Liver transplantation-induced antihistone H1 autoantibodies suppress mixed lymphocyte reaction.
BACKGROUND
In a rat model of orthotopic liver transplantation (OLT), recipient serum after OLT (post-OLT serum) has been reported to prevent allograft rejection. However, the molecular identities of immunosuppressive factors, which are in the early stage of post-OLT, remain elusive. This study was aimed to identify immunodominant suppressive factors present in early post-OLT serum.


METHODS
The immunosuppressive activities of post-OLT serum, immunoglobulin (Ig) G-depleted serum, and purified IgG were evaluated in vitro by inhibition of the mixed lymphocyte reaction (MLR). Autoantigens recognized by the MLR-inhibitory IgG in early post-OLT serum were identified by the internal protein sequencing.


RESULTS
Recipient post-OLT serum inhibited MLR, and its immunosuppressive activity vanished by means of the elimination of OLT-inducible IgG. IgG from post-OLT sera (2-3 weeks) specifically reacted to 31-, 34-, and 73-kDa autoantigens on splenic cells. The internal sequences of the doublet 31- and 34-kDa antigens coincided completely with those of histone H1 molecules. The levels of histone H1-specific antibodies were transiently increased to a plateau around 2 to 3 weeks after OLT but decreased in the later tolerogenic phase. Immunodepletion of antihistone H1 autoantibodies from early post-OLT serum abolished the MLR-inhibitory activity. Furthermore, rabbit polyclonal antibody-directed histone H1 not only suppressed MLR but also prolonged allograft survival.


CONCLUSIONS
In this article, the authors provide evidence that autoreactive antibodies against histone H1, which are transiently induced at the early stage by liver transplantation, are a major OLT-induced graft survival factor.
Nakano
Toshiaki
T
Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8530, Japan.
Kawamoto
Seiji
S
Lai
Chia-Yun
CY
Sasaki
Tetsuya
T
Aki
Tsunehiro
T
Shigeta
Seiko
S
Goto
Takeshi
T
Sato
Shuji
S
Goto
Shigeru
S
Chen
Chao-Long
CL
Ono
Kazuhisa
K
D000818:Animals; D000954:Antigens, Surface / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology* / Q000494:pharmacology; D001324:Autoantigens / Q000276:immunology; D003429:Cross Reactions; D006657:Histones / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016031:Liver Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000954:Antigens, Surface; D001323:Autoantibodies; D001324:Autoantigens; D006657:Histones; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents