Antibodies to liver sinusoidal endothelial cells modulate immune responses in liver transplantation.
OBJECTIVE
Liver sinusoidal endothelial cells (LSECs) have been implicated to play a role in the induction of liver allograft rejections. Here, we studied the clinical consequences of preformed LSEC-reactive antibodies and their functional capacity in modulating T-cell responses.


METHODS
Pre- and posttransplant sera and T lymphocytes from 95 liver transplant patients were used in this study. LSECs were isolated from a normal healthy liver. Binding of antibodies to LSECs was detected using flow cytometric analysis. To study whether LSEC antibodies facilitated cell-mediated immunity, a mixed cell culture (MCC) assay was used. Cytokines in the supernatant of MCC were also measured by enzyme-linked immunosorbent assay. Immunohistochemical staining on liver biopsy sections was performed to detect deposition of immunoglobulins in LSEC during rejections.


RESULTS
Significantly higher numbers of patients with rejections had LSEC antibodies (35/50, 70%) compared with 8/45 (18%) without rejections (P < .0001). Purified fractions of LSEC antibodies induced the expression of the costimulatory marker CD86 on LSECs. Significantly higher numbers of patients with LSEC antibodies and rejections had an increased proliferation of T cells and markedly decreased levels of transforming growth factor (TGF)-beta in the MCC as compared with those without antibodies and rejections (P < .0001, P < .0001, respectively). Deposition of antibodies in LSECs during rejection episodes was observed in the biopsies of patients with LSEC antibodies but not in those without LSEC antibodies.


CONCLUSIONS
Our data suggest that antibodies to LSEC may facilitate acute liver allograft rejections by down-regulating the immune modulating cytokine TGF-beta and thus up-regulating alloreactive T-cell proliferation.
Ge
X
X
Division of Transplantation Surgery, Karolinska University Hospital-Huddinge, Karolinska Institute, S-141 86 Stockholm, Sweden. xupeng.ge@cfss.ki.se
Karrar
A
A
Ericzon
B-G
BG
Broomé
U
U
Sumitran-Holgersson
S
S
D000917:Antibody Formation; D001803:Blood Transfusion; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008099:Liver / Q000166:cytology* / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology* / Q000401:mortality; D008213:Lymphocyte Activation / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*
D007166:Immunosuppressive Agents