Fibronectin-Mononuclear Cell Interactions Regulate Type 1 Helper T Cell Cytokine Network in Tolerant Transplant Recipients

• Published in: The American journal of pathology Vol. 157; no. 4; pp. 1207 - 1218
• Main Authors: Coito, Ana J., Onodera, Kazuhiko, Kato, Hirohisa, Busuttil, Ronald W., Kupiec-Weglinski, Jerzy W.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.10.2000; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Cell Adhesion Molecules - metabolism; Cytokines - antagonists & inhibitors; Cytokines - genetics; Cytokines - metabolism; Cytokines - physiology; Fibronectins - metabolism; Fibronectins - physiology; Graft Rejection - etiology; Heart Transplantation - immunology; Immune Tolerance - physiology; Integrin alpha4beta1; Integrins - physiology; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - physiology; Macrophages - metabolism; Male; Medical sciences; Myocardium - cytology; Myocardium - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Lymphocyte Homing - physiology; Regular; RNA, Messenger - antagonists & inhibitors; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; T-Lymphocytes, Helper-Inducer - metabolism; Th1 Cells - metabolism; Transplantation, Homologous; Up-Regulation; Heart; Immunohistochemistry; Animal model; Rat; Pathogenesis; Rodentia; Cytokine; Cell adhesion molecule; Helper cell; Transplantation; Recipient; Homotransplantation; Fibronectin; Pathology; Vertebrata; Mammalia; Mononuclear cell; Surgery; Animal; Immune tolerance; T-Lymphocyte; Graft; Skin; Molecular biology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)64636-6

Fibronectin (FN), expressed primarily by macrophages, endothelial cells, and smooth muscle cells, represents an integral feature of the rejection response in transplant recipients. Here we demonstrate a unique pattern of cellular FN expression in rat recipients of cardiac allografts rendered tolerant in an infectious manner with either nondepleting CD4 mAb or regulatory spleen cells. Unlike in rejecting controls, cellular FN in tolerant hosts was restricted to the graft vessels and no vascular cell adhesion molecule-1 or intercellular adhesion molecule-1 expression could be found, supporting the role of FN in leukocyte sequestration at the graft site. The lack of myocardial FN in tolerant rats, despite dense macrophage infiltration, correlated with profound depression of Th1 (interleukin-2 and interferon-γ) cytokines. Treatment with CD4-depleting mAb prevented tolerance induction and restored myocardial expression of FN in parallel with marked increase in the expression of interleukin-2 and interferon-γ mRNA/protein. Furthermore, connective segment-1 peptide-facilitated adjunctive blockade of FN-α4β1 interactions in recipients conditioned with CD4 depleting mAb, significantly depressed intragraft expression of interleukin-2 and interferon-γ mRNA/protein. Hence, the lack of FN associated with infiltrating leukocytes plays an important role in the maintenance of tolerance in transplant recipients by depressing local expression of Th1 cytokines that otherwise facilitate acute graft rejection.