Experimental Drug-Induced Allergic Nephritis Mediated by Antihapten Antibody

Abstract

Experimental drug-induced allergic nephritis (DIAN) was mediated by an antihapten antibody. It has been postulated that DIAN is induced by cellular and humoral mechanisms. We tried to induce DIAN in mice, where the mechanism depends on humoral immunity. The first attempt was made in mice actively producing antibodies against cephem antibiotics, i.e. cephalothin (CET). Acute interstitial nephritis (AIN), morphologically similar to human disease, was obtained by injection of a CET-protein conjugate into the renal cortex in mice producing anti-CET-IgE and IgG antibodies. AIN could also be induced when normal mice, passively given anti-CET IgG antibody, received a subsequent intrarenal challenge with CET-protein conjugate. These preliminary results indicate that IgG antibody has an important role in the genesis of DIAN. Further experiments were performed with monoclonal antibodies directed against haptens instead of antibiotics in order to clarify the Ig isotype concerned. In mice passively given anti-Dansyl-IgG2a or anti-NP-IgG2a monoclonal antibodies, a challenge with an appropriate hapten-protein conjugate into the renal cortex resulted in AIN. However, transfer of anti-Dansyl-IgE or anti-DNP-IgE monoclonal antibodies, followed by challenge, did not induce AIN. In the experimental systems described, the involvement of a cellular immune mechanism is excluded. The results suggest that IgG, but not IgE antibody, is essential for the induction of DIAN by humoral immune mechanism.

Drug-Induced Hypersensitivity Nephritis: Lymphocyte Stimulation Testing and Renal Biopsy in 10 Cases

“…Several observations have supported the idea that cell-mediated immunity is involved in the genesis of this condition, although humoral immunity may also play a role [30]: (1) la-positive activated T cells are prominent in the renal infiltrate [31]; (2) the so-called hypersensi tive granuloma is often seen [32], and (3) lymphocytes have shown a blastogenic response when incubated with suspect drugs, both in our study and in those of others [33,34], On the other hand, no immunoglobulins were found on the tubular basement membrane in our study, in agreement with previous reports [23,35], Only a few cases of positive anti-tubular basement membrane anti body in the serum of patients with DIHN have been reported [36,37], These results indicate that cellular immunity plays an important role in the development of DIHN and provide the basis for the use of the term 'drug-induced hypersenstivitiy nephritis'.…”

Membranous Nephropathy Associated With Fluconazole Treatment

“…12 Likewise, it can be speculated that fluconazole may damage proximal tubular cells, leading to the release of nephritogenic antigens with subsequent antibody production. Another speculation is that fluconazole may induce antibody production through fluconazole-specific T cells, or it may act as hapten by being bound to blood proteins, 13 and induce a secondary antibody response.…”

Clinical Characterization of Drug-Induced Allergic Nephritis

“…This model is thought to be gen erated by the mechanisms of cellular immunity [14], However, in this model there are no data associated with a drug like hapten. We tried to design a DIAN model by introducing an antibody against the suspected drug like hapten [15,16], This model was generated under the mechanisms of humoral immunity. IgG class of the anti body might play a role in the onset of AIN in animals, but not the IgE class of the antibody.…”