Delayed‐type hypersensitivity mediates Bowman's capsule rupture in Tamm—Horsfall protein‐induced tubulointerstitial nephritis in the rat

Abstract

Summary: It is generally thought that disruption of Bowman's capsule, a feature of progressive forms of glomerulonephritis, is mediated by leucocytes which accumulate within Bowman's space. However, we have recently shown that periglomerular T cell and macrophage accumulation is associated with Bowman's capsule rupture irrespective of crescent formation in rat crescentic glomerulonephritis. Thus, to determine whether periglomerular leucocytes can mediate rupture of Bowman's capsule, we have examined Bowman's capsule integrity in a model of immune cell‐mediated interstitial nephritis which is devoid of glomerular inflammation. Tubulointerstitial nephritis was induced in rats by repeated immunization with autologous Tamm‐Horsfall protein (THP) or adjuvant alone (control) and groups of animals were killed on weeks 26, 30 and 34. All animals immunized with autologous THP developed a humoral immune response to the antigen as measured by serum antibodies. In addition, a cellular immune response to autologous THP was demonstrated by a skin delayed‐type hypersensitivity (DTH) response and prominent interstitial T cell and macrophage infiltration around THP+ tubules. Marked periglomerular leucocyte infiltration developed around some glomeruli in association with granular THP deposition and increased local expression of intercellular adhesion molecule‐1 (ICAM‐1) and the classic DTH associated cytokine macrophage migration inhibitory factor. On week 26 of the disease, disruption of Bowman's capsule was evident in 5.5 ± 2.8% of glomeruli and this increased to 9.5 ± 4.8% of glomeruli by week 34. Disruption of Bowman's capsule integrity was invariably associated with THP deposition and a significant periglomerular infiltrate of T cells and macrophages, whereas glomeruli with little periglomerular infiltration retained an intact Bowman's capsule. Strong lysozyme staining of macrophage‐like cells at sites of rupture suggest that degradation of Bowman's capsule was mediated by macrophages through the production of proteolytic enzymes. In conclusion, these results demonstrate that periglomerular leucocytes can cause Bowman's capsule rupture through a DTH mechanism.