The receptor-mediated adhesion of cells to ligand-coated surfaces in viscous shear flow is an important step in many physiological processes, such as the neutrophil-mediated inflammatory response, lymphocyte homing, and tumor cell metastasis. This paper describes a calculational method which simulates the interaction of a single cell with a ligand-coated surface under flow. The cell is idealized as a microvilli-coated hard sphere covered with adhesive springs. The distribution of microvilli on the cell surface, the distribution of receptors on microvilli tips, and the forward and reverse reaction between receptor and ligand are all simulated using random number sampling of appropriate probability functions. The velocity of the cell at each time step in the simulation results from a balance of hydrodynamic, colloidal and bonding forces; the bonding force is derived by summing the individual contributions of each receptor-ligand tether. The model can simulate the effect of many parameters on adhesion, such as the number of receptors on microvilli tips, the density of ligand, the rates of reaction between receptor and ligand, the stiffness of the resulting receptor-ligand springs, the response of springs to strain, and the magnitude of the bulk hydrodynamic stresses. The model can successfully recreate the entire range of expected and observed adhesive phenomena, from completely unencumbered motion, to rolling, to transient attachment, to firm adhesion. Also, the method can generate meaningful statistical measures of adhesion, including the mean and variance in velocity, rate constants for cell attachment and detachment, and the frequency of adhesion. We find a critical modulating parameter of adhesion is the fractional spring slippage, which relates the strain of a bond to its rate of breakage; the higher the slippage, the faster the breakage for the same strain. Our analysis of neutrophil adhesive behavior on selectin-coated (CD62-coated) surfaces in viscous shear flow reported by Lawrence and Springer (Lawrence, M.B., and T.A. Springer 1991. Cell. 65:859-874) shows the fractional spring slippage of the CD62-LECAM-1 bond is likely below 0.01. We conclude the unique ability of this selectin bond to cause neutrophil rolling under flow is a result of its unique response to strain. Furthermore, our model can successfully recreate data on neutrophil rolling as function of CD62 surface density.
Previously, we demonstrated that purified hepatocytes (in the absence of donor-type antigen-presenting cells) are immunogenic in vitro in mixed lymphocyte hepatocyte culture (MLHC) by virtue of expression of major histocompatibility complex (MHC) class I. 1-5 Tumor necrosis factor ␣ (TNF-␣) is an inflammatory cytokine known to up-regulate MHC class I and adhesion molecule expression, and has been demonstrated to be important in the rejection of vascularized organ allografts. [6][7][8] In some models, host treatment with a monoclonal antibody directed against this cytokine prolongs graft survival of rat cardiac, liver, and renal allografts. 6-12 However, the mechanism by which immunotherapy directed against this cytokine influences graft survival is unknown.Adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]) also appear to play important roles in vascularized organ allograft rejection since monoclonal antibodies directed against ICAM-1 and VCAM-1 have been shown to be effective in prolonging graft survival of murine cardiac allografts, cynomologous monkey renal transplants, and human renal transplants. [13][14][15][16][17] 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 expression during liver allograft rejection. Parenchymal cells (including liver 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 MHC antigens by parenchymal cells is not known. Cytokines, including interleukin-1, interferon gamma, and TNF-␣, have been shown to up-regulate hepatocyte expression of ICAM-1 and their adhesion to T lymphocytes in vitro. 18 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 on the immunogenicity of liver cells has not been studied. The current studies were undertaken to determine the effect of the inflammatory cytokine Abbreviations: MLHC, mixed lymphocyte hepatocyte culture; MHC, major histocompatibility complex; TNF-␣, tumor necrosis factor ␣; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; HC, hepatocyte; NPC, nonparenchymal cell; FBS, fetal bovine serum; MLNPC, mixed lymphocyte nonparenchymal cell culture; cpm, counts per minute; E:T, effector-to-target; GART-FITC, goat-anti-rat-fluorescein isothiocyanate conjugated; MFI, mean fluorescent intensity; allo-CTL, allospecific cytotoxic T lymphocyte; SMA, sponge matrix allograft.From the
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