin (0.2–0.3 g/kg body weight) after completing theextracorporeal sessions leading to maximal deple-tion of autoantibodies and CIC (85,86).

Myasthenia and the Guillain-Barre syndromeThe Guillain-Barre syndrome, or acute exacerba-

tions of myasthenia gravis are standard indicationsfor IVIG administration and/or plasma exchange. Inthese diseases with a physiopathology that relates toautoantibodies against structures of the nervous sys-tem or the muscular end plate, Immunosorba treat-ment has also been applied successfully (87–91). Itis, however, not conceivable where to placeImmunosorba among alternative treatment possibili-ties. It may have certain advantages when patientsare treated chronically, and the possible reuse of col-umns generates advantages in costs, or when anti-body removal has to be achieved very rapidly (87–92). Mentionable in this context is the successfulapplication of off-line plasma perfusion over Pro-sorba columns in paraneoplastic neurologic syn-dromes (93–95).

Remaining possible indicationsTraditionally, SPA-mediated immunoadsorption

has been applied as a last resort treatment in dis-eases not responding to conventional treatment andphysiopathology related to autoantibodies (36).Concerning the overall capability of autoantibodyelimination, Immunosorba represents the system ofchoice in autoimmune diseases with a close connec-tion between auto- or alloantibody specifity, serumtiters, and disease activity. It has been applied incases of hemolytic anemia, Glanzmann’s disease (al-loantibodies against platelet surface glycoproteins),and alloimmunized patients after platelet transfusion(36,96–98). Another substantial indication docu-mented by a number of publications is the removalof antibodies against human leukocyte antigens inthe context of transplantation (96,99–101).

From the limited number of prospectiveclinical trials that have been conducted withImmunosorba, it is difficult to draw precise conclu-sions. The debate on cost-efficiency cannot be easily



resolved. Nevertheless, with Immunosorba and pe-ripheral venous access, the rate of serious adverseevents is <1% (data from Rostock derived from>1,000 double column apheresis sessions). Thus,given an antibody-mediated disease, a considerablechance of success is usually combined with a minorrisk for the patient. With Prosorba, presently avail-able, clinical data do not suggest regular use outsidethe approved indications for rheumatoid arthritisand ITP.

CONCLUSIONS

The number of SPA-based extracorporeal immu-noadsorption therapies performed worldwide willprobably increase, and in certain disease entities,also increasingly replace plasma exchange. Furthertechnical development of the SPA-based systems in-cluding intelligent membrane concepts may lead toproducts with substantial advantages. We also expectan increasing employment in clinical studies that willhelp to clarify the position of SPA-based immuno-adsorption and further improve the situation for theclinician.

REFERENCES

1. Levinson AI, Kozlowski L, Zheng Y, Wheatley L. B-cellsuperantigens: definition and potential impact on the im-mune response. J Clin Immunol 1995;15:26S–36S.

2. Silverman GJ, Cary SP, Dwyer DC, Luo L, Wagenknecht R,Curtiss VE. A B cell superantigen-induced persistent “Hole”in the B-1 repertoire. J Exp Med 2000;192:87–98.

3. Kozlowski LM, Li W, Goldschmidt M, Levinson AI. In vivoinflammatory response to a prototypic B cell superantigen:elicitation of an Arthus reaction by staphylococcal proteinA. J Immunol 1998;160:5246–52.

4. Catalona WJ, Ratliff TL, McCool RE. Gamma-Interferoninduced by S. aureus protein A augments natural killing andADCC. Nature 1981;291:77–9.

5. Lofdahl S, Guss B, Uhlen M, Philipson L, Lindberg M. Genefor staphylococcal protein. A. Proc Natl Acad Sci USA 1983;80:697–701.

6. Graille M, Stura EA, Corper AL, Sutton BJ, Taussig MJ,Charbonnier JB, Silverman GJ. Crystal structure of a Staph-ylococcus aureus protein A domain complexed with the Fabfragment of a human IgM antibody: structural basis for rec-ognition of B-cell receptors and superantigen activity. ProcNatl Acad Sci USA 2000;97:5399–404.

7. Alonso DO, Daggett V. Staphylococcal protein A: unfoldingpathways, unfolded states, and differences between the Band E domains. Proc Natl Acad Sci USA 2000;97:133–8.

8. Jensen K. Acta Allerg 1959;13:89–100.9. Forsgren A, Sjoquist J. “Protein A” from S. aureus I. Pseudo-

immune reaction with human gamma-globulin. J Immunol1966;97:822–7.

10. Lofquist T, Sjoquist J. Int Archs Allergy ApII Immunol 1963;23:289–305.

11. Forsgren A, Sjoquist J. “Protein A” from Staphylococcusaureus 3. Reaction with rabbit gamma-globulin. J Immunol1967;99:19–24.

12. Uhlen M, Guss B, Nilsson B, Gatenbeck S, Philipson L,Lindberg M. Complete sequence of the staphylococcal gene

encoding protein A. A gene evolved through multiple dupli-cations. J Biol Chem 1984;259:1695–702.

13. Ljungberg UK, Jansson B, Niss U, Nilsson R, Sandberg BE,Nilsson B. The interaction between different domains ofstaphylococcal protein A and human polyclonal IgG, IgA,IgM and F(ab�)2: separation of affinity from specificity. MolImmunol 1993;30:1279–85.

14. Potter KN, Li Y, Mageed RA, Jefferis R, Capra JD. Anti-idiotypic antibody D12 and superantigen SPA both interactwith human VH3-encoded antibodies on the external face ofthe heavy chain involving FR1, CDR2 and FR3. Mol Immu-nol 1998;35:1179–87.

15. Sinha P, Ghosh AK, Das T, Sa G, Ray PK. Protein A ofStaphylococcus aureus evokes Th1 type response in mice.Immunol Lett 1999;67:157–65.

16. Hartleib J, Kohler N, Dickinson RB, Chhatwal GS, Sixma JJ,Hartford OM, Foster TJ, Peters G, Kehrel BE, HerrmannM. Protein A is the von Willebrand factor binding protein onStaphylococcus aureus. Blood 2000;96:2149–56.

17. Terman DS. Protein A and staphylococcal products in neo-plastic disease. Crit Rev Oncol Hematol 1985;4:103–24.

18. Balint J Jr, Totorica C, Stewart J, Cochran S. Detection,isolation and characterization of staphylococcal enterotoxinB in protein A preparations purified by immunoglobulin Gaffinity chromatography. J Immunol Methods 1989;116:37–43.

19. Schrezenmeier H, Fleischer B. Mitogenic activity of staphy-lococcal protein A is due to contaminating staphylococcalenterotoxins. J Immunol Methods 1987;105:133–7.

20. Das C, Langone JJ. Dissociation between murine spleen cellmitogenic activity of enterotoxin contaminants and anti-tumor activity of staphylococcal protein A. J Immunol 1989;142:2943–8.

21. Balint J Jr, Jones FR. Perfusion of canine serum over Staph-ylococcus aureus Cowan 1: Evidence for release of protein Aand changes in specific antibody activity. Immunol Commun1983;12:573–91.

22. Balint J Jr, Ikeda Y, Langone JJ, Shearer WT, Daskal I,Meek K, Cook G, Henry J, Terman DS. Tumoricidal re-sponse following perfusion over immobilized protein A:identification of immunoglobulin oligomers in serum afterperfusion and their partial characterization. Cancer Res1984;44:734–43.

23. Balint JP Jr, Jones FR. Evidence for proteolytic cleavage ofcovalently bound protein A from a silica based extracorpo-real immunoadsorbent and lack of relationship to treatmenteffects. Transfus Sci 1995;16:85–94.

24. Bertram JH, Grunberg SM, Shulman I, Apuzzo ML, Bo-quiren D, Kunkel L, Hengst JC, Nelson J, Waugh WJ, Plot-kin D. Staphylococcal Protein A column: correlation of mi-togenicity of perfused plasma with clinical response. CancerRes 1985;45:4486–94.

25. Richner J, Schuff-Werner P, Batge R, Beyer JH, Nagel GA.In vitro adsorption of colon cancer sera over staphylococcusprotein A: lymphocyte stimulation by leakage of adsorbance.Klin Wochenschr 1987;65:353–8.

26. Persson U, Inganas M, Smith CI, Hammarstrom I, Johans-son SG. Recombinant protein A of non-staphylococcal ori-gin is not mitogenic for human peripheral lymphocytes. Mi-togenicity of natural protein A is caused by a contaminant.Scand J Immunol 1989;29:151–8.

27. Bansal SC, Bansal BR, Thomas HL, Siegel PD, Rhoads JEJr, Cooper DR, Terman DS, Mark R. Ex vivo removal ofserum IgG in a patient with colon carcinoma: some bio-chemical, immunological and histological observations. Can-cer 1978;42:1–18.

28. Fer MF, Oldham RK. Protein A immunoadsorption/immu-noactivation: a critical review. Contemp Top Immunobiol1985;15:257–76.

29. Korec S, Smith FP, Schein PS, Phillips TM. Clinical experi-

G. MATIC ET AL.400


ences with extracorporeal immunoperfusion of plasma fromcancer patients. J Biol Response Mod 1984;3:330–5.

30. MacKintosh FR, Bennett K, Hall SW. Trials of staphylococ-cal protein A-treated plasma infusions in cancer therapy:clinical effects and implications for mode of action. ContempTop Immunobiol 1985;15:239–56.

31. Nand S, Molokie R. Therapeutic plasmapheresis and proteinA immunoadsorption in malignancy: a brief review. J ClinApheresis 1990;5:206–12.

32. Terman DS, Yamamoto T, Tillquist RL, Henry JF, CookGL, Silvers A, Shearer WT. Tumoricidal response inducedby cytosine arabinoside after plasma perfusion over proteinA. Science 1980;209:1257–9.

33. Terman DS, Young JB, Shearer WT, Ayus C, Lehane D,Mattioli C, Espada R, Howell JF, Yamamoto T, Zaleski HI,Miller L, Frommer P, Feldman L, Henry JF, Tillquist R,Cook G, Daskal Y. Preliminary observations of the effectson breast adenocarcinoma of plasma perfused over immobi-lized protein A. N Engl J Med 1981;305:1195–200.

34. Engelman RW, Good RA, Day NK. Clearance of retrovire-mia and regression of malignancy in cats with leukemia-lymphoma during treatment with staphylococcal protein A.Cancer Detect Prev 1987;10:435–44.

35. Liu WT, Good RA, Trang LQ, Engelman RW, Day NK.Remission of leukemia and loss of feline leukemia virus incats injected with Staphylococcus protein A: association withincreased circulating interferon and complement-dependentcytotoxic antibody. Proc Natl Acad Sci USA 1984;81:6471–5.

36. Samuelsson G. What’s happening? Protein A columns: cur-rent concepts and recent advances. Transfus Sci 1999;21:215–7.

37. Freiburghaus C, Ohlson S, Nilsson IM. Extracorporeal sys-tems for adsorption of antibodies in hemophilia A and B.Methods Enzymol 1988;137:458–66.

38. Gjorstrup P, Berntorp E, Larsson L, Nilsson IM. Kineticaspects of the removal of IgG and inhibitors in hemophiliacsusing protein A immunoadsorption. Vox Sang 1991;61:244–50.

39. Matic G, Hofmann D, Winkler R, Tiess M, Michelsen A,Schneidewind JM, Hebestreit G, Keysser M, Muller W,Kinze EM, Ramlow W. Removal of immunoglobulins by aprotein A versus an antihuman immunoglobulin G-basedsystem: evaluation of 602 sessions of extracorporeal immu-noadsorption. Artif Organs 2000;24:103–7.

40. Matic G, Winkler RE, Tiess M, Ramlow W. Selective apher-esis—time for a change. Int J Artif Organs 2001;24:4–7.

41. Matic G, Schutt W, Winkler RE, Tiess M, Ramlow W. Ex-tracorporeal removal of circulating immune complexes: fromnon-selective to patient-specific. Blood Purif 2000;18:156–60.

42. Nilsson IM, Berntorp E, Freiburghaus C. Treatment of pa-tients with factor VIII and IX inhibitors. Thromb Haemost1993;70:56–9.

43. Felson DT, LaValley MP, Baldassare AR, Block JA,Caldwell JR, Cannon GW, Deal C, Evans S, Fleischmann R,Gendreau RM, Harris ER, Matteson EL, Roth SH, Schuma-cher HR, Weisman MH, Furst DE. The Prosorba column fortreatment of refractory rheumatoid arthritis: a randomized,double-blind, sham-controlled trial. Arthritis Rheum 1999;42:2153–9.

44. Snyder HW Jr, Cochran SK, Balint JP Jr, Bertram JH, Mit-telman A, Guthrie TH Jr, Jones FR. Experience with proteinA-immunoadsorption in treatment-resistant adult immunethrombocytopenic purpura. Blood 1992;79:2237–45.

45. Snyder HW Jr, Henry DH, Messerschmidt GL, MittelmanA, Bertram J, Ambinder E, Kiprov D, Balint JP Jr, Mac-Kintosh FR, Hamburger M. Minimal toxicity during proteinA immunoadsorption treatment of malignant disease: anoutpatient therapy. J Clin Apheresis 1991;6:1–10.

46. Case records of the Massachusetts General Hospital. Weeklyclinicopathological exercises. Case 35-1994. A 55-year-old

woman with a skin rash and hemiparesis after staphylococcalprotein A column therapy. N Engl J Med 1994;331:792–800.

47. Bourelly PE, Grossman ME. Leukocytoclastic vasculitis fol-lowing staphylococcal protein A column immunoadsorptiontherapy for idiopathic thrombocytopenic purpura. Cutis1999;64:250–2.

48. Kabisch A, Kroll H, Wedi B, Kiefel V, Pralle H, Mueller-Eckhardt C. Severe adverse effects of protein A immunoad-sorption. Lancet 1994;343:116.

49. Morrison FS, Huestis DW. Toxicity of the staphylococcalprotein A immunoadsorption column. J Clin Apheresis 1992;7:171–2.

50. Smith RE, Gottschall JL, Pisciotta AV. Life-threatening re-action to staphylococcal protein A immunomodulation. JClin Apheresis 1992;7:4–5.

51. Wallmark A, Grubb A, Freiburghaus C, Flodgren P, Hus-berg B, Lindholm T, Lindstrom C, Thysell H, Sjogren HO.Feasibility of extracorporeal on-line large-scale plasma ad-sorptions on protein A-sepharose columns in cancer pa-tients. Artif Organs 1984;8:72–81.

52. Balint JP Jr, Hussein MA, Quagliata F, Cochran S, JonesFR. Modulation of idiotypic and antiidiotypic immunoglob-ulin G responses in an alloimmune thrombocytopenic pa-tient associated with extracorporeal protein A immunoad-sorption. Artif Organs 1996;20:266–70.

53. Bosch T. Current status in extracorporeal immunomodula-tion: immune disorders. Artif Organs 1996;20:902–5.

54. Snyder HW Jr, Seawell BW, Cochran SK, Balint JP Jr, JonesFR. Specificity of antibody responses affected by extracor-poreal immunoadsorption of plasma over columns of proteinA silica. J Clin Apheresis 1992;7:110–8.

55. Hehmke B, Salzsieder E, Matic GB, Winkler RE, Tiess M,Ramlow W. Immunoadsorption of immunoglobulins altersintracytoplasmic type 1 and type 2 T cell cytokine productionin patients with refractory autoimmune diseases. Ther Apher2000;4:296–302.

56. Wiesenhutter CW, Irish BL, Bertram JH. Treatment of pa-tients with refractory rheumatoid arthritis with extracorpo-real protein A immunoadsorption columns: a pilot trial. JRheumatol 1994;21:804–12.

57. Prosorba column for rheumatoid arthritis. Med Lett DrugsTher 1999;41:69–70.

58. Howe RB, Christie DJ. Protein A immunoadsorption treat-ment in hematology: an overview. J Clin Apheresis 1994;9:31–2.

59. Matic GB, Hofmann D, Konrad H, Anders O, Barz D, TiessM, Winkler RE, Ramlow W. Clinical course in a patient withmalignant idiopathic thrombocytopenic purpura treatedchronically with immunoadsorption. Abstract. Int J Artif Or-gans 2001;21:643.

60. Nilsson IM, Sundqvist SB, Freiburghaus C. Extracorporealprotein A-sepharose and specific affinity chromatographyfor removal of antibodies. Prog Clin Biol Res 1984;150:225–41.

61. Nilsson IM, Freiburghaus C. Apheresis. Adv Exp Med Biol1995;386:175–84.

62. Uehlinger J, Button GR, McCarthy J, Forster A, Watt R,Aledort LM. Immunoadsorption for coagulation factor in-hibitors. Transfusion 1991;31:265–9.

63. Freiburghaus C, Berntorp E, Ekman M, Gunnarsson M,Kjellberg BM, Nilsson IM. Immunoadsorption for removalof inhibitors: update on treatments in Malmo-Lund between1980 and 1995. Haemophilia 1998;4:16–20.

64. Freiburghaus C, Berntrop E, Ekman M, Gunnarsson M,Kjellberg B, Nilsson IM. Tolerance induction using theMalmo treatment model 1982–1995. Haemophilia 1999;5:32–9.

65. Watt RM, Bunitsky K, Faulkner EB, Hart CM, Horan J,Ramstack JM, Viola JL, Yordy JR. Treatment of congenitaland acquired hemophilia patients by extracorporeal removalof antibodies to coagulation factors: a review of US clinical



studies 1987–1990. Hemophilia Study Group. Transfus Sci1992;13:233–53.

66. Taleghani BM, Grossmann R, Keller F, Wiebecke D.Therapy of coagulation factor VIII autoantibodies with long-term extracorporeal protein A adsorption and immunosup-pression. Transfus Sci 1998;19(Suppl):39–42.

67. Dantal J, Testa A, Bigot E, Soulillou JP. Disappearance ofproteinuria after immunoadsorption in a patient with focalglomerulosclerosis. Lancet 1990;336:190.

68. Esnault VL, Besnier D, Testa A, Coville P, Simon P, SubraJF, Audrain MA. Effect of protein A immunoadsorption innephrotic syndrome of various etiologies. J Am Soc Nephrol1999;10:2014–7.

69. Kaplan AA. Therapeutic apheresis for renal disorders. TherApher 1999;3:25–30.

70. Matic G, Michelsen A, Hofmann D, Winkler R, Tiess M,Schneidewind JM, Muller W, Ramlow W. Three cases ofC-ANCA-positive vasculitis treated with immunoadsorp-tion: possible benefit in early treatment. Ther Apher 2001;5:68–72.

71. Palmer A, Cairns T, Dische F, Gluck G, Gjorstrup P, Par-sons V, Welsh K, Taube D. Treatment of rapidly progressiveglomerulonephritis by extracorporeal immunoadsorption,prednisolone and cyclophosphamide. Nephrol Dial Trans-plant 1991;6:536–42.

72. Stegmayr BG, Almroth G, Berlin G, Fehrman I, Kurkus J,Norda R, Olander R, Sterner G, Thysell H, Wikstrom B,Wiren JE. Plasma exchange or immunoadsorption in pa-tients with rapidly progressive crescentic glomerulonephritis.A Swedish multi-center study. Int J Artif Organs 1999;22:81–7.

73. Dantal J, Bigot E, Bogers W, Testa A, Kriaa F, Jacques Y,Hurault DL, Niaudet P, Charpentier B, Soulillou JP. Effectof plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. NEngl J Med 1994;330:7–14.

74. Dantal J, Godfrin Y, Koll R, Perretto S, Naulet J, BouhoursJF, Soulillou JP. Antihuman immunoglobulin affinity immu-noadsorption strongly decreases proteinuria in patients withrelapsing nephrotic syndrome. J Am Soc Nephrol 1998;9:1709–15.

75. Howe RB, Christie DJ. Protein A immunoadsorption treat-ment in hematology: an overview. J Clin Apheresis 1994;9:31–2.

76. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA,Brenner B, Krause M, Scharrer I, Aumann V, Mittler U,Solenthaler M, Lammle B. von Willebrand factor-cleavingprotease in thrombotic thrombocytopenic purpura and thehemolytic-uremic syndrome. N Engl J Med 1998;339:1578–84.

77. Rock G, Shumak KH, Sutton DM, Buskard NA, Nair RC.Cryosupernatant as replacement fluid for plasma exchangein thrombotic thrombocytopenic purpura. Members of theCanadian Apheresis Group. Br J Haematol 1996;94:383–6.

78. Rock G, Herbert C. The Canadian Apheresis Group andtherapeutic plasma exchange. Transfus Sci 1999;20:145–50.

79. Borghardt EJ, Kirchertz EJ, Marten I, Fenchel K. ProteinA-immunoadsorption in chemotherapy associated hemo-lytic-uremic syndrome. Transfus Sci 1998;19(Suppl):5–7.

80. Bueno D Jr, Sevigny J, Kaplan AA. Extracorporeal treat-ment of thrombotic microangiopathy: a ten year experience.Ther Apher 1999;3:294–7.

81. Drew MJ. Resolution of refractory, classic thromboticthrombocytopenic purpura after staphylococcal protein Aimmunoadsorption. Transfusion 1994;34:536–8.

82. Snyder HW Jr, Mittelman A, Oral A, Messerschmidt GL,Henry DH, Korec S, Bertram JH, Guthrie TH Jr, CiavarellaD, Wuest D. Treatment of cancer chemotherapy-associated

thrombotic thrombocytopenic purpura/hemolytic uremicsyndrome by protein A immunoadsorption of plasma. Can-cer 1993;71:1882–92.

83. Zeigler ZR, Shadduck RK, Nath R, Andrews DF III. Pilotstudy of combined cryosupernatant and protein A immuno-adsorption exchange in the treatment of grade 3–4 bonemarrow transplant-associated thrombotic microangiopathy.Bone Marrow Transplant 1996;17:81–6.

84. Langone JJ. Immune complex formation enhances the bind-ing of staphylococcal protein A to immunoglobulin G. Bio-chem Biophys Res Commun 1980;94:473–9.

85. Braun N, Gutenberger S, Erley CM, Risler T. Immunoglob-ulin and circulating immune complex kinetics during immu-noadsorption onto protein A sepharose. Transfus Sci1998;19(Suppl):25–31.

86. Braun N, Erley C, Klein R, Kotter I, Saal J, Risler T. Im-munoadsorption onto protein A induces remission in severesystemic lupus erythematosus. Nephrol Dial Transplant2000;15:1367–72.

87. Benny WB, Sutton DM, Oger J, Bril V, McAteer MJ, RockG. Clinical evaluation of a staphylococcal protein A immu-noadsorption system in the treatment of myasthenia gravispatients. Transfusion 1999;39:682–7.

88. Berta E, Confalonieri P, Simoncini O, Bernardi G, BusnachG, Mantegazza R, Cornelio F, Antozzi C. Removal of anti-acetylcholine receptor antibodies by protein-A immunoad-sorption in myasthenia gravis. Int J Artif Organs 1994;17:603–8.

89. Flachenecker P, Taleghani BM, Gold R, Grossmann R, Wie-becke D, Toyka KV. Treatment of severe myasthenia graviswith protein A immunoadsorption and cyclophosphamide.Transfus Sci 1998;19:43–6.

90. Ruiz JC, Berciano J, Polo JM, de Francisco AL, Arias M.Treatment of Guillain-Barre syndrome with protein-A im-munoadsorption: report of two cases. Ann Neurol 1992;31:574–5.

91. Schneidewind JM, Zettl UK, Winkler RE, Ramlow W, TiessM, Hofmann D, Michelsen A, Weber G, Kinze EM, AdamU, Hauk L, Behnecke R, Klinkmann H. Therapeutic apher-esis in myasthenia gravis patients: a six year follow-up. TherApher 1999;3:298–302.

92. Ullrich H, Mansouri-Taleghani B, Lackner KJ, Schalke B,Bogdahn U, Schmitz G. Chronic inflammatory demyelinat-ing polyradiculoneuropathy: superiority of protein A immu-noadsorption over plasma exchange treatment. Transfus Sci1998;19:33–8.

93. Cher LM, Hochberg FH, Teruya J, Nitschke M, ValenzuelaRF, Schmahmann JD, Herbert M, Rosas HD, Stowell C.Therapy for paraneoplastic neurologic syndromes in six pa-tients with protein A column immunoadsorption. Cancer1995;75:1678–83.

94. Nitschke M, Hochberg F, Dropcho E. Improvement of para-neoplastic opsoclonus-myoclonus after protein A columntherapy. N Engl J Med 1995;332:192.

95. Weinstein R, Sato PT, Shelton K, Hartigan N, Ropper AH,Hayes M, Cardillo K. Successful management of parapro-tein-associated peripheral polyneuropathies by immunoad-sorption of plasma with staphylococcal protein A. J ClinApheresis 1993;8:72–7.

96. Braun N, Faul C, Wernet D, Schnaidt M, Stuhler G, Kanz L,Risler T, Einsele H. Successful transplantation of highly se-lected CD34+ peripheral blood stem cells in a HLA-sensitized patient treated with immunoadsorption onto pro-tein A. Transplantation 2000;69:1742–4.

97. Christie DJ, Howe RB, Lennon SS, Sauro SC. Treatment ofrefractoriness to platelet transfusion by protein A columntherapy. Transfusion 1993;33:234–42.

G. MATIC ET AL.402


98. Rock G. The application of protein A immunoadsorption toremove platelet alloantibodies. Transfusion 1993;33:192–4.

99. Higgins RM, Bevan DJ, Carey BS, Lea CK, Fallon M,Buhler R, Vaughan RW, O’Donnell PJ, Snowden SA, Be-wick M, Hendry BM. Prevention of hyperacute rejection byremoval of antibodies to HLA immediately before renaltransplantation. Lancet 1996;348:1208–11.

100. Mastrangelo F, Pretagostini R, Berloco P, Poli L, Cinti P,

Patruno P, Alfonso L, Pompei L, Carboni F, Rizzelli S. Im-munoadsorption with protein A in humoral acute rejectionof kidney transplants: multicenter experience. TransplantProc 1995;27:892–5.

101. Palmer A, Taube D, Welsh K, Bewick M, Gjorstrup P, ThickM. Removal of anti-HLA antibodies by extracorporeal im-munoadsorption to enable renal transplantation. Lancet1989;1:10–2.



Background and Indications for Protein A-Based Extracorporeal Immunoadsorption

Documents

Transcript of Background and Indications for Protein A-Based Extracorporeal Immunoadsorption