Effective treatment of experimental lupus nephritis by combined administration of anti-CD11a and anti-CD54 antibodies

Abstract

SUMMARYMice with chronic graft-versus-host disease (GVHD), induced by injection of DBA/2 lymphocytes in (C57BL10*DBA/2) F 1 hybrids, develop a syndrome resembling systemic lupus erythematosus (SLE) with immune complex glomerulonephritis. In this model we evaluated the role of interactions between CD11a (LFA-1a) and CD54 (intercellular adhesion molecule-1 (ICAM-1)) molecules on leucocytes in the development of renal disease in systemic autoimmunity. Two weeks after induction of GVHD, when anti-nuclear autoantibodies were detected in the circulation and immune complexes had formed in the glomeruli, mice were injected twice per week with rat anti-CD11a and anti-CD54 MoAbs, or with their vehicle PBS, or with control rat IgG. MoAb treatment significantly lowered albuminuria and increased survival compared with control mice with GVHD. In the glomeruli of MoAb-treated mice there was markedly less binding of immunoglobulin and C3, while anti-renal tubular epithelium autoantibodies, but not anti-glomerular basement membrane autoantibodies, were significantly lowered in the circulation 4 weeks after disease induction. In addition, MoAb treatment inhibited the glomerular influx of CD11a + cells and decreased development of histological abnormalities in the kidneys. Both rat IgG-and MoAb-treated mice developed anti-rat immunoglobulin antibodies. Furthermore, a marked splenomegaly with an increase of the T cell compartment was observed in MoAb-treated mice with GVHD. These results show that CD11a/CD54 interactions are crucial for the full-blown development of lupus nephritis in this model. Treatment aimed at blocking the activity of these molecules profoundly attenuated the development of renal disease in chronic GVHD even if started when first symptoms of SLE (i.e. anti-nuclear autoantibodies in sera and glomerular binding of immunoglobulins) were already detectable.

Intercellular Adhesion Molecule-1/LFA-1 Cross Talk Is a Proximate Mediator Capable of Disrupting Immune Integration and Tolerance Mechanism at the Feto-Maternal Interface in Murine Pregnancies

“…Molecules that play a proximate and critical role in controlling tethering (adhesion) and spreading of T cells are integrins such as LFA-1 (CD11a/CD18, ␣ 1 ␤ 1 integrin) (18,19). Blocking of LFA-1 by injection of mice with mAb against LFA-1 in vivo has been described to prevent fetal rejection (20), to reduce the severity of graft-vs-host reactions (21), to prolong allograft survival (22), to inhibit the development of autoimmunity (23), and to block neuropeptide substance P-induced leukocyte migration (24). The latter observation is particularly striking because our previous findings revealed that the lack of immune tolerance, similar to graft-vs-host reactions, is mediated via substance P in stress-triggered murine pregnancy failure (25).…”

Stress-Induced Neurogenic Inflammation in Murine Skin Skews Dendritic Cells Towards Maturation and Migration

“…Because the cross talk between co-stimulatory molecules on APCs, such as ICAM-1, and the respective ligand LFA-1 on leukocytes is crucial in inflammatory settings, 21,[23][24][25][26]49 we analyzed the phenotype of APC clusters in the skin in response to LFA-1/ICAM-1 blockade. As depicted in Figure 3, C and D, such blockade of ICAM-1/LFA-1 cross talk significantly abolished the stress-induced increase of cell clusters expressing the DC maturation markers MHC II and ICAM-1.…”

“…21,22 Blocking of LFA-1/ICAM-1 in mice in vivo can abrogate the onset of inflammation, hereby preventing fetal rejection. 23 Moreover, LFA-1/ICAM-1 interactions also are important during graft-versus-host reactions, 24 the development of autoimmunity, 25 and neuropeptide SP-induced leukocyte migration. 26 The latter observation is particularly striking since we were recently able to show that stress leads to neurogenic inflammation in murine skin, comprised of sprouting nerve fibers, increased number and activation of MHC II ϩ APCs and mast cells, upregulation of nerve growth factor, and the neuronal plasticity of dorsal root ganglia toward an increased presence of SP ϩ neurons.…”

Cellular Interactions in the Pathogenesis of Human Proliferative Glomerulonephritis

“…Combined administration of anti-LFA-1 and anti-ICAM-1 antibodies was reported to attenuate the development of histological changes in experimental lupus nephritis [26]. In human GN, Canton et al [27]reported that de novo mesangial expression of ICAM-1 in primary focal segmental glomerulosclerosis was a marker for activation of mesangial cells, possibly associated with local cytokine release.…”

“…ICAM-1 is mainly expressed on the endothelial cells of peritubular venules, on interstitial mononuclear cells and sometimes on the luminal side of tubular epithelial cells [26, 27, 28, 60, 61, 62]. Tubulointerstitial injury and interstitial leukocyte influx were reported to be significantly milder in nephrotoxic nephritis in ICAM-1 knockout mice than in nephritic control mice [63].…”