Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.
Inhibition of endothelial receptor expression and of T-cell ligand activity by mycophenolate mofetil.
Transpl Immunol. 1998 Dec;6(4):251-9. Unique Identifier : AIDSLINE MED/99272167 Blaheta RA; Leckel K; Wittig B; Zenker D; Oppermann E; Harder S; Scholz M; Weber S; Schuldes H; Encke A; Markus BH; Department of General Surgery, Johann Wolfgang Goethe-University,; Frankfurt am Main, Germany. Blaheta@em.uni-frankfurt.de
Abstract:
The novel immunosuppressive drug mycophenolate mofetil (CellCept, MMF) blocks DNA-synthesis by the inhibition of the enzyme inosine monophosphate dehydrogenase (IMDH). IMDH is also involved in the synthesis of adhesion receptors which are known to play an important role in the regulation of cell-cell contacts. Therefore, application of MMF might lead to a reduction of cellular infiltrates in the course of transplant rejection. To evaluate the therapeutic value of MMF, we investigated to what extent MMF blocks T-lymphocyte infiltration in vitro with regard to (a) adhesion to endothelial cells, (b) horizontal migration along these cells and (c) penetration through the endothelial cells. The results demonstrated a strong inhibition of both CD4+ and CD8+ T-cell adhesion and penetration by MMF. The ID50 value for CD4+ T-cell adhesion was calculated to be 0.03 microM and the ID50 value for CD4+ T-cell penetration 1.21 microM. MMF did not significantly influence the horizontal migration of T-lymphocytes along the human vascular endothelial cell (HUVEC) borders. FACS-analysis revealed a diminished E-selectin and P-selectin expression on endothelial cell membranes in the presence of MMF. Although MMF did not interfere with the synthesis of T-cell adhesion ligands, the binding activity of lymphocytic leucocyte function associated antigen 1 (LFA-1), very late antigen 4 (VLA-4) and PSGL-1 (P-selectin glycoprotein ligand 1) to immobilized intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P-selectin was impaired. Moreover, MMF prevented VLA-4 and PSGL-1 receptor accumulation on the membranes of T-cell pseudopodia. It can be concluded that MMF possesses potent infiltration blocking properties. MMF evoked down-regulation of specific endothelial membrane molecules and the loss of protein localization in the lymphocyte protrusions might be predominantly responsible for the observed blockade of cell adhesion and penetration.
Keywords: JOURNAL ARTICLE Antigens, CD15/METABOLISM Cell Adhesion Molecules/*BIOSYNTHESIS Cells, Cultured CD4-Positive T-Lymphocytes/*DRUG EFFECTS/METABOLISM CD8-Positive T-Lymphocytes/*DRUG EFFECTS/METABOLISM E-Selectin/BIOSYNTHESIS Endothelium, Vascular/CYTOLOGY Human Immunosuppressive Agents/*PHARMACOLOGY/TOXICITY Integrins/METABOLISM Intercellular Adhesion Molecule-1/BIOSYNTHESIS IMP Dehydrogenase/*ANTAGONISTS & INHIB Ligands Lymphocyte Function-Associated Antigen-1/METABOLISM Membrane Glycoproteins/METABOLISM Mycophenolic Acid/*ANALOGS & DERIVATIVES/PHARMACOLOGY/TOXICITY Oligosaccharides/METABOLISM P-Selectin/BIOSYNTHESIS Receptors, Lymphocyte Homing/*METABOLISM Support, Non-U.S. Gov't Vascular Cell Adhesion Molecule-1/BIOSYNTHESIS 991030
A99A0930
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.
