59. Eicosapentaenoic acid attenuate allograft rejection in HLA-B27/EGFP transgenic rat cardiac transplantation model

Introduction: Current immunosuppressive therapies are broad based and nonspecific. Induction of peripheral tolerance in transplant antigen specific manner is an unrealized clinical goal. Major histocompatibility complex (MHC) class I molecules are cell-surface proteins that present peptides to CD8 T-cells in antigen-specific MHC restricted T-cell responses. Development of an animal model bearing definite antigen is important to facilitate evaluation and modulation of specific alloantigen responses after transplantation.
Methods and results: First, heterotopic cardiac transplatation was performed from F344.Tg/EGFP and F344.Tg/HLA-B27 rats to F344 rats. We found that F344 recipients definitely accepted F344.Tg/EGFP, whereas rejected F344.Tg/HLA-B27 rat on 39.4±6.5 days (MST, n=5), due to high production of anti-HLA IgM and IgG specific antibodies. In addition, immunization of F344 rat with skin grafts from F344.Tg/HLA-B27 rat two weeks before resulted in robust production of anti-HLA IgM ang IgG antibodies, and accelerated rejection of a secondary cardiac allograft (n=5; 7.4±1.9 days). Even more interestingly findings were F344 recipients rejected cardiac graft from double transgenic F344.Tg/HLA-B27 & EGFP rat on 9.0±3.2 days (n=8), associated with significantly increase of infiltration lymphocytes on day 7, suggesting a role for cellular immune rejection. Eicosapentaenic acid (EPA), one of the omega-3 polyunsaturated fatty acids in fish oil, could attenuate the anti- HLA IgG antibodies production and B cell population, prolong double transgenic F344. Tg/HLA-B27 & EGFP to F344 rat cardiac allografts survial significantly (n=9, 36.1±13.6 days). Moreover, the mRNA expression of the grafts was asscessed by quantitative real time reverse-transcription polymerase chain reaction (qRT-PCR), revealing the increase of HO-1, IL-10, TGC-β and IDO mRNA expression in the EPA-treated group compare to the control's.
Conclusions: Hence our data indicated that HLA-B27 and/ or GFP transgenic proteins are useful for establish a unique animal transplantation model to clarify the mechanism of the allogeneic cellular and humoral immune response, in which the transplant antigens are presented specifically. Furthermore, we also provided that the EPA was effective in the treatment of rat cardiac allograft rejection and may allow the development of novel immunomodulatory strategies in organ transplantation.