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.