We investigated immunohistochemically the distribution in rats of the homologous proteins gp330 and the LDL receptorrelated protein (LRP/ a2MR), and a receptor-associated protein (RAP), and the sites to which soluble exogenous RAP binds. We found gp330 in a restricted group of epithelial cells, including renal proximal tubule cells, podocytes, Type II pneumocytes, cells of the parathyroid, thyroid, epididymis, lining of the uterus, ependyma, retina, ciliary body, yolk sac, and placenta. In these cells gp330 was detected mainly at the cell surface, except for parathyroid and retinal epithelial cells, where diffuse cell staining was found. LRP/a2MR was widely distributed in interstitial cells, notably in fibroblasts and maaophages, and was also present in a selected group of epithelial or specialized cells, including hepatocytes, adrenal cortical cells, follicular cells of the ovary, cells of the choroid plexus, ciliary M y , mesangial cells, and some neurons. In certain cells, notably hepatocytes and adrenal cortical cells, LRPIa2MR was detected mainly on the surface, but in others, including maaophages, fibroblasts, and epi-

No abstract

SBmlTlftryIn patients with glomerulonephritis widespread crescents are associated with a poor prognosis. Crescent formation appears to depend on the migration of mononuclear cells into Bowman's space, and therefore the interaction between leukocytes and glomerular endothelium may be a critical event in the genesis of crescents. We performed the present study to determine the effects of mouse monoclonal antibodies to the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1) in a model of crescentic glomerulonephritis in Wistar-Kyoto rats, induced by immunization with bovine glomerular basement membrane (GBM). By 10-14 d after immunization, the rats had developed circulating anti-GBM antibodies, reactive with the oL3 chain of type IV collagen (the Goodpasture antigen), accompanied by proteinuria, accumulation of rat immunoglobulin (Ig)G in the GBM, increased expression of ICAM-1 by glomerular endothelial cells, infiltration of glomerular tufts with LFA-1 + T cells and monocyte/macrophages, and early crescents. At 5 wk all rats had diffuse fibrocellular crescents, glomerular sclerosis, and tubulointerstitial damage. All rats developed severe renal insufficiency and died by 5 or 6 wk. The administration of monoclonal antibodies to rat ICAM-1 and LFA-1 markedly decreased the severity of the renal disease. In a group of rats injected three times a week with the monoclonal antibodies, from 2 d before immunization with GBM to day 14, glomerular abnormalities and proteinuria were virtually absent at day 14; even at 5 wk glomerular disease was quite mild, with only slight crescent formation and with only a mild decrease in renal function. When treatment was continued until 5 wk, the beneficial effects were even more marked, with virtual absence of crescents and with preservation of normal renal function. In a group of rats in which treatment was initiated on day 14, shortly after the appearance of glomerular abnormalities, progression of the disease was appreciably retarded, and the decrease in renal function was inhibited. The kidneys of rats treated from days -2 to 14 with antibodies to ICAM-1 and LFA-1 showed bright linear staining for rat IgG along the GBM, which did not differ in intensity from that seen in untreated rats. Furthermore, the titers of anti-GBM antibodies at 2 wk in treated rats were not lower than that seen in most of the untreated rats. There was, however, moderate reduction of anti-GBM antibodies at 5 wk in the treated rats. In addition, in rats in which treatment was started after onset of the disease, the titers of anti-GBM antibodies did not decrease, although the progression of disease was inhibited. We conclude that the preventive or therapeutic effects of antibodies to ICAM-1 and LFA-1 in rat anti-GBM glomerulonephritis probably resulted mainly from interference with interaction between leukocytes and activated glomerular endothelium, although reduction in the autoimmune response may have contributed to the beneficial effects. The res...

SumlTlaryCD5 is a 67-kD glycoprotein that is expressed on most T lymphocytes and on a subset of mature B cells. Although its physiologic function is unknown, several lines of evidence suggest that CD5 may play a role in the regulation ofT cell activation and in T cell-antigen presenting cell interactions. Using a CDS-immunoglobulin fusion protein (CD5Rg, for receptorglobulin), we have uncovered a new CD5 ligand (CD5L) expressed on the surface of activated splenocytes. Stimulation of murine splenocytes with anti-CD3 and anti-CD28 antibodies induces transient expression of CD5L on B lymphocytes that lasts for "72 h. Binding of CD5Rg to activated splenocytes is trypsin-resistant and independent of divalent cations. However, it is pronase sensitive and dependent on N-linked glycosylation of CD5, since treatment of CD5Rg with PNGaseF or N-glycanase completely abrogates its ability to bind activated splenocytes. In addition to splenocytes, CD5L is expressed on activated murine T cell clones. Immunoprecipitation, antibody, and recombinant protein blocking studies indicate that CDSL is distinct from CD72, which has been proposed to be a CD5 ligand. To determine whether CD5-CD5L interaction might play a role in vivo, we tested the effect of CD5Rg in a murine model of antibody-mediated membranous glomerulonephritis. Injection of CD5Rg was found to abrogate development of the disease. Taken together, our results help identify a novel ligand of CD5 and propose a role for CD5 in the regulation of inmmne responses. C D5 is a 67-kD glycoprotein that is structurally related to the scavenger receptor cysteine-rich family (1), and expressed on thymocytes, T lymphocytes and subpopulations of mature and activated B cells. In particular, autoreactive B lymphocytes are observed to express CD5 (2) and, at least in the mouse, the development ofCD5 + B cells appears to be regulated in part by IL-10 (3). The precise physiologic function of CD5 has yet to be elucidated. CD5 may play a significant role in T lymphocyte activation, however, based on observations that anti-CD5 antibodies can augment T cell intracellular calcium concentration (4), proliferation (5, 6), and IL-2 release (7, 8). CD5 associates with the TCR ~ chain, and is rapidly phosphorylated after ligation of CD3/TCR (9, 10). Recently, deletion of the CD5 gene was shown to influence the development of thymocytes in transgenic mice (11). In vivo, down-modulation of CD5 by mAb induces T cell unresponsiveness, and is reported to prevent experimental autoimnmne encephalomyelitis in the rat (12). In addition, anti-CD5 antibody treatment has a partial therapeutic effect on collagen type II-induced arthritis in DBA/1 mice (13). Taken together, these studies suggest that CD5 may play an important role in transducing signals that are relevant to thymic development and to immune responses.Purified biotin-labeled CD5 has been proposed to bind CD72/Lyb-2 on both human and routine cells (14,15). CD72 is a type II glycoprotein of 42 kD that is costitutively expressed on all cells of the B ...