ABSTRACT
BACKGROUND: Adhesion molecules are involved in multiple steps of the continuum of allograft rejection. We studied the effects of blockade of the interactions between alpha4 integrin and its ligands, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, on allograft survival. METHODS: Streptozotocin-induced diabetic CBA (H-2k) mice received islet transplants from BALB/c (H-2d) donors. Recipient mice were treated with antibodies against alpha4 integrin (PS/2), VCAM-1 (MK 2.7), and a peptide corresponding to the binding site of alpha4 integrin on fibronectin (connecting segment 1 peptide, CS1-peptide). Graft function was measured by daily tail vein blood glucose levels, with rejection defined as the return of hyperglycemia. Graft-bearing kidneys were removed for immunohistochemical analysis. RESULTS: Treatment with anti-alpha4 integrin antibody, anti-VCAM-1 antibody, or with CS1-peptide led to long-term survival of islet allografts. Recipients with long-surviving islet grafts did not show tolerance, in that they rejected a second donor-type islet allograft. Although both anti-alpha4 integrin antibody and CS1-peptide completely abolished cellular infiltration of the islet graft 7 days after transplantation, anti-VCAM-1-treated recipients showed a dense peri-islet infiltrate of activated, alpha4 integrin+, cytotoxic T cells. CONCLUSIONS: These data show that alpha4 integrin is critically important to allograft rejection. Anti-VCAM-1 antibody appears to prevent rejection without qualitatively affecting either T cell activation or migration to the graft. Conversely, anti-alpha4 integrin antibody and CS1-peptide may prevent islet allograft rejection by altering either T cell activation or lymphocyte trafficking. Blocking interactions between alpha4 integrin and its ligands may provide novel forms of immunosuppression.
Subject(s)
Antigens, CD/metabolism , Graft Rejection/metabolism , Islets of Langerhans Transplantation , Islets of Langerhans/metabolism , Animals , Antibodies/pharmacology , Antigens, CD/immunology , Graft Survival , Immune Tolerance , Integrin alpha4 , Intercellular Signaling Peptides and Proteins , Islets of Langerhans/drug effects , Islets of Langerhans/pathology , Islets of Langerhans Transplantation/immunology , Lymphocyte Culture Test, Mixed , Lymphocytes/drug effects , Lymphocytes/pathology , Lymphocytes/physiology , Male , Mice , Mice, Inbred BALB C , Peptides/pharmacology , Reoperation , Time Factors , Vascular Cell Adhesion Molecule-1/immunologyABSTRACT
The experimental advance made by Camillo Golgi's 'black reaction' has been universally recognized as the start of the modern revolution in the study of the nervous system. By contrast, his concepts of nervous organization, particularly his support for the idea of a 'nervous reticulum', have been universally rejected. The premise of the present paper is that ideas of a biologist of this stature deserve re-examination. Golgi's arguments for considering the holistic function of the brain seem to come from his experience as a physician, and presage the views of the gestaltists and, more recently, the conceptual underpinnings of artificial neural networks. His interest in the possible nutritional roles of neuronal dendrites can be seen to anticipate current investigations, at the cellular level, of the metabolic basis of brain imaging. These and other currents in Golgi's thought deserve further study.
