Perspectives On Animal Research

Volume 1, Supplement

An Evaluation of Ten Randomly-Chosen Animal Models of Human Disease

Anti-Tubular-Basement-Membrane-AntIbody Tubulolnterstitial Nephritis (Guinea Pigs)

(1,2)

Description of the Model:

Steblay and Rudofsky described the induction of experimental anti-tubular-basement-membrane (anti-TBM) tubulointerstitial nephritis (TIN) in guinea pigs by the injection of heterologous rabbit renal tubular basement membrane (TBM) and complete Freund's adjuvant.(1,2) These animals developed cortical tubular disease with glucosuria, azotemia, and proteinuria. Immunofluorescence studies showed characteristic linear staining along the TBM, and anti-TBM autoantibodies were demonstrated in the serum and in kidney eluates. In addition, there was mononuclear and multinuclear giant cell inifitration in the kidney interstitium. The authors stated:

This new model may be relevant to man in certain types of acute or chronic tubule-interstitial disease, renal homograft reactions and the pathogenesis of tubule-interstitial damage superimposed on some primary process.(1)

When the guinea pig model of anti-TBM TIN was developed in 1971, little was known about human anti-TBM TIN. Some investigators credited the animal research for the recognition of anti-TBM TIN.(3) In fact, Baldwin et al. in 1968 described the condition in a human patient, which he attributed to an allergic response to penicillin and methicillin. At that time, however, it was unclear whether or not anti-TBM TIN was itself a disease because the patient also had glomerulonephritis, which could explain the renal dysfunction.(4) The animal model, being a discrete anti-TBM TIN without glomerulonephritis, demonstrated the potential of anti-TBM TIN to cause renal disease.

While anti-TBM TIN is rare in people, it has been associated with many conditions. In the early to mid 1970s, anti-TBM antibodies (Ab) were found in drug-induced acute interstitial nephritis, Goodpasture's syndrome, renal allografts, progressive post-streptococcal nephritis,(5) lupus nephritis,(6) and other forms of immune complex-mediated renal injury.(7) The rarity of the condition and its range of presentation have made clinical characterization difficult.

Criterion I: Concordance between the Animal Model and the Human Disease

Clinical Manifestations:

Littile is known about the clinical significance of anti-TBM Ab. Immunologically, there appear to be important similarities between human anti-TBM TIN and the experimental animals. Rudofsky et al. isolated a monoclonal anti-TBM Ab from mouse hybridoma cells, which causing TIN in animals. (sic) This reacted with a common epitope found in rabbit, rat, hamster, horse, guinea pig, sheep, and human kidney.(8) Clayman et al. also found similar TBM antigens among species. In addition, they found that human anti-TBM Ab had shared specificity with Ab from rats and mice with experimental anti-TBM disease. This indicates that both the antigen and the antibody are similar in animals and humans. Clayman et al. stated, "...(these) findings establish two important links between human anti-TBM disease and its animal model."(9)

Despite these similarities, human and guinea pig anti-TBM TIN have differences in clinical presentations. For example, the presence of multinucleated giant cells is extremely rare in human patients, but these cells are usually present in guinea pigs. However, McCluskey and Colvin believed that, "Giant cells are not an essential feature of anti-TBM disease in guinea pigs."(10)

A problem in the evaluation of human anti-TBM TIN is that almost all patients with anti-TBM TIN have glomerulonephritis. Consequently, the importance of anti-TBM Ab in most patients is uncertain. Andres and McCluskey concluded:

It is difficult to evaluate the pathogenetic role of anti-TBM Ab since the glomerular disease is often severe enough to cause marked impairment of renal function. The observation that many such patients have severe inflammatory tubulointerstitial changes and the reports that anti-TBM nephritis can occur without apparent association with anti-GBM (glomerular basement membrane) Ab, indicate that the anti-TBM Ab are of importance. The results of this study strengthen this interpretation and suggest that Ab to TBM may occasionally be associated with tubulointerstitial changes reminiscent of the experimental anti-TBM nephritis of guinea pigs or BN rats.(11)

The applicability of the animal model appears to be limited, because human patients almost never present with isolated anti-TBM TIN. Cameron observed, "...anti-tubular basement membrane antibodies are so rare in human tubulo-interstitial nephritis, models of purely cell-mediated injury are probably of greater relevance."(12) He mentioned that possible mechanisms of damage in cell-mediated immune disease include delayed hypersensitivity, direct cytotoxicity, and antibody-dependent cell-mediated cytotoxicity. He continued:

Obviously all three channels of reaction as well as antibody-mediated injury could operate together in vivo in animal models or human disease, which makes it particularly difficult to sort out what may be happening.(12)

Finally, the clinical course of anti-TBM TIN varies, as noted by McCluskey and Bhan:

The temporal evolution of the disease and the nature of the infiltrate differ among the strains and species. In susceptible strain XIII guinea pigs, tubulointerstitial nephritis develops quickly, and severe lesions are often seen by 14 days; at all stages the infiltrate is virtually devoid of granulocytes. In susceptible rat species, such as BN, histologic lesions may also appear fairly quickly, the lesions are initially characterized by polymorphonuclear leukocytes, but the infiltrate soon becomes predominantly mononuclear. In mice, histologic lesions, which are characterized by mononuclear cell infiltrates, require many weeks to develop and generally appear only several weeks after anti-TBM antibodies have been evident.(13)

The significance of these differences is difficult to assess because the temporal evolution of human anti-TBM disease is not well known. However, these findings do suggest distinct species variability, which may limit the usefulness of the animal model.

Pathogenesis:

The pathophysiological processes in the animal model and in human patients contain some important similarities. Studies with guinea pigs have shown that transfer of anti-TBM TIN can be inhibited by Cobra Venom Factor, a complement-depleting agent.(14) This strongly suggests that in guinea pigs complement is involved in the pathological progression of this disease. In addition, Rudofsky et al. showed that guinea pigs genetically deficient in C4 are still susceptible to anti-TBM TIN, implying activation of the alternative complement pathway.(15) Furthermore, Rudofsky et at. later identified C3PA (properdin factor B) deposits along the TBM in guinea pigs with experimental TIN.(16) There is similar evidence of a role played by complement in human anti-TBM TIN. Orfila et al. found linear deposits of IgG and C3 along the TBM of several patients with renal diseases of various kinds.(17) More recently, Lin and Chiang, reporting a patient with valproate-induced nephritis, found evidence for involvement of the alternative pathway of complement activation and circulating anti-TBM Ab, IgG, and C3 deposits along the renal tubules.(18)

Although similar immune mechanisms may be involved in both human and experimental anti-TBM TIN, there may be fundamental differences in pathophysiology. The experimental animal receives an injection of tubular basement membrane tissue from another species with complete Frçund's adjuvant, which tends to enhance sensitivity reactions. This sensitization process could differ significantly from that of humans with anti-TBM TIN, who do not receive tissue from other species or chemicals that enhance their immune response. Although humans do apparently develop anti-TBM TIN under a broad range of conditions, it is not known if any of these conditions are similar to those occurring in the guinea pig.

Do anti-TBM Ab cause disease in man? Citing human clinical evidence, Andres et al. found, 'TIN is most frequent and severe when anti-TBM Ab is detectable."(19) While it is generally accepted that anti-TBM Ab can produce renal damage in man, there is controversy about the impact of these antibodies in specific disease states. Ooi et al. found anti-TBM Ab in two of nine cases of drug-induced acute interstitial nephritis and concluded:

There may be subpopulations of this form of renal disease in which several mechanisms of renal injury are operative. It should be pointed out that in the experimental model of TIN ... the histological appearance of the kidney bears only a superficial resemblance to that seen in drug-induced acute interstitial nephritis, especially in the absence of eosinophils which appear to be a distinctive feature of this pathological entity.(20)

Similarly, Zacherle et al. commented that, with respect to drug induced acute interstitial nephritis, "This animal model may or may not be analogous to the human disease."(21)

The specific role of anti-TBM Ab in renal transplantation is also unclear. Kashiwabara et al. stated, "...the data suggest that the antibody formation to TBM, as an organ-specific antigen of the kidney, may be partially responsible for the renal injury in acute rejection after kidney transplantation."(22)

In a recent study, however, Rotellar et al. found that anti-TBM Ab in renal allografts were a transient phenomenon that resolved within 8-9 months. They noted:

...some authors have concluded that linear IgG fixation along TBM in renal transplants may contribute to allograft failure. Others found that anti-TBM Ab were associated with acute rejection episodes and were partially responsible for the renal injury. However, it has been noted that the clinical evolution with anti-TBM Ab varies from patient to patient and is not always dramatic. Our series shows that anti-TBM Ab have no consequence on transplant survival.(23)

In summary, it is difficult to assess the relevance of experimental antiTBM TIN for humans. First, anti-TBM is rarely seen as an isolated phenomenon in man. Second, human anti-TBM TIN is usually associated with other forms of renal disease, making the contribution of anti-TBM Ab unclear. Third, it is not known whether or not the pathophysiology of anti-TBM TIN in this animal model resembles any of the wide range of processes in which anti-TBM Ab are seen in humans. Fourth, there are histological differences between human and guinea pig anti-TBM TIN, raising further doubts about the similarities of these diseases.

Criterion II: Citations

Many investigators have studied the guinea pig model of anti-TBM tubulointerstitial nephritis. Two reports by Steblay and Rudofsky defined this animal model,(1,2) and we found 120 of the 121 English language journal articles listed in the Science Citation Index from 1971 to 1988, which cited at least one of them. (See Appendix A.) Of these, 32 were clinical studies.

Some investigators cited the animal model as evidence of the involvement of the humoral component of the immune system in anti-TBM TIN.(20,24-31) However, Baldwin had described anti-TBM Ab prior to the development of the animal model.(4) Most of the clinical references to the animal model mentioned only that the model demonstrated that anti-TBM TIN can cause renal damage.(21-23,26,26a,28,31-47) For example, Lehman et al. stated:

...anti-TBM Ab might have been merely a secondary effect of interstitial disease rather than a cause of it. However animal studies have clearly demonstrated that anti-TBM Ab can induce interstitial nephritis, and so, they are likely to be pathogenic in human subjects as well.(26)

Similarly, Mathew and Bolton wrote, "The significance of apparent immune mechanisms involving TBM following transplantation is uncertain. In experimental models, anti-TBM disease can be induced by immunization with heteroglogous TBM."(26a) Whether or not anti-TBM TIN causes renal damage in many human patients is not known. As was discussed above, human anti-TBM TIN is almost always associated with glomerulonephritis, and the glomerulonephritis could be responsible for renal dysfunction.

Several articles cited the animal model to address other issues. Bergstein and Litman cautiously suggested that the animal model may be relevant to the study of the human disease:

Pathophysiological correlates have been found between experimental immune complex and anti-GBM-antibody disease and several forms of nephritis in man. Although the relations between recently described animal models of anti-TBM antibody disease and human disease are unclear, it is interesting to compare our data to these experimental animals.(48)

On the other hand, McLeish et al. raised doubts about the value of the animal model: "Animal models indicate that acute interstitial nephritis similar to that seen in patients can be produced by anti-TBM antibodies. Many patients with drug-induced nephritis, however, have no evidence of anti-TBM antibodies"(49)

Also, when citing the guinea pig model, Lin and Chiang observed, "Several studies suggest that antitubular basement membrane antibody alone is invariably not sufficient to cause the disease."(18) Two years previously, Rotellar et al., in a paper on human kidney transplantation, concluded, "If several hypotheses can be proposed to explain the presence of anti-TBM antibodies after renal transplantation, it appears that this phenomenon does not depend on only one mechanism."(23) Despite extensive research on animals and human patients, we still do not understand the exact mechanisms of the underlying pathological processes.

Finally, Rudofsky et al. used human and animal serum in a new technique to induce anti-TBM TIN in animals.(50) This finding is relevant to experimental induction of anti-TBM TIN, but its clinical impact remains speculative.

Criterion III: Historical Impact

Although Baldwin et al. identified immunoglobulin at the tubular basement membrane, his patient also had antibodies at the glomerular basement membrane, the tubular interstitium, and the interstitium.(4) Isolated anti-TBM TIN with renal dysfunction was first seen in the guinea pig animal model. There have been a few subsequent case reports of isolated anti-TBM TIN in humans with renal failure.(48,51) Most cases have involved methicillin exposure or were associated with systemic lupus erythematosus. As discussed by Ooi et al., eosinophils appear to be characteristic of drug-induced anti-TBM TIN but are not found in the animal model.

The Science Citation Index list included 21 review articles, some of which were clinically oriented. Most authors felt the animal models could assist in the understanding of human anti-TBM TIN. For example, Martinez-Hernandez and Amenta stated:

Our knowledge of immune-mediated TIN is even more unsatisfactoiy than that of glomerular disease. However, it is likely that some of these models will provide important new clues for our understanding of basement membrane composition and heterogeneity.(52)

Work on this and other models of immunological diseases has helped to elucidate aspects of T-cell interaction and the interaction between cellular and humoral immune response mechanisms. Much of this work is recent and remains limited to basic science. Neilson and Zakheim noted, "Most of what we know about the role of regulatory systems in immune mediated renal disease comes from the study of experimental animals."(53) The exact basic science contributions of the guinea pig model of anti-TBM TIN are beyond the scope of this study.

Many authors questioned the clinical validity of this model. However, a major difficulty has been that; since human anti-TBM TIN is so rare, there has been little clinical data available to help us understand human anti-TBM TIN. Thus, for lack of clinical data, researchers and clinicians have tended to assume that the animal model data is valid for human anti-TBM TIN. As was discussed above, there are good reasons to doubt this assumption.

While the differences in clinical presentation and pathophysiology between human and experimental anti-TBM TIN raise doubts about the relevance of the animal model, renal biopsies enable us to perform a broad range of studies. This diagnostic procedure is frequently performed in patients with renal dysfunction of unclear etiology. The tissue obtained at biopsy might be used for histological and immunological research. In addition, studies of serum antibody and cellular components can yield insights into immune mechanisms of the disease process. Thus, even though the guinea pig animal model can provide pathologic tissue, biopsies of human patients permit the study of anti-TBM TIN in human patients. While the rarity of human antiTBM TIN makes clinical studies more difficult, they may be more valid.

It is unclear whether or not the animal model has assisted in the diagnosis of anti-TBM TIN. Even before the animal model was developed, researchers used immunofluorescent staining to demonstrate antibodies on human tubular basement membrane. This model has not altered our methods for identifying the disease in man. Indeed, researchers and clinicians used immunofluorescent staining of the kidney for years prior to the animal model research in search of anti-glomerular basement membrane antibodies.

Although several experimental therapies were studied in the animal model, it does not appear that the animal model has been helpful in the treatment of human anti-TBM TIN. Idikio, in 1982, reported that cyclophosphamide reduced renal injury in anti-TBM TIN in guinea pigs.(54) In 1985, Mann and Neilson, who did not cite Idikio's report, did suggest that cyclophosphamide might be used if steroid therapy fails. However, they stressed that "..no data exist on the use of cytotoxic agents."(55) Either Mann and Neilson were unaware of Idikio's work or they did not consider Idlkio's findings relevant.

Human anti-TBM TEN is rare, and consequently it is almost impossible to study different therapies using clinical studies. Thus, current treatment has been based on the therapies of other autoimmune processes. As in other autoimmune diseases, Mann and Neilson proposed using steroid therapy initially, followed, if necessary, by cytotoxic agents. Indeed, regardless of the animal data, one would expect immunosuppressive therapy to influence the course of this autoimmune condition. Whether or not the risks outweigh the benefits is difficult, if not impossible, to ascertain in the laboratory.

Other treatments, including anti-idiotypic antibodies,(56) cyclosporin A,(57) and suppressor T-cells with their soluble factors,(58) have been tried in experimental models, but we found no mention of these in clinical studies. The recent nature of these experiments and the infrequency of human anti-TBM TIN make it impossible to assess the efficacy of these therapies at this time.

The most recent general review of anti-TBM TIN in human patients was a 1988 paper by J. Stewart Cameron entitled, "Allergic interstitial nephritis: Clinical features and pathogenesis."(13) Cameron wrote that TIN was first described in detail in humans: "...acute allergic interstitial nephritis was first described in detail by Councilman in 1898, in association with diphtherial and streptococcal infections."(13) Cameron cited the guinea pig model in the following passage:

There are a number of animal models of anti-tubular membrane interstitial nephritis induced by the injection of a variety of crude or purified tubular basement membrane preparations, either heterologous or autologous, in the guinea pig, rat and mouse.(13)

He continued to discuss the specific immunological features of anti-TBM TIN in patients and in the different animal models. He noted similarities and differences between the animal models and the human disease, and he concluded that the animal model is of questionable relevance:

Our information is scanty for human disease, and much extrapolation from animal models is needed to provide even the inadequate account which is all we have at the moment. As with the study of glomerular injury, a disproportionate amount of thinking and experimental effort has gone into understanding disease dependent upon direct combination of Ab specifically directed against tubular structures, i.e. anti-TBM nephritis. This is because these are the mechanisms most easily understood, and also those most accessible to experiment. This accessibility should not mislead us into thinking that it is, clinically, other than an occasional curiosity.(13)

Conclusions:

There are important differences between the histological and immunological characteristics of human anti-TBM TIN and those of guinea pigs, but there are also significant similarities. Therefore, several clinical investigators have concluded, with caution, that research with the animal model is relevant to the understanding of the human disease. However, the human data is limited, and in order to determine the validity of the animal data for human anti-TBM TIN, there must be a considerable body of clinical investigation.

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