|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-10-3078.
TRANSFUSION MEDICINE
From Transfusion Medicine Research and the Department
of Laboratory Medicine and Pathobiology, St Michael's Hospital,
Toronto, ON; and the Canadian Blood Services and the Toronto Platelet
Immunobiology Group, ON, Canada.
Intravenous immunoglobulin (IVIG) is used to treat immune
thrombocytopenia resulting from a variety of autoimmune and
nonautoimmune diseases such as idiopathic thrombocytopenic purpura
(ITP), heparin-induced thrombocytopenia, and posttransfusion purpura.
IVIG is a limited resource and although considered safe, may
nevertheless carry some risk of transferring disease. Its high cost
makes monoclonal antibodies, capable of mimicking the clinical effects
of IVIG, highly desirable. We show here, using a murine model of ITP,
that selected monoclonal antibodies can protect against
thrombocytopenia. SCID mice were pretreated with 1 of 21 monoclonal antibodies before induction of thrombocytopenia by
antiplatelet antibody. Four antibodies reacted with the CD24
antigen on erythrocytes. Two antibodies were of the IgM
class, and although one IgM antibody caused a minimal degree of
anemia (P < .05), neither antibody ameliorated immune
thrombocytopenia. One of 2 anti-CD24 antibodies of the IgG class
ameliorated immune thrombocytopenia and blocked
reticuloendothelial system function at the same doses that protected
against thrombocytopenia. Some antibodies reactive with other
circulating cell types also protected against immune-mediated
thrombocytopenia while no antibody without a distinct target antigen in
the mice was protective. Protective monoclonal antibodies significantly
prevented thrombocytopenia at down to a 1000-fold lower dose (200 µg/kg) as compared with standard IVIG treatment (2 g/kg). It is
concluded that monoclonal IgG with specificity for a circulating
cellular target antigen may provide an alternative therapeutic approach
to treating immune thrombocytopenia.
(Blood. 2003;101:3708-3713) Intravenous immunoglobulin (IVIG) is prepared from
large pools of human plasma from more than 5000 normal healthy donors. Most preparations consist of IgG with low levels of "contaminants" such as IgM. The IgG is present in predominantly monomeric form, with a
subclass distribution characteristic of normal serum. IVIG has been
used successfully to treat idiopathic thrombocytopenic purpura (ITP)
since 1981, where it was initially reported that high doses of IVIG
promoted fast recovery of ITP in children.1 Despite its
extensive clinical use, the mechanism of action of IVIG remains unclear.
In addition to IVIG, intravenous preparations of human immunoglobulin
with specificity for erythrocytes have also been demonstrated to
effectively inhibit immune thrombocytopenia. In particular, polyclonal
anti-D can reverse thrombocytopenia in patients with ITP who express
the D antigen.2-11 In one study, 3 D-negative but c
antigen-positive patients were successfully treated with anti-c.5 Thus, an antibody reactive with an Rh antigen on
erythrocytes (whether to the D or c antigen or possibly any other
appropriate antigen) can potentially reverse immune thrombocytopenia.
Although the mechanism of action of IVIG is controversial, one of the
major proposed mechanisms of action for both IVIG and anti-D is via reticuloendothelial system (RES) blockade by immune complexes. This
theory has been strengthened by studies showing that anti-D appears to
be ineffective in most patients who are Rh D
antigen-negative,3,5,12 which suggests a requirement for
antibody/antigen binding. A small prospective study to test a single
human (IgG1) monoclonal anti-D in 7 D-positive patients
with chronic ITP was unsuccessful.13 The ability of this
monoclonal anti-D antibody to block RES function in the treated
patients was not evaluated; however, the failure of this monoclonal
antibody to ameliorate ITP, and even the concept of testing monoclonal
antibodies in ITP therapy, has generated much
criticism.14-17 Because of the failed trial with this one antibody and the resultant controversy,13-17 it would not
be considered ethical to test other such antibodies in humans. In this
report, we revisit and challenge the hypothesis that monoclonal
antibodies are not useful in treating immune forms of thrombocytopenia.
We clearly demonstrate that some, but not all, monoclonal IgGs that bind cell surface-associated antigens can protect against immune thrombocytopenia in a well-described murine model of
ITP.18-20 These monoclonal antibodies that mimic
the effect of IVIG may offer an alternative therapeutic approach to
polyclonal IVIG or anti-D preparations.
Reagents
Mice
Induction and treatment of passive-immune thrombocytopenia As previously described,18 ITP was induced in mice by intraperitoneal injection of antiplatelet antibody (2 µg MWReg30 or 10 µg 2C9.G2) in 200 µL phosphate-buffered saline [PBS], pH 7.2; 24 hours later, 100 µL whole blood was collected via the tail vein into microvette tubes (Sarstedt, Montreal, QC, Canada) preloaded with 10 µL of 1% EDTA (ethylenediaminetetraacetic acid) in PBS. Then, 5 µL of this mouse blood was diluted into 100 µL of 1% EDTA/PBS. The blood was then further diluted in PBS to a final dilution of 1:12 000. The samples were acquired for 2 minutes on a flow rate-calibrated FACScan flow cytometer (Becton Dickinson, San Jose, CA) using forward scatter (FSC) versus side scatter (SSC) to gate and count the platelets as previously detailed.18 Reference samples were incubated with fluorescein isothiocyanate (FITC)-conjugated antimouse platelet antibody to identify the platelet population. For IVIG pretreatment, mice were injected intraperitoneally with 1 mL of 5% IVIG (about 2 g/kg) 24 hours prior to induction of ITP. Initial experiments demonstrated that the protective effect of IVIG was equally successful whether the intraperitoneal or intravenous route (3 injections of 333 µL over an 8-hour period) was used (data not shown); we have employed the intraperitoneal route for IVIG itself due to the large volume (1 mL per mouse) of IVIG injected. For pretreatment with monoclonal antibodies, mice were injected intravenously with the indicated amount of monoclonal antibody in a volume of 200 µL 24 hours prior to induction of ITP.Antibody binding to erythrocytes Antibody binding was assessed by flow cytometry. For the in vitro binding, washed erythrocytes (10 µL) were incubated with 2 µL of the indicated concentration of monoclonal antibodies in 96-well round-bottomed microtiter plates and gently swirled at 22°C for 30 minutes. The cells were then washed twice with 250 µL PBS and the pellets incubated with 10 µg/mL FITC-labeled antirat IgG (H+L) in a volume of 100 µL for 30 minutes at 22°C. The cells were washed a further 3 times, transferred to tubes, and acquired on FACScan flow cytometer.To assess in vivo binding, the indicated antierythrocyte monoclonal antibody was intravenously administered (50 µg per mouse) to SCID mice. Twenty-four hours later, 50 µL blood was withdrawn from the tail vein into 5 µL of 1% EDTA, and 2 µL of this blood was incubated with 1 µg FITC-labeled antirat IgG (H+L) for 30 minutes in a volume of 100 µL at 22°C. Cells were washed 3 times with PBS prior to acquisition on a FACScan flow cytometer. RES blockade Whole blood (2 mL, diluted with 1:5 volume 1% EDTA in PBS) from unmanipulated SCID mice was pooled and centrifuged at 200g for 15 minutes to obtain 1 mL packed erythrocytes. These packed erythrocytes were resuspended in 4 mL PBS and incubated with 10 µg anti-TER-119 antibody (Table 1) at 22°C for 30 minutes. The resulting opsonized erythrocytes were then washed twice with PBS and labeled with a fluorescent marker (PKH26 Kit, Sigma, St Louis, MO) according to the manufacturer's directions. Briefly, the opsonized erythrocytes were resuspended in 3 mL PKH26 diluent C and mixed with another 4 mL diluent C containing 10 µL of the "PKH26 linker." After a 5-minute incubation with constant swirling, the mixture was incubated for 5 minutes with an equal volume of PBS containing 1% bovine serum albumin. The erythrocytes were washed 5 times and resuspended in 2 mL PBS. Mice were then injected via the tail vein with 200 µL of these labeled cells. All mice were bled via the tail vein at 3 minutes, 10 minutes, 30 minutes, 120 minutes, and 960 minutes after injection, and the total number of erythrocytes, as well as the percent of PKH26-fluorescent erythrocytes, were counted by flow cytometry. The percentage of fluorescent erythrocytes at the 3-minute time point was considered to be 100%.Statistical analysis Unless otherwise indicated, data are expressed as mean ± SEM. The Student t test was used to evaluate the significance of observed differences between the groups. The significance level was set at P < .05.
Monoclonal antibodies with specificity for erythrocytes can inhibit ITP As shown in Figure 1, SCID mice injected with a rat anti- IIb antibody became
thrombocytopenic by 24 hours (Figure 1, shaded area), compared with
unmanipulated control mice (Figure 1, dashed line). However, SCID mice
pretreated with 50 mg IVIG per mouse (about 2 g/kg body weight) 24 hours prior to administration of the anti-IIb antibody
were significantly protected from thrombocytopenia (Figure 1, column 1 for all panels). SCID mice pretreated with 50 µg anti-TER-119
monoclonal antibody were significantly protected from ITP, compared
with untreated mice (Figure 1A). SCID mice pretreated with an anti-CD24
monoclonal antibody (IgG2b) were also significantly
protected against ITP at dosages of 50 µg per mouse and 5 µg per
mouse (Figure 1B). In contrast, as demonstrated in Figure 1C, SCID mice
treated with a different anti-CD24 antibody (IgG2c) or with
2 IgM anti-CD24 antibodies (Table 1) were
not protected from thrombocytopenia at any dosage. Nine monoclonal antibodies that do not have specificity for a corresponding target antigen in SCID mice failed to prevent ITP in dosages up to 50 µg per
mouse (about 2 mg/kg body weight) (Table 1).
The ability of monoclonal antibodies to ameliorate thrombocytopenia in
normal mice induced by 2 different antiplatelet antibodies was also
examined. BALB/c mice pretreated with 50 µg anti-TER-119 monoclonal
antibody were significantly protected from
anti-
The above therapeutic antibodies were evaluated for their ability to bind to erythrocytes, to induce anemia or, in the case of the IgG antibodies, to block the RES. The rank order of the ability of antibodies to bind to erythrocytes as assessed by flow cytometry was as follows (mean log fluorescence intensity ± the SEM): TER-119 (484.2 ± 37.9) more than CD24 (IgG2b) (353.1 ± 40.7), more than CD24 (IgG2c) (96.7 ± 36.0), more than CD24 (IgM, clone IOTHSA) (26.5 ± 7.5), more than CD24 (IgM, clone J11d) (3.1 ± 0.2), and more than IgG control (1.8 ± 0.06). In vivo, the TER-119 antibody also bound erythrocytes with the highest avidity (18.3 ± 3.1) followed by anti-CD24 IgG2b (11.8 ± 1.5), about the same as anti-CD24 IgG2c (11.1 ± 2.1), and more than IgG control (2.1 ± 0.2). Thus, the anti-TER-119 antibody and both anti-CD24 antibodies (IgG2b and IgG2c) successfully sensitized erythrocytes under in vivo therapeutic conditions. Because treatment of ITP with anti-D may be associated with anemia,
mice were evaluated for the number of circulating erythrocytes 24 hours
following injection of the antierythrocyte antibodies. Anti-TER-119
(Figure 3A) and anti-CD24
(IgG2b) (Figure 3B) induced significant decreases (50% and
25%, respectively) in the number of circulating erythrocytes. The IgM
anti-CD24, clone IOTHSA, (not shown) also induced a significant
decrease in erythrocyte numbers at 5 µg per mouse. In contrast, this
was not seen with the IgG2c (Figure 3C) or the J11d IgM
clone of anti-CD24 (not shown).
The IgG2b and IgG2c anti-CD24 antibodies were
tested for their ability to inhibit RES function as assessed by
clearance of TER-119 antibody-sensitized erythrocytes. Both IVIG and
the IgG2b anti-CD24 significantly blocked RES function as
reflected by the impaired ability of anti-CD24-treated mice to clear
sensitized erythrocytes as compared with albumin-treated mice (Figure
4A). In contrast, the IgG2c
anti-CD24 had no measurable effect on RES function (Figure 4A). The
TER-119 antibody also inhibited RES function as assessed by clearance
of sensitized erythrocytes (not shown). Anti-CD24 (IgG2b)
blocked the RES at the 50 and 5 µg doses but not at the 0.5 µg dose
(Figure 4B).
Monoclonal antibodies directed against nonerythrocyte antigens can also inhibit ITP The ability of monoclonal antibodies reactive with white blood cell antigens to inhibit ITP was also assessed. Two of 7 antibodies tested protected against immune thrombocytopenia: an anti-CD16/32 at a dosage of 50 µg per mouse (Table 1) and an IgG1 anti-CD44 at dosages of 50 and 5 µg per mouse (Table 1). In contrast, other antileukocyte antibodies (anti-CD21/35, anti-CD11, anti-CD126, anti-CD44 (IgG2b), anti-CD47) failed to ameliorate thrombocytopenia at the doses tested (Table 1).Monoclonal anti-TER-119 antibody demonstrates an enduring therapeutic effect on ITP SCID mice were rendered thrombocytopenic 1 day before treatment with 50 µg anti-TER-119 monoclonal antibody (Figure 5A). Continued injection of antiplatelet antibody induced thrombocytopenia in otherwise untreated mice for the duration of the experiment. Mice that were exposed to a single injection of anti-TER-119 on day 2 underwent a reversal of thrombocytopenia, peaking at day 5, and returning to pre-anti-TER-119 treatment levels by day 9 of the experiment (Figure 5A). The increase in platelet numbers induced by the anti-TER-119 antibody correlated inversely with the number of circulating erythrocytes in the mice (Figure 5B).
IVIG has been widely utilized in the treatment of both autoimmune and inflammatory diseases such as immune thrombocytopenic purpura (ITP).1,2,8,21-29 IVIG is inherently a preparation of polyclonal antibodies representing a multitude of specificities. Preparations of human IgG containing high titers of polyclonal anti-D have been used as an alternative for IVIG in D-positive patients with ITP. One monoclonal anti-D has been tested in patients with chronic ITP, but it failed to ameliorate the thrombocytopenia.13 The failure of this monoclonal anti-D has generated much controversy14-17 as well as a hypothesis that the polyclonality of IVIG, as well as that of anti-D, is critical to its effectiveness in ITP.16 We have recently demonstrated that some of the attributes of polyclonal immunoglobulins, such as anti-idiotypic antibodies, may play a role in mediating the amelioration of some disease states, such as alloimmunization to platelet transfusion.30 However, we have also provided evidence that in murine passive immune thrombocytopenia, anti-idiotype antibodies are not at all required for the acute therapeutic effects of IVIG.18 We have hypothesized that the protective effect of IVIG and polyclonal anti-D may not, in fact, be directly due to their polyclonal nature but rather due to their ability to inhibit RES function; it is thus feasible to speculate that administration of monoclonal antierythrocyte antibodies could inhibit RES function and mimic the acute actions of IVIG. We demonstrate here that 2 monoclonal antierythrocyte antibodies,
anti-TER-119 and IgG2b anti-CD24, can significantly
inhibit antibody-induced thrombocytopenia in SCID mice at down to a 4 log-fold lower dose than standard IVIG treatment. Both these monoclonal antibodies, as well as an IgM anti-CD24 antibody (clone IOTHSA), caused
a decrease in the number of circulating erythrocytes. The anti-CD24
antibody of the IgG2c isotype did not ameliorate ITP; although this antibody did bind to erythrocytes at a moderate level in
vitro, it bound to erythrocytes to virtually the same extent as the
therapeutically successful anti-CD24 (IgG2b) antibody under
in vivo conditions. This apparent contradiction remains unexplained,
but the inability of the anti-CD24 IgG2c to inhibit the RES
may be due to the antibody having a poor interaction with Fc Salama and coworkers initially postulated that the success of IVIG in treating ITP was due to competitive inhibition of the RES by sensitized erythrocytes.2,3 In agreement with this, Fehr et al demonstrated that infusion of IVIG in 4 patients with ITP prolonged the in vivo clearance of radiolabeled antibody-sensitized erythrocytes.31 This has been confirmed by others, using both erythrocytes and platelets as target cells.27,28,32 Several studies comparing intact IVIG to F(ab')2 fragments from IVIG have clearly indicated that the intact preparations are more efficacious in reversing the thrombocytopenia,33,34 and our work has clearly demonstrated that F(ab')2 fragments of IVIG lack the ability to inhibit immune thrombocytopenia.18 To address whether antierythrocyte antibodies inhibit thrombocytopenia due to inhibition of the RES, RES function after exposure to monoclonal antibody was assessed. Pretreatment of mice with anti-TER-119 and anti-CD24 (IgG2b) but not with anti-CD24 (IgG2c) resulted in prolonged clearance of antibody-sensitized erythrocytes, suggesting a relationship between RES inhibition and the therapeutic effect of monoclonal antibody in preventing thrombocytopenia. Modulation of complement is one of the several documented immunomodulatory properties of IVIG that may contribute to its clinical effects.35-37 However, in a murine model of ITP very similar to the model of ITP employed in the current studies, IVIG was shown to increase platelet counts in complement-knock-out mice exposed to an antiplatelet antibody.19 In addition, IgM is a potent complement activator via the classical cascade,38 but our data show that a monoclonal anti-CD24 antibody of IgM class, which resulted in a significant decline in erythrocyte counts, did not exert any inhibitory effect on thrombocytopenia induced in SCID mice. Finally, anti-CD21/35, an antibody against complement receptor CR2/CR1,39 did not prevent thrombocytopenia. It therefore appears that in this murine model of ITP, complement may not play a role in the amelioration of thrombocytopenia by IVIG or monoclonal antibodies. Infusion of a murine-derived monoclonal anti-Fc In the treatment of ITP, it has been observed that the ability of IVIG to ameliorate thrombocytopenia can continue for several days after treatment.43,44 Analysis of platelet counts in anti-TER-119 antibody-treated thrombocytopenic mice indicated that the monoclonal antibody protected against thrombocytopenia for at least 4 days after treatment. An elegant model to study murine ITP would be based upon mice that are
transgenic and functional for the human Fc In conclusion, monoclonal antibodies are capable of substituting for IVIG in inhibiting immune thrombocytopenia and may provide an effective alternative to IVIG in the treatment of ITP; it may also be less expensive to produce, in more abundant supply, and less susceptible to transmission of viral diseases than the human-derived product.
We thank Mr Hoang Le-Tien, Ms Alison Starkey, and Mr Davor Brinc for assistance and helpful discussion and the St Michael's Hospital Research Vivarium staff.
Submitted October 10, 2002; accepted December 17, 2002.
Prepublished online as Blood First Edition Paper, December 27, 2002; DOI 10.1182/blood-2002-10-3078.
Supported by a grant from Bayer-Canadian Blood Services-Hema Quebec Partnership Fund.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Alan H. Lazarus, Transfusion Medicine Research, St Michael's Hospital, 30 Bond St, Toronto, ON, Canada M5B 1W8; e-mail: lazarusa{at}smh.toronto.on.ca.
1. Imbach P, Barandun S, d'Apuzzo V, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet. 1981;1:1228-1231[Medline] [Order article via Infotrieve]. 2. Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet. 1983;2:193-195[Medline] [Order article via Infotrieve]. 3. Salama A, Kiefel V, Amberg R, Mueller-Eckhardt C. Treatment of autoimmune thrombocytopenic purpura with rhesus antibodies (anti-Rh0(D)]. Blut. 1984;49:29-35[CrossRef][Medline] [Order article via Infotrieve]. 4. Becker T, Kuenzlen E, Salama A, et al. Treatment of childhood idiopathic thrombocytopenic purpura with Rhesus antibodies (anti-D). Eur J Pediatr. 1986;145:166-169[CrossRef][Medline] [Order article via Infotrieve]. 5. Oksenhendler E, Bierling P, Brossard Y, et al. Anti-RH immunoglobulin therapy for human immunodeficiency virus-related immune thrombocytopenic purpura. Blood. 1988;71:14991502.
6.
Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM.
Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect.
Blood.
1991;77:1884-1893
7.
Scaradavou A, Woo B, Woloski BM, et al.
Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients.
Blood.
1997;89:2689-2700 8. Lazarus AH, Freedman J, Semple JW. Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura (ITP): mechanisms of action. Transfus Sci. 1998;19:289-294[CrossRef][Medline] [Order article via Infotrieve]. 9. Zimmerman SA, Malinoski FJ, Ware RE. Immunologic effects of anti-D (WinRho-SD) in children with immune thrombocytopenic purpura. Am J Hematol. 1998;57:131-138[CrossRef][Medline] [Order article via Infotrieve]. 10. Tarantino MD, Madden RM, Fennewald DL, Patel CC, Bertolone SJ. Treatment of childhood acute immune thrombocytopenic purpura with anti-D immune globulin or pooled immune globulin. J Pediatr. 1999;134:21-26[CrossRef][Medline] [Order article via Infotrieve]. 11. Waintraub SE, Brody JI. Use of anti-D in immune thrombocytopenic purpura as a means to prevent splenectomy: case reports from 2 University Hospital Medical Centers. Semin Hematol. 2000;37:45-49[CrossRef][Medline] [Order article via Infotrieve].
12.
Bussel J, Graziano JN, Kimberly RP.
Anti-D Ig for treatment of immune thrombocytopenic purpura [letter].
Blood.
1991;78:2157-2158 13. Godeau B, Oksenhendler E, Brossard Y, et al. Treatment of chronic autoimmune thrombocytopenic purpura with monoclonal anti-D. Transfusion. 1996;36:328-330[CrossRef][Medline] [Order article via Infotrieve]. 14. Engelfriet CP, Reesink HW, Bussel J, et al. The treatment of patients with autoimmune thrombocytopenia with intravenous IgG-anti-D. Vox Sang. 1999;76:250-255[CrossRef][Medline] [Order article via Infotrieve].
15.
Godeau B, Bierling P.
Treatment of chronic autoimmune thrombocytopenic purpura with monoclonal anti-D: lack of efficiency due to absence of Fc 16. Atrah HI. Monoclonal anti-D is not effective in the treatment of chronic autoimmune thrombocytopenic purpura [letter]. Transfusion. 1997;37:444[Medline] [Order article via Infotrieve].
17.
Neppert J, von Witzleben-Schurholz EM.
Treatment of chronic autoimmune thrombocytopenic purpura with monoclonal anti-D: lack of efficiency due to absence of Fc 18. Crow AR, Song S, Semple JW, Freedman J, Lazarus AH. IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity. Br J Haematol. 2001;115:679-686[CrossRef][Medline] [Order article via Infotrieve].
19.
Samuelsson A, Towers TL, Ravetch JV.
Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor.
Science.
2001;291:484-486
20.
Teeling JL, Jansen-Hendriks T, Kuijpers TW, et al.
Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia.
Blood.
2001;98:1095-1099 21. van der Meche FG, Schmitz PI. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. Dutch Guillain-Barre Study Group. N Engl J Med. 1992;326:1123-1129[Abstract]. 22. Gajdos P, Outin H, Elkharrat D, et al. High-dose intravenous gammaglobulin for myasthenia gravis. Lancet. 1984;1:406-407[Medline] [Order article via Infotrieve]. 23. Sultan Y, Kazatchkine MD, Maisonneuve P, Nydegger UE. Anti-idiotypic suppression of autoantibodies to factor VIII (antihaemophilic factor) by high-dose intravenous gammaglobulin. Lancet. 1984;2:765-768[CrossRef][Medline] [Order article via Infotrieve].
24.
Dalakas MC, Illa I, Dambrosia JM, et al.
A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis.
N Engl J Med.
1993;329:1993-2000 25. Jayne DR, Davies MJ, Fox CJ, Black CM, Lockwood CM. Treatment of systemic vasculitis with pooled intravenous immunoglobulin. Lancet. 1991;337:1137-1139[CrossRef][Medline] [Order article via Infotrieve]. 26. LeHoang P, Cassoux N, George F, Kullmann N, Kazatchkine MD. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocul Immunol Inflamm. 2000;8:49-57[CrossRef][Medline] [Order article via Infotrieve].
27.
Bussel JB, Kimberly RP, Inman RD, et al.
Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura.
Blood.
1983;62:480-486 28. Uchida T, Yui T, Umezu H, Kariyone S. Prolongation of platelet survival in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. Thromb Haemost. 1984;51:65-66[Medline] [Order article via Infotrieve]. 29. Godeau B, Caulier MT, Decuypere L, Rose C, Schaeffer A, Bierling P. Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w. Br J Haematol. 1999;107:716-719[CrossRef][Medline] [Order article via Infotrieve].
30.
Semple JW, Kim M, Lazarus AH, Freedman J.
Gamma-globulins prepared from sera of multiparous women bind anti-HLA antibodies and inhibit an established in vivo human alloimmune response.
Blood.
2002;100:1055-1059 31. Fehr J, Hofmann V, Kappeler U. Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N Engl J Med. 1982;306:1254-1258[Abstract]. 32. Macintyre EA, Linch DC, Macey MG, Newland AC. Successful response to intravenous immunoglobulin in autoimmune haemolytic anaemia. Br J Haematol. 1985;60:387-388[Medline] [Order article via Infotrieve]. 33. Newland AC, Macey MG. Immune thrombocytopenia and Fc receptor-mediated phagocyte function. Ann Hematol. 1994;69:61-67[CrossRef][Medline] [Order article via Infotrieve]. 34. Tovo PA, Miniero R, Fiandino G, Saracco P, Messina M. Fc-depleted vs intact intravenous immunoglobulin in chronic ITP. J Pediatr. 1984;105:676-677[Medline] [Order article via Infotrieve].
35.
Ruiz-Arguelles GJ, Apreza-Molina MG, Perez-Romano B, Ruiz-Arguelles A.
The infusion of anti-RhO-(D) opsonized erythrocytes may be useful in the treatment of patients, splenectomized or not, with chronic, refractory autoimmune thrombocytopenic purpura
36.
Basta M, Langlois PF, Marques M, Frank MM, Fries LF.
High-dose intravenous immunoglobulin modifies complement-mediated in vivo clearance.
Blood.
1989;74:326-333 37. Mollnes TE, Hogasen K, De Carolis C, et al. High-dose intravenous immunoglobulin treatment activates complement in vivo. Scand J Immunol. 1998;48:312-317[CrossRef][Medline] [Order article via Infotrieve]. 38. Frank MM, Fries LF. Complement. In: Paul WE, ed. Fundamental Immunology. 2nd ed. New York, NY: Raven Press; 1989:679-702. 39. Martin BK, Weis JH. Murine macrophages lack expression of the Cr2-145 (CR2) and Cr2-190 (CR1) gene products. Eur J Immunol. 1993;23:3037-3042[Medline] [Order article via Infotrieve].
40.
Clarkson SB, Bussel JB, Kimberly RP, Valinsky JE, Nachman RL, Unkeless JC.
Treatment of refractory immune thrombocytopenic purpura with an anti-Fc
41.
Unkeless JC.
Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors.
J Exp Med.
1979;150:580-596
42.
Araujo-Jorge T, Rivera MT, el Bouhdidi A, Daeron M, Carlier Y.
An Fc 43. Nuchprayoon I, Seksarn P, Vanichsetakul P, O-chareon R. Low dose intravenous immunoglobulin for acute immune thrombocytopenic purpura in children. Asian Pac J Allergy Immunol. 2001;19:11-16[Medline] [Order article via Infotrieve]. 44. Jahnke L, Applebaum S, Sherman LA, Greenberger PA, Green D. An evaluation of intravenous immunoglobulin in the treatment of human immunodeficiency virus-associated thrombocytopenia. Transfusion. 1994;34:759-764[CrossRef][Medline] [Order article via Infotrieve].
45.
McKenzie SE, Taylor SM, Malladi P, et al.
The role of the human Fc receptor Fc
© 2003 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  O. Speer, M. Schmugge, I. Azzouzi, M. L. Rand, and S. Kroiss Apoptosis in Platelets from Pediatric Patients with Acute Immune Thrombocytopenic Purpura (ITP) Is Ameliorated by IV Ig. Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 3417 - 3417. [Abstract] [Full Text]
|
|
|
|
 |
|
 Y. Li, M. E. Williams, J. B. Cousar, A. W. Pawluczkowycz, M. A. Lindorfer, and R. P. Taylor Rituximab-CD20 Complexes Are Shaved from Z138 Mantle Cell Lymphoma Cells in Intravenous and Subcutaneous SCID Mouse Models J. Immunol., September 15, 2007; 179(6): 4263 - 4271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Deng and J. P. Balthasar Comparison of the effects of antibody-coated liposomes, IVIG, and anti-RBC immunotherapy in a murine model of passive chronic immune thrombocytopenia Blood, March 15, 2007; 109(6): 2470 - 2476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Crow, S. Song, J. W. Semple, J. Freedman, and A. H. Lazarus A role for IL-1 receptor antagonist or other cytokines in the acute therapeutic effects of IVIg? Blood, January 1, 2007; 109(1): 155 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Olsson, P. Bruhns, W. A. Frazier, J. V. Ravetch, and P.-A. Oldenborg Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia Blood, May 1, 2005; 105(9): 3577 - 3582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Song, A. R. Crow, V. Siragam, J. Freedman, and A. H. Lazarus Monoclonal antibodies that mimic the action of anti-D in the amelioration of murine ITP act by a mechanism distinct from that of IVIg Blood, February 15, 2005; 105(4): 1546 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lamoureux, E. Aubin, and R. Lemieux Autoantibodies purified from therapeutic preparations of intravenous immunoglobulins (IVIg) induce the formation of autoimmune complexes in normal human serum: a role in the in vivo mechanisms of action of IVIg? Int. Immunol., July 1, 2004; 16(7): 929 - 936. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
and
light chains (clones RT-39 and RL-6) and the PKH26 red fluorescent cell linker kit were purchased from Sigma (Oakville, ON, Canada). The
monoclonal antibody specific for integrin 
3 (antiglycoprotein IIIa, clone 2C9.G2;
hamster IgG, group 1, 
) was
administered to SCID mice followed by anti-
) or anti-CD24 (IgG2c, 
) or
intraperitoneally with 50 mg IVIG (
) or albumin (
receptors (Fc
a prospective study.
Am J Hematol.
1993;43:72-73