Efficacy of anti-intercellular adhesion molecule-1 immunotherapy on immune responses to allogeneic hepatocytes in mice

Abstract

Adhesion molecules appear to play important roles in vascularized organ allograft rejection, because antibodies directed against them are effective in prolonging survival of vascularized organ allografts in rodents. However, the efficacy of these agents for cellular allografts is unknown. The current studies were undertaken to determine the role of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on host immune responses to purified hepatocytes. Host mice (C3H, H-2 k ) grafted with hepatocytes in sponge matrix allografts (HC-SMA) received IgG isotype control, anti-ICAM-1, or anti-VCAM-1 monoclonal antibody (mAb) on days 0 through 9 after grafting. Twelve to 14 days later, host cells infiltrating the HC-SMA were assessed for the development of allospe- Adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are expressed on endothelial and some parenchymal cells. These adhesion molecules (ICAM-1 and VCAM-1) also appear to play important roles in vascularized organ allograft rejection, because antibodies directed against ICAM-1 and VCAM-1 have been shown to be effective in prolonging survival of vascularized murine cardiac allografts, cynomolgous monkey renal transplants, and human renal transplants, [1][2][3][4][5][6] as well as nonvascularized skin allografts. 7 ICAM-1 has been implicated in liver transplant rejection by studies that show increased levels of soluble ICAM-1 during rejection episodes and histological detection of increased ICAM-1 during liver allograft rejection. [8][9][10] Parenchymal cells may constitutively express or may be induced to express adhesion molecules by various cytokines. However, the role of adhesion molecules in the presentation of major histocompatibility complex (MHC) antigens by parenchymal cells is not known. Cytokines, including interleukin-1, interferon gamma, and tumor necrosis factor (TNF), have been shown to up-regulate hepatocyte expression of ICAM-1 and their adhesion to T lymphocytes in vitro. 11 However, the in vivo effects of various cytokines on adhesion molecule expression in the liver has not been described, and the consequences of in vivo cytokine exposure upon the immunogenicity of liver cells has not been reported.Previously, we demonstrated that purified hepatocytes in the absence of donor-type antigen-presenting cells are immunogenic in vitro in mixed lymphocyte hepatocyte culture as determined by their ability to stimulate proliferation and the development of allospecific cytolytic effector T cells (alloCTLs) in mixed lymphocyte hepatocyte culture. The observed immunogenicity was correlated with the expression of MHC class I antigens. 12 We have further demonstrated that purified hepatocytes are immunogenic in vivo and stimulate the development of allo-CTLs in sponge matrix allografts (SMA) bearing allogeneic hepatocytes. 13,14 In this report, we extend our previous in vivo studies using the hepatocytesponge matrix allograft (HC-SMA) model to examine the role of ICA...

Immunologic Considerations for Therapeutic Strategies Utilizing Allogeneic Hepatocytes: Hepatocyte-Expressed Membrane-Bound Major Histocompatibility Complex Class I Antigen Sensitizes While Soluble Antigen Suppresses the Immune Response in Rats

“…The immunologic sensitizing effect of purified allogeneic hepatocytes that we report in this study is consistent with recent reports by Bumgardner et al, 26,46 where they have shown that normal, unaltered, allogeneic hepatocytes are rejected by CD4 and CD8 cell-dependent immunologic mechanisms. However, in contrast to our results, a study by Foster et al 47 has reported that intravenous administration of viable donor hepatocytes protects renal allografts against rejection in a rat model.…”

Different Costimulation Signals Used by CD4+ and CD8+ Cells That Independently Initiate Rejection of Allogenic Hepatocytes in Mice

“…8). Thus, hepatocytes appear to stimulate strong immune responses in the context of strong expression of MHC class I and ICAM-1 30 but in the absence of MHC II, B7-2, or CD40 expression. These results suggest that costimulation blockade involved interruption of costimulation signaling between host FIG.…”

Adoptive transfusion of tolerant dendritic cells prolong the survival of renal allografts: a systematic review

“…Tol‐DCs could be deactivated and IL‐4 and IL‐10 production reduced by the additional infusion of anti‐OX‐2 mAb (monoclonal Ab) (not shown), but not by anti‐mouse CD28 or anti‐mouse CTLA4 antibodies . Intercellular adhesion molecule‐1 (ICAM‐1) is important in regulating immune responses . The survival of renal allografts from ICAM‐1 knockout mice (‐/‐) was longer than from wild type mice (+/+) following the infusion of p.v.…”