title: Human platelet antigen (HPA)-1a peptides do not reliably suppress anti-HPA-1a responses using a humanized severe combined immunodeficiency (SCID) mouse model.
abstract: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs most frequently when human platelet antigen (HPA)-1a-positive fetal platelets are destroyed by maternal HPA-1a immunoglobulin (Ig)G antibodies. Pregnancies at risk are treated by administration of high-dose intravenous Ig (IVIG) to women, but this is expensive and often not well tolerated. Peptide immunotherapy may be effective for ameliorating some allergic and autoimmune diseases. The HPA-1a/1b polymorphism is Leu/Pro33 on β3 integrin (CD61), and the anti-HPA-1a response is restricted to HPA-1b1b and HLA-DRB3*0101-positive pregnant women with an HPA-1a-positive fetus. We investigated whether or not HPA-1a antigen-specific peptides that formed the T cell epitope could reduce IgG anti-HPA-1a responses, using a mouse model we had developed previously. Peripheral blood mononuclear cells (PBMC) in blood donations from HPA-1a-immunized women were injected intraperitoneally (i.p.) into severe combined immunodeficient (SCID) mice with peptides and HPA-1a-positive platelets. Human anti-HPA-1a in murine plasma was quantitated at intervals up to 15 weeks. HPA-1a-specific T cells in PBMC were identified by proliferation assays. Using PBMC of three donors who had little T cell reactivity to HPA-1a peptides in vitro, stimulation of anti-HPA-1a responses by these peptides occurred in vivo. However, with a second donation from one of these women which, uniquely, had high HPA-1a-specific T cell proliferation in vitro, marked suppression of the anti-HPA-1a response by HPA-1a peptides occurred in vivo. HPA-1a peptide immunotherapy in this model depended upon reactivation of HPA-1a T cell responses in the donor. For FNAIT, we suggest that administration of antigen-specific peptides to pregnant women might cause either enhancement or reduction of pathogenic antibodies.
authors.affiliation: International Blood Group Reference Laboratory, Bristol Institute for Transfusion Sciences, NHS Blood and Transplant, Bristol, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Jackson
authors.forename: J L
authors.initials: JL
authors.lastname: Eastlake
authors.forename: B M
authors.initials: BM
authors.lastname: Kumpel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016824:Antigens, Human Platelet / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D059826:HLA-DRB3 Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007231:Infant, Newborn; D039661:Integrin beta3; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology*; D017713:Platelet Transfusion; D011247:Pregnancy; D016511:Severe Combined Immunodeficiency / Q000097:blood / Q000276:immunology* / Q000601:surgery; D054098:Thrombocytopenia, Neonatal Alloimmune / Q000097:blood / Q000276:immunology; D014183:Transplantation, Heterologous
chemical_list: D016824:Antigens, Human Platelet; D016207:Cytokines; D059826:HLA-DRB3 Chains; C061248:ITGB3 protein, human; D007074:Immunoglobulin G; D039661:Integrin beta3; D010455:Peptides; C083451:human platelet antigen 1b
keywords: HPA-1a peptides; SCID mice; alloimmune thrombocytopenia; anti-HPA-1a; peptide immunotherapy