title: Abacavir induced T cell reactivity from drug naïve individuals shares features of allo-immune responses.
abstract: Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57∶01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of abacavir-reacting CD8+ T cells, which release IFNγ and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was independent of co-stimulatory signals, as neither DC maturation nor release of inflammatory cytokines were observed upon abacavir exposure. Abacavir induced T cells arose in the absence of professional APC and stemmed from naïve and memory compartments. These features are reminiscent of allo-reactivity. Screening for allo-reactivity revealed that about 5% of generated T cell clones (n = 136) from three donors were allo-reactive exclusively to the related HLA-B*58∶01. The addition of peptides which can bind to the HLA-B*57∶01-abacavir complex and to HLA-B*58∶01 during the induction phase increased the proportion of HLA-B*58∶01 allo-reactive T cell clones from 5% to 42%. In conclusion, abacavir can alter the HLA-B*57∶01-peptide complex in a way that mimics an allo-allele ('altered self-allele') and create the potential for robust T cell responses.
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Adam
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Natascha
authors.initials: N
authors.lastname: Wuillemin
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Watkins
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Jamin
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Klara K
authors.initials: KK
authors.lastname: Eriksson
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Villiger
authors.affiliation: Regional Blood Transfusion Service of the Swiss Red Cross, Bern, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fontana
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Yerly
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D002451:Cell Compartmentation / Q000187:drug effects; D002999:Clone Cells; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D015224:Dideoxynucleosides / Q000494:pharmacology*; D015235:HLA-B Antigens / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007156:Immunologic Memory / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D014019:Tissue Donors; D000099227:Abacavir
chemical_list: D015224:Dideoxynucleosides; D015235:HLA-B Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D000099227:Abacavir
references.citation: J Exp Med. 1994 Apr 1;179(4):1155-61
references.pmid: 7511682
references.citation: AIDS. 2012 Jul 17;26(11):F21-9
references.pmid: 22617051
references.citation: N Engl J Med. 2008 Feb 7;358(6):568-79
references.pmid: 18256392
references.citation: Eur J Immunol. 2005 Mar;35(3):996-1007
references.pmid: 15726667
references.citation: Transpl Infect Dis. 2012 Aug;14(4):422-6
references.pmid: 22650490
references.citation: Allergol Int. 2006 Mar;55(1):17-25
references.pmid: 17075282
references.citation: Pharmacogenomics. 2012 Aug;13(11):1285-306
references.pmid: 22920398
references.citation: Bioinformatics. 2006 Jan 15;22(2):195-201
references.pmid: 16301204
references.citation: Allergy. 2012 Nov;67(11):1338-46
references.pmid: 22943588
references.citation: Am J Transplant. 2009 Sep;9(9):2057-66
references.pmid: 19624567
references.citation: Eur J Immunol. 2012 Jul;42(7):1706-16
references.pmid: 22585534
references.citation: Nature. 2012 Jun 28;486(7404):554-8
references.pmid: 22722860
references.citation: J Allergy Clin Immunol. 2011 Dec;128(6):1266-1276.e11
references.pmid: 21924464
references.citation: Nat Rev Immunol. 2012 Jan 13;12(2):114-24
references.pmid: 22240625
references.citation: Immunogenetics. 2009 Jan;61(1):1-13
references.pmid: 19002680
references.citation: Int Immunol. 2002 Jun;14(6):615-26
references.pmid: 12039913
references.citation: Transplantation. 2000 Apr 27;69(8):1637-44
references.pmid: 10836375
references.citation: Nature. 1998 Mar 19;392(6673):245-52
references.pmid: 9521319
references.citation: J Burns Wounds. 2006 Jan 28;5:e1
references.pmid: 16921414
references.citation: Int Immunol. 2001 Jul;13(7):877-85
references.pmid: 11431418
references.citation: Br J Clin Pharmacol. 2011 May;71(5):701-7
references.pmid: 21480949
references.citation: J Virol. 2003 May;77(9):5226-40
references.pmid: 12692225
references.citation: Nat Rev Immunol. 2007 Dec;7(12):942-53
references.pmid: 18007679
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):9959-64
references.pmid: 22645359
references.citation: J Immunol. 2001 Jan 15;166(2):973-81
references.pmid: 11145675
references.citation: J Immunol. 1996 Aug 1;157(3):1071-9
references.pmid: 8757611
references.citation: J Immunol. 2013 May 15;190(10):4956-64
references.pmid: 23596311
references.citation: Toxicology. 2005 Apr 15;209(2):95-100
references.pmid: 15767019
references.citation: Cell Mol Life Sci. 2012 Mar;69(5):763-81
references.pmid: 21997384
references.citation: Immunity. 2008 Jun;28(6):822-32
references.pmid: 18549801