alpha 4 integrin in islet allograft rejection

Background Adhesion molecules are involved in multiple steps of the continu um of allograft rejection. We studied the effects of blockade of the intera ctions between alpha4 integrin and its ligands, vascular cell adhesion mole cule-1 (VCAM-1) and fibronectin, on allograft survival. Methods. Streptozotocin-induced diabetic CBA (H-2(k)) mice received islet t ransplants from BALB/c (H-2(d)) donors. Recipient mice were treated with an tibodies against alpha4 integrin (PS/2), VCAM-1 (MK 2.7), and a peptide cor responding to the binding site of alpha4 integrin on fibronectin (connectin g segment 1 peptide, CS1-peptide), Graft function was measured by daily tai l vein blood glucose levels, with rejection defined as the return of hyperg lycemia, Graft-bearing kidneys were removed for immunohistochemical analysi s. Results, Treatment with anti-alpha4 integrin antibody, anti-VCAM-1 antibody , or with CS1-peptide led to long-term survival of islet allografts, Recipi ents with long-surviving islet grafts did not show tolerance, in that they rejected a second donor-type islet allograft, Although both anti-alpha4 int egrin antibody and CS1-peptide completely abolished cellular infiltration o f the islet graft 7 days after transplantation, anti-VCAM-1-treated recipie nts showed a dense peri-islet infiltrate of activated, alpha4 integrin+, cy totoxic T cells. Conclusions. These data show that a4 integrin is critically important to al lograft rejection. Anti-VCAM-1 antibody appears to prevent rejection withou t qualitatively affecting either T cell activation or migration to the graf t. Conversely, anti-alpha4 integrin antibody and CS1-peptide may prevent is let 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.