title: Determination of thrombopoietin-derived peptides recognized by both cellular and humoral immunities in healthy donors and patients with thrombocytopenia.
abstract: Thrombopoietin (TPO) is a cytokine that promotes megakaryocytopoiesis and thrombopoiesis and is considered a drug suitable for patients with thrombocytopenia. However, unexpected severe thrombocytopenia has developed in some healthy individuals participating in phase I clinical trials with a pegylated recombinant human megakaryocyte growth factor (PEG-rHuMGDF) that contained the first 163 amino acids of endogenous TPO, which resulted in hampering the further development of clinical trials. Autoimmune responses to PEG-rHuMGDF, which cross-reacted with endogenous TPO, were suggested to be involved in this rare but severe adverse event, although the immunogenic epitopes have not yet been determined. To better understand the molecular basis of such autoimmune reactions, we investigated the reactivity of 18 TPO-derived peptides with HLA-A2-binding motifs to plasma and T cells, both from patients with thrombocytopenia (n=24) and from healthy donors (HDs) (n=24). Four peptides, including those possessing amino acids in receptor-binding sites, were preferentially reactive to plasma from at least 20% of the patients, whereas one peptide at position 101-109 was equally reactive to those of the patients and the HDs. Each of the five peptides had the ability to induce peptide-specific cytotoxic T lymphocytes (CTLs) in both groups, albeit with less frequency among the patients. More important, each of these five peptides had the ability to induce HLA-A2-restricted and peptide-specific CTL activity reactive to cells that produce TPO. These results may provide new insights to gain a better understanding of autoimmune reactions to TPO.
authors.affiliation: Department of Immunology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan. takedatu@med.kurume-u.ac.jp
authors.forename: Hiroko
authors.initials: H
authors.lastname: Takedatsu
authors.forename: Kohji
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
authors.forename: Kyogo
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020816:Amino Acid Motifs; D000917:Antibody Formation; D015551:Autoimmunity; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000737:chemistry; D005260:Female; D015789:HLA-A2 Antigen / Q000737:chemistry; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000737:chemistry; D008297:Male; D008533:Megakaryocytes / Q000166:cytology; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013601:T-Lymphocytes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013921:Thrombocytopenia / Q000276:immunology* / Q000378:metabolism; D013926:Thrombopoietin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000939:Epitopes; D015789:HLA-A2 Antigen; D007074:Immunoglobulin G; D010455:Peptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D013926:Thrombopoietin