Xenobiotic-Induced Loss of Tolerance in Rabbits to the Mitochondrial Autoantigen of Primary Biliary Cirrhosis Is Reversible

Katsushi Amano, Patrick S Leung, Qingchai Xu, Jan Marik, Chao Quan, Mark J. Kurth, Michael H. Nantz, Aftab A. Ansari, Kit Lam, Mikio Zeniya, Ross L. Coppel, M. Eric Gershwin

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Previous work has demonstrated that immunization of rabbits with the xenobiotic 6-bromohexanoate coupled to BSA breaks tolerance and induces autoantibodies to mitochondria in rabbits. Such immunized rabbits develop high-titer Abs to pyruvate dehydrogenase complex (PDC)-E2, the major autoantigen of primary biliary cirrhosis. In efforts to map the fine specificity of these autoantibodies, rabbits were immunized biweekly with 6-bromohexanoate-BSA and screened for reactivity using a unique xenobiotic-peptide-agarose microarray platform with an emphasis on identifying potential structures that mimic the molecular image formed by the association of lipoic acid with the immunodominant PDC-E2 peptide. Essentially, a total of 23 xenobiotics and lipoic acid were coupled to the 12-mer peptide backbones, PDC, a mutant PDC, and albumin. As expected, we succeeded in breaking tolerance using this small organic molecule coupled to BSA. However, unlike multiple experimental methods of breaking tolerance, we report in this study that, following continued immunization, the rabbits recover tolerance. With repeated immunization, the response to the rPDC-E2 protein increased with a gradual reduction in autoantibodies against the lipoic acid-peptide, i.e., the primary tolerance-breaking autoantigen. Detailed analysis of this system may provide strategies on how to restore tolerance in patients with autoimmune disease.

Original languageEnglish (US)
Pages (from-to)6444-6452
Number of pages9
JournalJournal of Immunology
Volume172
Issue number10
StatePublished - May 15 2004

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Biliary Liver Cirrhosis
Xenobiotics
Thioctic Acid
Rabbits
Dihydrolipoyllysine-Residue Acetyltransferase
Autoantibodies
Pyruvate Dehydrogenase Complex
Immunization
Peptides
Autoantigens
Systems Analysis
Molecular Structure
Sepharose
Autoimmune Diseases
Albumins
Mitochondria
To autoantigen
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

Xenobiotic-Induced Loss of Tolerance in Rabbits to the Mitochondrial Autoantigen of Primary Biliary Cirrhosis Is Reversible. / Amano, Katsushi; Leung, Patrick S; Xu, Qingchai; Marik, Jan; Quan, Chao; Kurth, Mark J.; Nantz, Michael H.; Ansari, Aftab A.; Lam, Kit; Zeniya, Mikio; Coppel, Ross L.; Gershwin, M. Eric.

In: Journal of Immunology, Vol. 172, No. 10, 15.05.2004, p. 6444-6452.

Research output: Contribution to journalArticle

Amano, K, Leung, PS, Xu, Q, Marik, J, Quan, C, Kurth, MJ, Nantz, MH, Ansari, AA, Lam, K, Zeniya, M, Coppel, RL & Gershwin, ME 2004, 'Xenobiotic-Induced Loss of Tolerance in Rabbits to the Mitochondrial Autoantigen of Primary Biliary Cirrhosis Is Reversible', Journal of Immunology, vol. 172, no. 10, pp. 6444-6452.
Amano, Katsushi ; Leung, Patrick S ; Xu, Qingchai ; Marik, Jan ; Quan, Chao ; Kurth, Mark J. ; Nantz, Michael H. ; Ansari, Aftab A. ; Lam, Kit ; Zeniya, Mikio ; Coppel, Ross L. ; Gershwin, M. Eric. / Xenobiotic-Induced Loss of Tolerance in Rabbits to the Mitochondrial Autoantigen of Primary Biliary Cirrhosis Is Reversible. In: Journal of Immunology. 2004 ; Vol. 172, No. 10. pp. 6444-6452.
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