Mechanisms of liver allograft rejections

Sammanfattning: Liver transplantation (M) has become a standard treatment for many end-stage liver diseases. However, acute rejections still occur in about half of the liver transplant recipients even treated with a combination of different modem immunosuppressants. The ultimate goal of liver transplantation is tolerance induction, which largely relies on the understanding of mechanisms involved in acute rejection process. The exact mechanisms of liver allograft rejections are not yet elucidated and there is a great paucity of data regarding the role of humoral immunity. We were therefore interested in elucidating some of the mechanisms underlying liver allograft rejections. Specifically, we were interested in: i) Detection and clinical correlation of the presence of antibodies in liver transplant patients to surface antigens expressed on the clinically relevant target cells of destruction and ii) Determining the possible functional role of these antibodies in mediating liver allograft rejections. iii) In addition, we also attempted to define the role of liver sinusoidal endothelial cells in allograft rejections in an experimental model. We performed the following studies to evaluate the significance of antibodies to liver specific cells such as biliary epithelial cells (BEC) and liver sinusoidal endothelial cells (LSEC) in 95 liver transplant patients. In paper 1, we found that preformed antibodies to BEC are associated with acute liver allograft rejections. In paper 11, antibodies to BEC in the post-LTx period were found to be associated with cholangitis. Functional analysis of post-transplant antibodies to BEC showed they are capable of inducing toll-like receptor 2 and 3 as well as proinflammatory cytokine and chemokine expression. In paper Ill, the role of antibodies to LSEC in LTx was studied. Antibodies to LSEC significantly correlate to acute liver allograft rejections. We demonstrated that antibodies to LSEC may facilitate acute rejection episodes by regulating cellular immune responses. We further observed in vivo antibody deposition in liver biopsies taken from patients with antibodies to BEC or LSEC during acute rejection and cholangitis episodes. We found that majority of the antibodies to BEC and LSEC are not specific for human leukocyte antigens (HLA), and they do not cross react with other control cell types. Immunoglobulin classes of these antibodies are a mixture of IgG and IgM. In paper IV, by using a fully MHC mismatched rat liver transplantation model, we were able to compare the difference between rejection and spontaneous acceptance (tolerance) of rat liver allografts. One of the earliest and most profound detectable differences between the two groups was the significantly decreased endocytic functional capacity of LSEC in the rejecting group. Our findings indicate that presence of non-HLA antibodies to tissue specific antigens is a risk factor for rejections or post-transplant complications. Antibodies may contribute to liver allograft rejections by modulating cellular immune responses. B cell targeting therapy and strategies to help maintain LSEC functional integrity after transplantation may be beneficial for liver transplant patients.