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Ferrata Storti Foundation
Cell Therapy & Immunotherapy
Combination peptide immunotherapy suppresses antibody and helper T-cell responses to the major human platelet autoantigen glycoprotein IIb/IIIa
in HLA-transgenic mice
Lindsay S. Hall,1,2 Charlotte S. Lennon,1 Andrew M. Hall,1
Stanislaw J. Urbaniak,1,2 Mark A. Vickers1,2* and Robert N. Barker1*
*MAV and RNB are joint senior authors
ABSTRACT
Platelet destruction in immune thrombocytopenia is caused by autoreactive antibody and T-cell responses, most commonly direct- ed against platelet glycoprotein IIb/IIIa. Loss of self-tolerance in the disease is also associated with deficient activity of regulatory T cells. Having previously mapped seven major epitopes on platelet glycopro- tein IIIa that are recognized by helper T cells from patients with immune thrombocytopenia, the aim was to test whether peptide therapy with any of these sequences, alone or in combination, could inhibit responses to the antigen in humanized mice expressing HLA-DR15. None of the individual peptides, delivered by a putative tolerogenic regimen, consis- tently suppressed the antibody response to subsequent immunization with human platelet glycoprotein IIb/IIIa. However, the combination of glycoprotein IIIa peptides aa6-20 and aa711-725, which contain the pre- dominant helper epitopes in patients and elicited the strongest trends to suppress when used individually, did abrogate this response. The pep- tide combination also blunted, but did not reverse, the ongoing antibody response when given after immunization. Suppression of antibody was associated with reduced splenocyte T-cell responsiveness to the antigen, and with the induction of a regulatory T-cell population that is more responsive to the peptides than to purified platelet glycoprotein IIb/IIIa. Overall, these data demonstrate that combinations of peptides contain- ing helper epitopes, such as platelet glycoprotein IIIa aa6-20 and aa711- 725, can promote in vivo suppression of responses to the major antigen implicated in immune thrombocytopenia. The approach offers a prom- ising therapeutic option to boost T-cell regulation, which should be taken forward to clinical trials.
Introduction
Immune thrombocytopenia (ITP) is a bleeding disorder defined by an isolated thrombocytopenia and caused by immune responses against self-antigens expressed on platelets and/or megakaryocytes.1-4 The most commonly targeted autoantigen is platelet glycoprotein (GP) IIb/IIIa, with responses against other glycoproteins such as GPIb/IX or GPIV seen in a minority of cases.5-7 GPIIb/IIIa, also known as integrin aIIbβ3, functions as the main fibrinogen and von Willebrand factor receptor and is highly expressed on the plasma membranes of platelets. Characterization of this major autoantigen is a key step in the development of specific immunotherapy that could selectively inhibit the pathogenic responses against platelets.7
Platelet destruction in ITP is believed to be mediated by IgG autoantibodies, which opsonize platelet and/or megakaryocyte surfaces,8,9 leading to clearance via Fcγ-receptors on macrophages, predominantly in bone marrow, spleen and liver. T-
Haematologica 2019 Volume 104(5):1074-1082
1Institute of Medical Sciences, Ashgrove Road West, University of Aberdeen and
2
Scottish National Blood Transfusion Service, Foresterhill Road, Aberdeen, UK
Correspondence:
ROBERT N. BARKER r.n.barker@abdn.ac.uk
Received: September 4, 2017. Accepted: November 29, 2018. Pre-published: December 4, 2018.
doi:10.3324/haematol.2017.179424
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/1074
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