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 language | English (US) |
|---|---|
| Pages (from-to) | 6444-6452 |
| Number of pages | 9 |
| Journal | Journal of Immunology |
| Volume | 172 |
| Issue number | 10 |
| State | Published - May 15 2004 |
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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 journal › Article
}
TY - JOUR
T1 - Xenobiotic-Induced Loss of Tolerance in Rabbits to the Mitochondrial Autoantigen of Primary Biliary Cirrhosis Is Reversible
AU - Amano, Katsushi
AU - Leung, Patrick S
AU - Xu, Qingchai
AU - Marik, Jan
AU - Quan, Chao
AU - Kurth, Mark J.
AU - Nantz, Michael H.
AU - Ansari, Aftab A.
AU - Lam, Kit
AU - Zeniya, Mikio
AU - Coppel, Ross L.
AU - Gershwin, M. Eric
PY - 2004/5/15
Y1 - 2004/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=2442473106&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2442473106&partnerID=8YFLogxK
M3 - Article
C2 - 15128836
AN - SCOPUS:2442473106
VL - 172
SP - 6444
EP - 6452
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 10
ER -