NDT Advance Access originally published online on April 10, 2008
Nephrology Dialysis Transplantation 2008 23(7):2173-2175; doi:10.1093/ndt/gfn155
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Bacterial protease for the treatment of IgA nephropathy*
Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
Correspondence and offprint requests to: Prof. Frank Eitner, Klinikum der RWTH Aachen, Medizinische Klinik II (Nephrologie und Immunologie), Pauwelsstr 30, 52074 Aachen, Germany. Tel: +49-0-241-8089-532; Fax: +49-0-241-8082-446; E-mail: feitner{at}ukaachen.de
Keywords: glomerulonephritis; Haemophilus influenzae; IgA nephropathy; IgA protease
Mesangial IgA1 deposition accompanied by a mesangioproliferative glomerulonephritis is the key pathological finding in IgA nephropathy (IgAN) patients [1–3]. Although the pathogenesis of IgAN is still not completely understood, it is generally accepted that mesangial IgA1 deposits trigger local inflammatory mechanisms and thereby initiate and/or maintain the glomerulonephritis [2,3]. Consequently, the specific removal of mesangial IgA1 deposits might be a promising therapeutic approach for IgAN. Lamm et al. studied a bacterial IgA protease, isolated from Haemophilus influenzae, which exhibits substrate specificity for the hinge region of human IgA1. This protease cleaved human IgA1 and IgA1-containing immune complexes in vitro. They next studied the effects of this protease in mice with experimental glomerular IgA deposition. For this, healthy BALB/c mice first received an intravenous injection of immune complexes, consisting of human IgA1 and goat-anti-F(ab')2, which resulted in mesangial positivity for human IgA. Administration of the IgA protease 1 h after the injection of the immune complexes significantly reduced the degree of mesangial IgA immunofluorescence intensity within the next hour as compared to mice not treated with a protease. The authors conclude that IgA protease may have potential as a therapeutic agent for human IgAN.
The treatment of IgAN patients is a dilemma. We still do not have any specific therapeutic approach, which is largely due to our incomplete understanding of the pathogenesis of IgAN. Over the past years, we have made significant progress in identifying specific characteristics of the mesangial IgA deposits in IgAN patients, i.e. the di- or polymeric nature of IgA, the predominance of the IgA1 isoform and the relative undergalactosylation of the IgA1-hinge region [1–3,4–7]. However, precise mechanisms that lead to the mesangial deposition of IgA1 are unknown, as are mechanisms underlying the initiation of overt inflammatory glomerular injury. Today's IgAN therapy is directed against very late stages in the development of the disease (Figure 1). Both antihypertensive and immunosuppressive therapies have proven beneficial in IgAN patients with a risk for progressive disease [2,8–10]. However, because of the lack of large clinical trials and the lack of direct comparisons of different strategies, the best IgAN therapy for progressive IgAN is still a matter of debate [9,11].
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The study by Lamm et al. introduces a completely novel and more upstream treatment strategy by targeting the mesangial IgA1 deposits (Figure 1). The rationale behind aiming for this stage of the IgAN disease is quite convincing. The disappearance of IgA deposits is typically associated with a clinical and pathological resolution of the glomerulonephritis and vice versa [12]. It is therefore justified to hypothesize that specific removal of glomerular IgA deposits by a bacterial protease cleaving human IgA1 might benefit patients with IgAN.
There are a number of open issues that might prevent the immediate translation of this innovative therapeutic strategy to human IgAN patients. One of the most challenging problems in experimental IgAN research is the general lack of relevant IgAN animal models, which is largely explained by our incomplete knowledge of the pathogenesis of human IgAN [13–15]. The development of IgAN models is further complicated by the fact that there are major differences in the IgA systems of humans and rodents. Only humans and some non-human primate species have an IgA1 isoform with a characteristic O-galactosylation pattern within the hinge region [6,7,10]. A pure mouse model can therefore not reproduce the characteristics of the mesangial IgA1 deposits of the human disease as listed above. To at least partially address these problems, mouse models of IgAN have been created, in which human IgA1 was introduced into the mice. This typically results in relatively artificial model systems that leave open questions regarding their true relevance for the human IgAN disease, but such models offer clear advantages compared to naïve mice.
What are the potential obstacles that one may encounter when translating the experimental approach of Lamm et al. to patients with IgAN? First, the duration of treatment has to be considered: mice were treated for 1 h following a 1-h-long disease induction period. In contrast, human IgAN is a slowly progressive disease. In IgAN patients presenting with microhaematuria and no or minimal proteinuria, it took 2 years for the first cases of proteinuria to exceed 1 g/day and 8 years for the first cases of increasing serum creatinine [16]. It therefore remains unclear how long and how often human IgAN patients would need treatment to cleave their mesangial IgA1 deposits to induce a clinical remission of the glomerulonephritis. Given that the protease employed in the study of Lamm et al. is of bacterial origin, immunological responses resulting in the appearance of antagonistic antibodies, or even sensitization, may occur. The second obstacle concerns the specificity of the IgA1 cleavage: Lamm et al. performed the study in a model setting with human/goat IgA1-containing immune complexes injected into mice. Glomerular deposits of human IgA1 were reduced by the systemic protease treatment without any documented side effects. The bacterial protease does not cleave murine IgA, which explains the specificity in this particular model system. An obvious and important question would therefore be how the bacterial protease can achieve a similar specificity for glomerular IgA1 in a human organism, where huge amounts of IgA, mostly monomeric, are circulating. It is currently unclear whether the IgA protease exhibits different specificities for di- or polymeric IgA1 as compared to monomeric IgA1. In contrast to the murine model described, it is very likely that the systemic administration of such an IgA1 cleaving protease in humans would also lead to the cleavage of circulating serum IgA1. While even total IgA deficiency in humans does not usually carry major clinical consequences, the dose requirements in humans may become very high, given that glomerular IgA deposits are only a minute fraction of the total IgA. Finally, it is unknown so far whether IgA cleavage products might exhibit side effects in a man.
In summary, strategies that induce a clearance of mesangial IgA deposits are a very interesting novel therapeutic concept in IgAN. However, the missing specificity for glomerular IgA1 and the likely need for long-term treatment may currently represent obstacles that, in the author's opinion, render the immediate clinical use of this approach in human IgAN patients difficult.
Conflict of interest statement. None declared.
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* Lamm ME, Emancipator SN, Robinson JK et al. Microbial IgA protease removes IgA immune complexes from mouse glomeruli in vivo: potential therapy for IgA nephropathy. Am J Pathol 2008; 172: 31–36
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Accepted in revised form: 28. 2.08
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