Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


A C5a Receptor Antagonist Ameliorates In Vivo Effects of Antiphospholipid Antibodies

Carrera-Marin1,  Ana Laura, Romay-Penabad1,  Zurina, Qu2,  HongChang, Papalardo1,  Elizabeth, Lambris2,  John, Reyes-Maldonado3,  Elba, Garcia-Latorre4,  Ethel

University of Texas Medical Branch, Galveston, TX,
Univeristy of Pennsylvania, Philadelphia, PA,
Instituto Politecnico Nacional/ENCB, Mexico D.F., Mexico,
Instituto Politecnico Nacional, Mexico D.F., Mexico

Purpose:

Studies in mouse models have shown involvement of C3 and C5 on antiphospholipid (aPL)-mediated thrombosis and endothelial cell (EC) activation. It has been proposed that in addition to their direct effects on target cells, aPL antibodies may further enhance endothelial cell activation and a pro-infllammatory/procoagulant state [upregulation of tissue factor (TF)] by activation of complement and interaction of complement split products (i.e. C3a and C5a), with specific receptors on the cell surface. The aim of this study was to examine the effects of a specific C5a receptor antagonist peptide (C5aR-AP) on aPL-mediated thrombosis and upregulation of TF in vivo.

Method:

C57BL/6J mice were injected i.p. twice with 500 mg of IgG isolated from a patient with Antiphospholipid Syndrome (APS) or with control IgG (IgG-NHS) preceded by i.p. injection of 25 mg of C5aR-AP (Ac-Phe-c[Orn-Pro-DCha-Trp-Arg] or control peptide (CP) (Ac-Phe-c[ORn-Pro-DCha-Ala-DARg]). Seventy-two hours after the first injection, the size of an induced thrombus was measured in the treated and control mice. TF activity in pM/mg/ml protein was determined in carotid artery homogenates and in lysates of peritoneal macrophages. Anticardiolipin (aCL) and anti-b2glycoprotein (anti-b2GPI) activity was determined by ELISA in the sera of the animals.

Results:

TreatmentThrombus size (mm2)TF carotid (pM/mg/ml)TF Macrophages (pM/mg/ml)aCL (GPL)anti-b2GPI (SGU)
IgG-APS + CP3236.0 ± 1729.869.3 ± 13.816.6 ± 3.057.8 ± 29.757.9 ± 16.1
IgG-APS + C5aR-AP802.8 ± 271.233.8 ± 4.16.7 ± 2.151.2 ± 8.761.0 ± 27.3
IgG-NHS + CP604.7 ± 94.039.1 ± 5.011.0 ± 1.01.2 ± 0.194.9 ± 0.3
IgG-NHS + C5aR-AP623.2 ± 117.425.3 ± 8.27.2 ± 1.10.9 ± 0.15.1 ± 0.6

Treatment of the mice with IgG-APS + CP induced significantly larger thrombi, TF in carotids and macrophages when compared to IgG-NHS + CP treated mice (p values=0.027, 0.045, 0.063, respectively). Mice treated with IgG-APS and C5aR-AP had significantly smaller thrombi and lower TF activity in carotid arteries and macrophages when compared to IgG-APS + CP-injected animals (p values= 0.034,0.036,0.045, respectively).

Conclusion:

The data provide relevant information on the involvement of complement activation in aPL-mediated pathogenic effects and underscore the possibility of utilizing complement inhibitors to ameliorate APS clinical manifestations.

To cite this abstract, please use the following information:
Carrera-Marin, Ana Laura, Romay-Penabad, Zurina, Qu, HongChang, Papalardo, Elizabeth, Lambris, John, Reyes-Maldonado, Elba, et al; A C5a Receptor Antagonist Ameliorates In Vivo Effects of Antiphospholipid Antibodies [abstract]. Arthritis Rheum 2009;60 Suppl 10 :2050
DOI: 10.1002/art.27122

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