The integrin ␣4␤1 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides costimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of ␣4␤1 during the formation of the immune synapse is currently unknown. Here, we show that ␣4␤1 is recruited to both human and murine antigen-dependent immune synapses, when the antigen-presenting cell is a B lymphocyte or a dendritic cell, colocalizing with LFA-1 at the peripheral supramolecular activation complex. However, when conjugates are formed in the presence of anti-␣4 antibodies, VLA-4 colocalizes with the CD3-chain at the center of the synapse. In addition, antibody engagement of ␣4 integrin promotes polarization toward a T helper 1 (Th1) response in human in vitro models of CD4 ؉ T cell differentiation and naïve T cell priming by dendritic cells. The in vivo administration of anti-␣4 integrin antibodies also induces an immune deviation to Th1 response that dampens a Th2-driven autoimmune nephritis in Brown Norway rats. These data reveal a regulatory role of ␣4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.A fter the recognition of antigens (Ag) presented by dendritic cells (DCs), naïve T lymphocytes proliferate and differentiate into T helper (Th) 1 or 2 effector cells. These effector lymphocytes are characterized by distinct patterns of cytokine production and homing behavior. Th1 cells mainly produce IFN-␥ and IL-2 and have a key role in the cellular immune responses. Conversely, Th2 cells produce IL-4, IL-5, IL-6, and IL-10 and promote the humoral immune responses (1). DCs are the only Ag-presenting cells (APCs) involved in the priming of naïve Th cells and their polarization toward Th1 or Th2 differentiation. To acquire this capacity, DCs must undergo a maturation process characterized by the loss of their Ag-capturing capacity and the increase of their expression of costimulatory and adhesion molecules, including ␣4␤1 integrin (2). However, other APCs (e.g., B lymphocytes) are also involved in regulating the cytokine profiles of Th cell responses, indicating the importance of postpriming events (3).The interaction between T cells and APCs plays an important role in directing Th cell polarization. The strength of antigenic stimulation, the duration of T cell receptor engagement, the presence of different cytokines, and the participation of distinct costimulatory molecules are critical in determining the phenotype of differentiated T cells. The cytokine IL-12, high doses of Ag, and CD28͞B7-1 interaction promote Th1 differentiation, whereas an environment enriched in IL-4, low doses of Ag, and CD28͞B7-2 or inducible costimulator (ICOS)͞ICOS ligand participation promote Th2 responses (4).Integrins are a large family of ␣␤ heterodimeric transmembrane proteins that mediate cell-cell and cell-extracellular matrix adhesion. Several integrins, lymphocyte functionassociated (LFA-1; ␣ L ␤ 2 ), very late activation antigen-4 (VLA-4; ␣4␤1), and VLA-1 (␣1␤1) have ...

Abstract. Slowly progressive renal injury is the major cause for ESRD. The model of progressive immune complex glomerulonephritis in autoimmune MRL lpr/lpr mice was used to evaluate whether chemokine receptor CCR1 blockade late in the disease course can affect progression to renal failure. Mice were treated with subcutaneous injections of either vehicle or BX471, a nonpeptide CCR1 antagonist, three times a week from week 20 to 24 of age. BX471 improved blood urea nitrogen levels (BX471, 35.1 Ϯ 5.3; vehicle, 73.1 Ϯ 39.6 mg/dl; P Ͻ 0.05) and reduced the amount of ERHR-3 macrophages, CD3 lymphocytes, Ki-67 positive proliferating cells, and ssDNA positive apoptotic cells in the interstitium but not in glomeruli. Cell transfer studies with fluorescence-labeled T cells that were pretreated with either vehicle or BX471 showed that BX471 blocks macrophage and T cell recruitment to the renal interstitium of MRL lpr/lpr mice. This was associated with reduced renal expression of CC chemokines CCL2, CCL3, CCL4, and CCL5 and the chemokine receptors CCR1, CCR2, and CCR5. Furthermore, BX471 reduced the extent of interstitial fibrosis as evaluated by interstitial smooth muscle actin expression and collagen I deposits, as well as mRNA expression for collagen I and TGF-␤. BX471 did not affect serum DNA autoantibodies, proteinuria, or markers of glomerular injury in MRL lpr/lpr mice. This is the first evidence that, in advanced chronic renal injury, blockade of CCR1 can halt disease progression and improve renal function by selective inhibition of interstitial leukocyte recruitment and fibrosis.

tRA treatment reduces lymphoproliferation and glomerulonephritis in MRL/lpr mice. This occurs in spite of unaltered anti-DNA titers and glomerular immune complex deposition, and cannot be overcome by T-cell transfer from nephritic MRL/lpr mice.

1 Puromycin aminonucleoside (PAN)-induced nephrosis is a model of human minimal change disease. In rats, PAN induces nephrotic-range proteinuria, renal epithelial cell (podocyte) damage, infiltration of mononuclear leukocytes, and apoptosis of several renal cell types. 2 Retinoic acid (RA) modulates a wide range of biological processes, such as inflammation and apoptosis. Since renal damage by PAN is characterized by inflammatory infiltration and epithelial cell death, the effect of treatment with all-trans RA (tRA) was examined in the PAN nephrosis model and in the cultured differentiated podocyte. 3 Treatment with tRA 4 days after PAN injection did not inhibit the proteinuria peak but reversed it significantly. However, treatment with tRA both before and 2 days after the injection of PAN protected the glomerular epithelial cells, diminishing the cellular edema and diffuseness of the foot process effacement. Preservation of the podocyte architecture correlated with the inhibition of proteinuria. The anti-inflammatory effect of tRA was evidenced by the inhibition of PAN-induced interstitial mononuclear cell infiltration and the decreased renal expression of two molecules involved in monocyte infiltration: fibronectin and monocyte chemoattractant protein-1. TUNEL assays showed that tRA inhibited the PAN-induced apoptosis of cultured differentiated mouse podocytes. 4 We conclude that tRA treatment may prevent proteinuria by protecting the podocytes from injury and diminishing the interstitial mononuclear infiltrate in the model of PAN nephrosis. Retinoids are a potential new treatment for kidney diseases characterized by proteinuria and mononuclear cell infiltration.