title: Fine specificities of natural regulatory T cells after IVIG therapy in patients with Kawasaki disease.
abstract: The activation of natural regulatory T cells (nTreg) recognizing the heavy constant region (Fc) of IgG is an important mechanism of action of intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD). Lack of circulating Fc-specific nTreg in the sub-acute phase of KD is correlated with the development of coronary artery abnormalities (CAA). Here, we characterize the fine specificity of nTreg in sub-acute (2- to 8-week post-IVIG) and convalescent (1- to 10-year post-IVIG) KD subjects by testing the immunogenicity of 64 peptides, 15 amino acids in length with a 10 amino acid-overlap spanning the entire Fc protein. About 12 Fc peptides (6 pools of 2 consecutive peptides) were recognized by nTreg in the cohorts studied, including two patients with CAA. To test whether IVIG expands the same nTreg populations that maintain vascular homeostasis in healthy subjects, we compared these results with results obtained in healthy adult controls. Similar nTreg fine specificities were observed in KD patients after IVIG and in healthy donors. These results suggest that T cell fitness rather than T cell clonal deletion or anergy is responsible for the lack of Fc-specific nTreg in KD patients who develop CAA. Furthermore, we found that adolescents and adults who had KD during childhood without developing CAA did not respond to the Fc protein in vitro, suggesting that the nTreg response induced by IVIG in KD patients is short-lived. Our results support the concept that peptide epitopes may be a viable therapeutic approach to expand Fc-specific nTreg and more effectively prevent CAA in KD patients.
authors.affiliation: Department of Pediatrics, Rady Children's Hospital, School of Medicine, University of California San Diego , La Jolla, CA , USA and.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Burns
authors.forename: Ranim
authors.initials: R
authors.lastname: Touma
authors.forename: Yali
authors.initials: Y
authors.lastname: Song
authors.forename: Robert L
authors.initials: RL
authors.lastname: Padilla
authors.forename: Adriana H
authors.initials: AH
authors.lastname: Tremoulet
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Alessandra
authors.initials: A
authors.lastname: Franco
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002648:Child; D003289:Convalescence; D003324:Coronary Artery Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007155:Immunologic Factors; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008969:Molecular Sequence Data; D009080:Mucocutaneous Lymph Node Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D061251:Primary Cell Culture; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D013997:Time Factors
chemical_list: C508609:IL10 protein, human; D007141:Immunoglobulin Fc Fragments; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D010455:Peptides; D016753:Interleukin-10
keywords: IVIG; Immunotherapy; Kawasaki disease; immune-regulation; natural Treg
references.citation: J Immunol. 2010 Jul 15;185(2):943-55
references.pmid: 20554959
references.citation: Blood. 2008 Oct 15;112(8):3303-11
references.pmid: 18660382
references.citation: Immunity. 2009 Jun 19;30(6):899-911
references.pmid: 19464196
references.citation: Cell Immunol. 2010;266(1):1-6
references.pmid: 20951371
references.citation: BMC Bioinformatics. 2010;11:568
references.pmid: 21092157
references.citation: J Immunol. 2012 Aug 15;189(4):1800-11
references.pmid: 22786768
references.citation: PLoS Pathog. 2013 Jan;9(1):e1003130
references.pmid: 23358848
references.citation: Clin Exp Immunol. 2013 Dec;174(3):337-44
references.pmid: 23901839
references.citation: Clin Dev Immunol. 2013;2013:467852
references.pmid: 24222776
references.citation: PLoS One. 2013;8(12):e81448
references.pmid: 24324693
references.citation: Autoimmunity. 2014 Mar;47(2):95-104
references.pmid: 24490882
references.citation: Nat Immunol. 2001 Apr;2(4):301-6
references.pmid: 11276200
references.citation: Lancet. 2004 Aug 7-13;364(9433):533-44
references.pmid: 15302199
references.citation: Immunity. 1994 Dec;1(9):751-61
references.pmid: 7895164
references.citation: J Immunol. 2005 Mar 15;174(6):3187-96
references.pmid: 15749848
references.citation: J Immunol. 2008 May 15;180(10):6472-6
references.pmid: 18453564
references.citation: Autoimmunity. 2010 Jun;43(4):317-24
references.pmid: 20166878