Article

Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia.

Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Academical Medical Center, University of Amsterdam, The Netherlands.
Blood (Impact Factor: 10.43). 09/2001; 98(4):1095-9.
Source: PubMed

ABSTRACT The clinical benefit of intravenous immunoglobulin (IVIG) preparations in the treatment of immune thrombocytopenic purpura (ITP) is supposed to be mediated by blockade of Fc gamma receptor--bearing phagocytes. In 2 experimental models for ITP, it is shown that the therapeutic efficacy of IVIG preparations is related to the IgG dimer content present in these preparations. A rat monoclonal antibody (mAb; MWReg30) directed to the murine platelet-specific integrin alpha(IIb)beta(3) (gpIIb/IIIa) was administered intraperitoneally either as bolus injection or continuous infusion. With bolus injection, the circulating platelet count dropped to almost zero within 3 hours. Pretreatment with cobra venom factor did not affect platelet depletion, whereas pretreatment with anti-Fc gamma RII/III mAb 2.4G2 or IVIG greatly reduced platelet clearance. With continuous infusion, platelet numbers reached a steady state after 4 days, at approximately 25% of control. This reduction in platelets was, however, not observed in mice deficient for the FcR gamma-chain, lacking Fc gamma RI, Fc gamma RIII, and Fc gamma RIII(-/-) mice. Infusion of a single dose of IVIG with a high IgG dimer content on the 4th day--ie, mimicking therapeutic administration--resulted in a platelet increase for several days. IVIG predominantly consisting of monomeric IgG had no effect on platelet numbers. In conclusion, continuous infusion of MWReg30 induces thrombocytopenia in mice by enhancing Fc gamma receptor--mediated clearance of platelets. In this model, it is shown that IgG dimers present in IVIG preparations are responsible for the increase in platelet counts. (Blood. 2001;98:1095-1099)

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Available from: Jessica L Teeling, Aug 10, 2015
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    • "Obviously, the rate and extent of oligomerization in soluble IgG samples are to be controlled. While the content of oligomers is to be kept at a minimum level to avoid serious side effects [4] [5], the presence of dimers appears to be necessary for effective immunomodulatory action [6] [7]. In a guidance document of the EU Committee for Proprietary Medicinal Products (Core SPC for human normal immunoglobulin for intravenous administration [IVIg], CPMP/BWG/859/95 rev. 1) the warning ''Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin'' is read. "
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    • "Although these authors proposed that this could be due to IVIg's impact to reduce endotoxin levels and Kupffer cell function, we propose that an alternative explanation could be that IVIg directly inhibits leucocyte adhesion. One final study worth mentioning is that IVIg could reduce aIIb/a3 integrin mediated platelet aggregation (Teeling et al., 2001). This is worth noting, as platelets can contribute quite Fig. 4 IVIg reduces interactions of human leucocytes with HUVECs. "
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    • "However, it is likely that the effects observed using these experimental protocols could also be observed in assays using thrombocytopenic animals made by the continuous infusion of antiplatelet antibodies, which would more closely mimic a clinical situation. Indeed Teeling et al (2001) and Crow et al (2001) showed that thrombocytopenia could be reversed by IVIg after continuous infusion of antiplatelet antibodies as efficiently as when IVIg was injected prior to induction of thrombocytopenia. It thus appears that the mouse model of thrombocytopenia is versatile and can be used with different experimental protocols to study the action of IVIg or their substitutes in ITP. "
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