relevance of experimental models for human nephropathology · of the glomerulonephritis models, we...

Kidney International, Vol. 35 (1989), pp. 1015—1 025

Relevance of experimental models for human nephropathology

PHILiP J. HOEDEMAEKER and JAN J. WEENING

Departments of Pathology, Universities of Leiden and Gronigen, The Netherlands

The relationship of experimentally produced renal lesions toBright's disease is still a major concern of present day pathol-ogy even though the problem has for many years held theattention and interest of numerous investigators.

Horn, 1937 [1]

Since Bright in 1827 [21 associated renal pathophysiologywith structural alterations in the kidney, many investigatorshave been concerned with the study of kidney diseases, inparticular their natural history. Because biopsy techniqueswere not available at that time, most cases of glomerulonephri-tis could not be studied before they had reached an end stage.In order to study the acute and early changes of glomerulone-phritis and to understand their pathogenesis, experimentalmodels were developed in laboratory animals.

Logically the experiments performed in this era were char-acterized by the prevailing thoughts on pathogenesis, and sinceglomerulonephritis was often associated with bacterial infec-tions, investigators tried to induce such a disease in animalswith bacterial toxins [3] or chemical compounds [1]. At the turnof the century it was realized that glomerulonephritis wascaused by immunologic or rather allergic reactions againstbacterial products [4—6] and this precipitated a series of exper-iments in which glomerulonephritis was induced by administra-tion of bacteria or bacterial products [7—9], serum [10—13] orpurified serum proteins [14—171.

The first successful experimental model was reported byLindemann in 1900 [18], who succeeded to induce a prolifera-tive glomerular lesion by injecting rats with an anti-kidneyantibody. Although a proliferative lesion was recognized in theglomeruli, which appeared to be similar to that seen in humanpost-infectious glomerulonephritis, the human counterpart ofthis model was not discovered until 1967 [19].

A major breakthrough in experimental glomerulonephritiscame in 1953 when Germuth [20] introduced a form of glomer-ulonephritis associated with experimental serum sickness. Withthis model his group and that of Dixon [21] demonstrated thatglomerulonephritis was caused by deposition of immune com-plexes which were formed in the circulation in a state of antigenexcess.

Another highlight in the history of experimental glomerulo-nephritis has been the demonstration that glomerular immuneaggregates also can be formed in situ through a reaction ofantibody with fixed or planted glomerular antigens [22—24].

Moreover the elucidation of the glomerular filter as a charge

© 1989 by the International Society of Nephrology

and size selective barrier [25, 26] had important implications forhypotheses on the pathogenesis of immunologically-inducedglomerular injury [27, 28].

And lastly progressive glomerulosclerosis spontaneously oc-curring in certain rat strains has contributed to our understand-ing of the progression of renal disease in man and its prevention[29].

Although models of glomerulonephritis have advanced ourknowledge on glomerular disease in general, the relevance ofsome aspects of experimental models has been questioned. Thehistopathological expression of several forms of glomerulone-phritis shows characteristics which prove difficult to attribute tothe immunological mechanisms thought to operate in experi-mental disease [30], and furthermore, glomerular lesions unre-lated to immunological mechanisms were shown to express asimilar variety of histopathological features. For the inductionof a glomerulonephritis, animals usually are immunized withlarge, non-physiological doses of antigen. Moreover, injectionof glomerulonephritis inducing antibodies elicits an immunereaction in the host to the injected foreign proteins whichcomplicates the disease and its pathogenesis.

Models of glomerulonephritis models induced by disturbedregulation of the immune system associated with polyclonalactivation of B-lymphocytes (PBA) [31] are complicated, unlikethe naturally occurring diseases, by a down-regulation [32] andtherefore lack the chronic course which is characteristic for thehuman situation. Glomerular lesions based on autoimmunereactions of long duration can therefore be studied only in thelesions occurring spontaneously in certain mice strains 133].

Notwithstanding these objections raised by the imperfectionof the glomerulonephritis models, we know that although noneof the existing models presents an identical copy of a form ofhuman glomerulonephritis, the total array of models provide areasonable complete picture of glomerulonephritis, each modelcontributing essential details to this picture. Although it re-mains hazardous to extrapolate the results from experimentalstudies to human pathology, we have to acknowledge thatmodels of glomerulonephritis have given us (and still do so) aninsight in the pathogenesis of glomerulonephritis, Much less isknown about the etiologic factors underlying the induction ofglomerulonephritis. Promising in this respect are recent studiesconcerning PBA as a common cause of different forms ofautoimmune glomerulonephritis, and also studies on genetical-ly-determined vascular reactivity as a cause for progressiveglomerular sclerosis.

It is not the intention of this paper to present a comprehen-sive overview of models of glomerulonephritis. Only some of

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1016 Hoedemaeker and Weening: Experimental models for human nephropathology

Table 1. Models of glomerulonephritis

Immunologically induced Nephrotoxic serum nephritisHeymann nephritisSerum sickness nephritisIgA glomerulonephritisModels with polyclonal B cell

activation

Spontaneously occurring Models of SLE nephritisFocal glomerulosclcrosis

the models will be discussed which in the past have contributedto the understanding of human glomerulonephritis and to ouropinion still may do so. The models to be discussed arepresented in Table 1.

Nephrotoxic serum nephritisNephrotoxic nephritis, Masugi nephritis, and anti-GBM gb-

merulonephritis are all descriptions of one renal disease medi-ated by heterologous antibody directed against antigens of theglomerular basement membrane (GBM) [34, 35].

Upon injection, the antibody binds linearly along the GBM asobserved in immunofluorescence [36] and the animals develop aproliferative glomerulonephritis with variable degrees of extra-capillary proliferation and crescent formation [37], furthercharacterized by an influx of polymorph nuclear leucocytes andmononuclear cells [38].

The lesions of the autologous phase during which the animalproduces antibodies against the injected protein, in principle donot differ from those in the heterologous phase, althoughproteinuria is a more constant feature. Eventually the diseaseresults in chronic glomerulonephritis and renal failure [39].

The nephritogenic antigen involved in the induction of neph-rotoxic serum nephritis is a glucose containing polysaccharideisolated from the GBM by digestion with trypsin [40], but thetrue nature of the antigen has not been elucidated. In the humancounterpart of the model, antibodies to the Goodpasture anti-gen are thought to react with the globular domain of type IVcollagen of bovine GBM [41]. The antigens were found to havea molecular weight of 26 and 58 kD, respectively [42].

In the so-called accelerated model of nephrotoxic serumnephritis published by Naish et al [43] rats are preimmunizedwith IgG from the species used to prepare the anti-GEMantibody. The ensuing proliferative glomerulonephritis is asso-ciated with an influx of polymorphonuclear leucocytes andmononuclear phagocytes [44], but also with an infiltration of Tcells consisting mainly of T helper cells. This infiltrate precedesan influx of macrophages as described by Tipping, Neale andHoldsworth [45]. The same group [46] demonstrated a macro-phage inhibition activity of these lymphocytes, indicating theiractive role in accelerated NTN. Moorthy and Abreo [47] foundthat in rats receiving subnephritic doses of nephrotoxic seruman increase of the proteinuria could be induced by transfer oflymphocytes sensitized to the nephrotoxic IgG.

Cyclosporine was able to prevent both T cell accumulationand the subsequent macrophage induced injury, thus suggestinga role for cell-mediated immunity experimental anti-GBM gb-merulonephritis [45].

Autologous models of anti-GBM glomerulonephritis areknown from the work of Steblay and Lepper [48]. They are

induced by immunizing animals with homologous or heterolo-gous GEM. The resulting anti-GEM antibody binds to the GEMin a linear fashion and induces a severe crescentic glomerulo-nephritis [49] which is sometimes associated with pulmonaryhemorrhage resembling Goodpasture's syndrome in man [50].The disease can be transferred to naive animals by antibodiespresent in the circulation [Sb]. EAG can be induced in a varietyof species. Bolton, Tucker and Sturgill [52] were able todemonstrate an important role for cellular immunity in experi-mental allergic glomerulonephritis in chickens. They showedthat bursectomy which abrogated antibody formation com-pletely did not influence the occurrence of the disease, and theywere able to transfer the disease to naive animals with lympho-cytes [53].

Nephrotoxic glomerulonephritis and its variants have beenimportant for the understanding of the role of antibodies,mediators and inflammatory cells in causing (functional) dam-age to the glomerubus [54].

Heymaun nephritis

In 1951 Heymann and Lund [55] introduced a form ofautoimmune glomerulonephritis induced through immunizationof Sprague-Dawley rats with kidney cortex homogenate. Thisregimen resulted in an immune complex glomerubonephritisassociated with the nephrotic syndrome. Later Edgington,Glassock and Dixson [56] baptized this nephritis "AutologousImmune Complex Glomerulonephritis" and demonstrated thatautologous antigens from the brush border of the proximaltubules of the rat kidney were present in the glomerular immuneaggregates and were involved in the induction of this experi-mental nephritis. Because of its morphological similarity tohuman membranous glomerulopathy and because of the asso-ciation with the nephrotic syndrome Heymann nephritis isregarded the model of human membranous glomerulopathy.Around 1970 a heterologous variant was introduced which wasinduced by one injection of heterologous antiserum directedagainst the mentioned tubular antigens [57, 58].

Both variants of Heymann nephritis belong to the moststudied gbomerulonephritis models, and especially in the pas-sive Heymann nephritis important discoveries were made thatresulted in a better understanding of experimental nephrologyin general and immune complex glomerulopathy in particular[59]. These studies have contributed enormously to the under-standing of the formation and disappearance of immune aggre-gates in the glomerular capillary wall [60], the mechanismsleading to proteinuria [61, 62], and the role of immune regula-tion considering the renal tubular antigens mentioned [31].

In this model it was demonstrated for the first time that theimmune aggregates present at the epithelial side of the gbomer-ular filter were not deposited there from the circulation, butinstead were formed in situ [22]. This local formation ofglomerular immune complex aggregates was also shown tooccur in other models of glomerulonephritis like passive serumsickness gbomerulopathy [63, 64], spontaneous glomerulone-phritis in New Zealand white rabbits [65], and many others.

The antigen involved in the Heymann nephritis was purifiedby Kerjaschki and Farquhar [66] and was shown to consist of aglycoprotein with a molecular weight of 330 kD. Apart from itspresence in the tubular brush border, the antigen was shown to

Hoedemaeker and Weening: Experimental models for human nephropathology 1017

presence in the tubular brush border, the antigen was shown tobe present on the cell membrane of the glomerular epithelialcells, especially in coated pits [671.

Soon thereafter a second breakthrough as to immune com-plex formation in this model was made by the group of Andres[68]. They demonstrated in vitro that following a reaction withthe antibody, the antigen on the epithelial cell membrane wascross linked, clustered and subsequently shed, probablythrough an association with intermediate filaments like micro-tubules [69]. It was furthermore demonstrated in vitro thatchioropromazine could prevent such a clustering and subse-quent shedding [70]. The authors hypothesized that similarevents may occur in vivo and that the formed aggregates areshed in the space between epithelial cells and basement mem-brane [68].

Several authors are convinced that more antigens than gp330are involved in this immune complex glomerulopathy. Theyclaim that a glycoprotein with a molecular weight of around 100kD might also be involved and which may be essential incrosslinking the gp330 molecules [71] and subsequent sheddingof the complex [72—76]. Bagchus et al [72] suggested that gp9Oplays such a role in the pathogenesis of passive Heymannnephritis. They showed that antisera from which the anti-gp9Oactivity had been removed did not bind to rat glomeruli afterperfusion.

In addition Hogendoorn et al [771 found that antibodiesdirected against extracellular matrix components like lamininand collagen type IV are present in the sera used to inducepassive Heymann nephritis and could also play a role in theformation of gp330 containing immune aggregates.

Sporadic reports in the literature on human nephropathologydeal with the presence of tubular brush border antigens (RTE)in the glomerular aggregates of idiopathic membranous glomer-ulopathy. Douglas et al [78] were able to detect circulatinganti-RTE antibodies in the serum of a patient with idiopathicmembranous glomerulopathy. They demonstrated RTE-likeantigens in the glomerular immune aggregates. These findingssuggest that RTE-like antigens might play a role in the patho-genesis of some cases of human idiopathic membranous gb-merulopathy. However, since the reports on the participation ofRTE antigens are limited despite an intensive search [79], andbecause other antigens are known to be involved in secondarymembranous glomerulopathy [80], it seems likely that moremembrane or planted antigens are involved in the pathogenesisof this disease.

In conclusion we can say that the study of Heymann nephri-tis, and especially its passive variant, has helped us understandthe formation of glomerular immune aggregates. These resultfrom binding of antibodies to glomerular epithelial antigens thatsubsequently are shed in the space between epithelial cell andGBM. It provided an opportunity to study the role of comple-ment and epithelial cell detachment as causes of increasedpermeability of the glomerular filter. That in human glomerulo-nephritis identical antigens are seldomly found doesn't neces-sarily imply that the pathogenetic mechanism shown for thiskind of glomerulonephritis is not operating in human disease.Studies along the line of those presented here for the Heymannnephritis may reveal pathogenetic antigens in man.

Serum sickness glomerulopathy

Serum sickness glomerubopathy is the classical model ofimmune complex disease. It was introduced by Germuth [20]and Dixon et al [21] and brought a new scientific region to thestudy of immune complex diseases in general and glomerulone-phritis in particular. The model consists of an acute and achronic variant induced in rabbits by one or more injections ofbovine serum albumin (BSA) resulting in most cases in glomer-ulonephritis.

The acute variant is induced by one bolus injection of BSA.The resulting anti-BSA antibodies combine with the antigen inthe circulation to form immune complexes.

Chronic serum sickness glomerulonephritis is induced bymultiple injections with BSA that are given daily in a dosagewhich is determined by the antibody titers in such a way that acontinuous antigen excess exists and that the immune com-plexes which are formed therefore remain small and soluble. Inboth models the glomerubonephritis is thought to result fromglomerular deposition of soluble immune complexes present inthe circulation. Depending on their size, the immune complexesare deposited either in the glomerular capillary wall (GCW) orin the mesangium [81].

It is known that physicochemical characteristics play animportant role in the deposition of immune complexes. Thesecharacteristics determine the equilibrium between immune ag-gregates and immune complexes on the one hand and betweenimmune complexes and their components on the other hand,[(AgAb)n AgAb Ag+Ab] [81, 82]. When immune com-plexes are formed with antibodies of low avidity the equilibriumshifts to the right, thus fulfilling a prerequisite for an in situformation of immune complexes in tissues, as was shown forthe Heymann nephritis. This hypothesis is consistent withresults obtained by various investigators [83, 84], who showedthat in chronic serum sickness, membranous glomerulonephri-tis developed only in animals producing low-affinity antibodies[85, 86].

Whether immune aggregates are formed in situ or are depos-ited from the circulation, the anionic charge of the GCW playsa significant role, either by providing a charge barrier [871, or asite for planted antigen, especially when the antigen possessesa positive charge [88]. For this reason, antigens bearing apositive net charge have become important in the induction ofexperimental glomerulonephritis, and presumably also in thegenesis of human gbomerubonephritis.

In 1982, Hoyer, Krueger and Seiler [89] demonstrated thatalternating renal perfusion with heparin and the polycationprotamine sulfate resulted in complexes with a localization inthe GCW that roughly indicated the negatively charged sites.The in situ formation of these spherical protamine-heparincomplexes was shown not to be related to the observedproteinuria [89, 90]. Following these experiments Fleuren,Grond and Hoedemaeker [91] demonstrated for the first timethat in situ formation of gbomerubar immune aggregates couldoccur when antigens, not related to the gbomerulus, were firstplanted in the GCW where they were able to react subsequentlywith the injected antibody. With an alternating perfusion sys-tem using BSA and anti-BSA antibodies, they demonstrated theformation of immune aggregates in the GCW of isolated ratkidneys. These investigations were extended by Border and


coworkers [28, 92, 93] and many other investigators [94—96]using a variety of charged antigens.

The net charge of immune complexes also influences deposi-tion in the glomerulus. When cationized immune complexes areinjected into an animal, a GCW localization may be obtained[85, 97, 98] through an interaction of the immune complexes andthe intrinsic negatively charged sites of the GCW. The charge ofthe antigen can also influence the nature of the resultingimmune complexes. Koyama et al [99] showed that both sizeand avidity were determined by the charge of the antigen.

Iskander and Jenette [100], Lew, Staines and Steward [83],and Lew and Steward [84] showed that high-affinity immunecomplexes were deposited exclusively in the mesangial area,whereas low-affinity immune complexes were localized in theGCW, suggesting that the immune complexes might easilydissociate and reform in situ in the GCW [101—104].

It can be said that the value of the serum sickness model istwofold. First it provided an insight in the formation andsubsequent deposition of immune complexes in tissues. In thisdeposition the charge of the antigen or the net charge of theimmune complexes play an important role. Moreover it showedthat glomerular immune complexes also can be formed locally,especially when charged antigens are involved. These antigensfirst are planted in the GCW and subsequently react withcirculating antibody.

Lastly, extra antigen or antibody or positively charged mol-ecules may under certain circumstances cause disappearance ofglomerular immune aggregates by competition of binding withthe glomerular negative charges.

IgA glomerulopathy

Glomerulonephritis which is associated with mesangial IgAdeposition includes Berger's disease, Henoch-Schönlein gb-merulonephritis and the so-called hepatic glomerulonephritis,This paper will only discuss the models associated with amesangial deposition or local formation of IgA-containing im-mune complexes.

Although IgA glomerulopathy has been studied since itsdiscovery in 1968 by Berger and Hinglais [105], it is still notclear how the mesangial deposits can elicit tissue damage,evolve and which possible antigens may be involved. For thisreason several investigators tried to induce similar glomerularlesions in animals.

The first model of IgA glomerulopathy was obtained inBABL/c mice bearing a IgA myeloma (MOPC-315) whichproduces antibodies with a specificity for albumin conjugatedDNP [106]. IgA immune complexes were found in the glomer-ular mesangium in the majority of such animals in vivo and wereshown to induce glomerular disease. When compared to IgGcomplexes formed under similar circumstances, IgA containingimmune complexes were shown to have a great propensity forglomerular deposition [107]. Johnson et al [108] demonstratedthat IgA containing immune complexes like those of IgG areable to elicit injury in pulmonary alveoli, by activation ofcomplement and generation of reactive oxygen species. Inmodels of IgA glomerulopathy it has been shown that theimmune aggregates are only nephritogenic when the antigen hasan independent ability of complement activation. If this is notthe case, in addition to the IgA containing complexes small

amounts of complement fixing IgG or 1gM antibody have tobind [109].

Since in human IgA nephropathy infiltrating leucocytes canseldomly be found, the mechanisms of tissue injury by IgAimmune complexes may be different.

Because it is believed that the mucosal immune system playsan important role in idiopathic recurrent hematuria or Berger'ssyndrome [105] and since deposition of IgA in the glomerularmesangium is often associated with viral respiratory or gastro-intestinal syndromes, attempts have been made to obtain amodel by oral immunization of animals.

Emancipator, Gallo and Lamm [1101 induced a IgA nephrop-athy by oral immunization of mice with ovalbumin. The fea-tures of the experimentally-induced renal lesion resembled thatseen in human IgA nephropathy, in the sense that mesangialdeposition of IgA was obtained. These experiments delineatedthe importance of the mucosal IgA immune response in theorigin of this disease, especially when it is associated with ablockade of the reticulo-endothelial system [111]. Other inves-tigators, however, reported that mice immunized orally withTNP-ovalbumin failed to induce a IgA nephropathy [112].These studies further showed that the immune complexescontained predominantly polymeric IgA, as determined by thedetection of the J-chain in the mesangial deposits [110]. Theaffinity of immune complexes containing polymeric IgA for themesangium contrasts with the lack of such affinity of immunecomplexes containing monomeric IgA [59]. It is possible thatmonomeric IgA may contribute to the formation of mesangialaggregates by in situ binding. This was demonstrated by Chen,Wong and Rifai [113] who showed that binding of monomericIgA occurred following mesangial deposition of polymeric IgAcontaining immune complexes.

In relation to the idea that polymeric IgA is transported to thebile circulation, investigators tried to induce mesangial IgAdeposition either through ligating the bile ducts [114] or render-ing livers cirrhotic [115] by carbon tetrachloride. Both regimensresulted in increased IgA containing macromolecules in themesangium. Secretory component (SC) was also found in themesangium in these experiments, since it is never found inmesangial deposits in clinical IgA disease, these experimentsshould be regarded critically as to their relevance for humandisease [116]. In humans the SC-dependent biliary transport ofIgA probably plays a much smaller role in the removal ofpolymeric IgA from the plasma than in rats [117].

Thus far, the study of the models of IgA nephropathy hasshown that mesangial IgA deposits can follow oral immuniza-tion of mice, but that this model does not mimic all features ofthe human disease; in particular the functional gbomerulardisorders seem to be missing. Mesangial IgA containing im-mune complexes, especially in aged mice, can be induced bythe ubiquitous occurring ocorna virus antigens [118]. Thismeans that the mouse is not an ideal animal for developing amodel for human IgA gbomerubopathy [119].

Models of glomerulonephritis associated with polyclonal Bcell activation

Common characteristics of the models described above isthat they occur spontaneously or are induced by immunizationwith a well defined antigen. This antigen is either a normal


constituent of the glomerular structures or becomes part of it bydeposition from the circulation. Upon binding, humoral and/orcellular reactants cause a characteristic pattern of inflammatoryinjury. Under normal conditions tolerance to self-antigens ofthe glomerulus prevents the induction of autoimmune reactionsleading to glomerulonephritis. Immunization in completeFreund's adjuvant is one of the mechanisms to by-pass or breakthis tolerance. Under normal conditions tolerance is maintainedby an active system of suppression by specific T cells andanti-idiotypic antibodies which control the expression of nor-mally existing autoreactive T and B cells. Defaulting the sup-pressor mechanisms will lead to uncontrolled expression ofautoreactive B cells resulting in the production of auto-anti-bodies or autoreactive cytotoxic T-cells to various self-constit-uents. Similarly, autoreactivity may be induced when B cellactivation is too strong to be controlled, for example by crosslinking of surface immunoglobulins, by stimulatory agents suchas LPS [120] or other viral or bacterial antigens [121], byalloreactive lymphocytes in graft versus host (GVH) [1221 orhost versus graft (HVG) reactions [123] and by toxic agentssuch as mercury [1241, and penicillamine [125].

Irrespective of the underlying cause, polyclonal B cell acti-vation results in a characteristic autoimmune syndrome withhypergammaglobulinemia including IgE, antinuclear antibod-ies, anti-red blood cell (RBC) antibodies and anti-basementmembrane antibodies (especially of IgG1 and IgG2 isotypes),vasculitis, glomerulonephritis and mucosal inflammation. Thesusceptibility to PBA and glomerulonephritis upon the appro-priate stimuli is genetically determined as shown in experimentswith LPS [126], mercury [127], the alloreactive stimulation byGVH [128] or HVG [129]. In rodents LPS has been shown toinduce anti-DNA antibodies [130], anti-idiotype antibodies andrheumatoid factor [131]. Glomerulonephritis has been found tobe associated with circulating immune complexes containingantibodies of various specificities, and these could be elutedfrom the diseased glomeruli. PBA and glomerulonephritis havebeen described in models of malaria [132], and of Trypanoso-miasis [133—135], and are characterized by genetically restrictedanti-DNA, rheumatoid factor and anti-basement membraneautoantibody activity.

Examples of PBA associated with glomerulopathy will bepresented in the next paragraphs. The first two examples dealwith induced forms like allogeneic disease caused by GVH orHVG and mercuric chloride-induced glomerulopathy. Modelsof SLE will also be discussed as an example of spontaneouslyoccurring PBA associated with glomerulopathy.

Al/ogeneic diseaseThe autoimmune phenomena induced by chronic allogeneic

disease can be found in murine experimental GVH disease andin HVG reactions in chimeras. GVH disease can be induced bytransfer of parental lymphocytes to an Fl hybrid derived froma cross with another parent strain differing at the MHC class IIregion. Genetic studies have revealed that such intra-class IIdifferences determine the susceptibility to stimulatory reactionsresulting in polyclonal B cell activation and auto-immune gb-merulonephritis [121, 128, 136]. Autoantibodies develop whichare directed against RBC, basement membrane antigens [1371and a renal tubular antigen with a molecular weight of 160 kD,the pathogenicity of which is still uncertain [138]. All these

specificities can also be found in normal unstimulated mice, andin increased amount upon exposure to certain stimuli, butusually they are of the 1gM subclass, whereas in GVH they areof IgG isotype [138]. The isotype switch which is under controlof IL-4 is probably of major importance in conditions associatedwith T cell dependent PBA [139], as was also suggested forHVG [140] and for mercury-induced autoimmune reactions[141].

The HVG model of autoimmune disease is induced bytransfer of Fl lymphocytes into neonatal mice of one of theparental strains. These mice develop tolerance to the graft butstimulate the grafted B cells semi-allogeneically because of thedifferent MHC antigens on their T helper cells [142]. Thegrafted B cells are not under normal control and this non-cognate T-B cell cooperation, similar as that in GVH diseaseresults in autoantibody production and glomerulonephritis [122,140].

Mercuric chloride-induced glomerulopathyPBA associated With different forms of gbomerulonephritis

[143—145] has been well established in rodents exposed tomercuric chloride. Depending upon the MHC and non-MHCgenes [1271, rats will develop either a stimulatory syndromecharacterized by PBA and glomerulonephritis, or suppressionphenomena as have been described in the Lewis rat [1461. Themodel has been most extensively studied in the Brown-Norwayrat, which develops a T cell-dependent transient syndrome ofhigh IgE levels and IgG1 and IgG2 auto-antibodies directedagainst components of the glomerular basement membraneresulting in a linear and later granular distribution [1411 ofimmune aggregates in the GCW [123, 132, 133, 141, 143]. Theearly phase is associated with an increase in B and T lympho-cytes, increased class II expression on lymphoid organs, epi-thelia of salivary glands and the tongue [141]. The recoveryphase is associated with the presence of anti-idiotype antibodies[147] and suppressor T cell activity [148] that can transfersuppression to naive recipients. In vitro and in vivo studieshave demonstrated that early in the disease autoreactive T cellsdevelop. These are directed against class II antigens as well asto other undefined T cell surface antigens and are likely to playan important role in the disease [149]. In addition, mercury hasbeen shown to induce thymic depletion [141] and to affectsuppressor T cell function [150], which may also play a permis-sive role in the induction of the disease.

SLE models

Murine models of lupus are often examples of PBA andglomerulonephritis which have been studied extensively, forexample in murine lupus models in the (NZB x NZW)F 1 (B/W)female mice, B x SD male and MRL-lpr/lpr mice [151, 152].

Following the report of Koffler, Schur and Kunkel [153] thatin human SLE glomerulonephritis the glomerular aggregateswere composed of DNA and anti-DNA, similar findings werereported for the B/W mice [154] and later in the other mousestrains [155—157]. After Izui, Lambert and Miescher [158] haddemonstrated an affinity of DNA for the collagen moiety of theGBM in vitro, it was believed that apart from being depositedfrom the circulation, glomerular immune aggregates in SLEglomerulonephritis could also be formed in situ.

In 1984 O'Regan and Turgeon [159] found that infusion of


DNA into normal mice resulted in mesangial binding and not ina binding to the GCW which did not support such in situformation. Subsequent experiments similarly failed to demon-strate in situ formation of glomerular immune aggregates inexperimental SLE [160], and rabbits infused with preformedDNA anti-DNA immune complexes get mesangial deposits, butnot localization along the glomerular capillary wall [1611. Thesefindings questioned the importance of DNA-anti-DNA immunecomplexes in the pathogenesis of SLE glomerulonephritis.Although Morimoto et al [162] reported that in SLE patients thedisease activity was directly correlated with circulating immunecomplexes consisting of DNA-anti-DNA, Izui, Lambert andMiescher [163] showed that only 6% of the circulating immunecomplexes in SLE patients consisted of DNA/anti-DNA andthat at least 52% of the immune complexes were of differentcomposition.

Comparable findings have been reported for the spontane-ously occurring SLE-like syndromes in mice. Cavallo, Grave,and Granholm [164] showed that the DNA anti-DNA contentwas low in eluates from glomeruli of B/W mice and Izui et al[165] showed that the presence of serum antibodies to single- ordouble-stranded DNA was not significantly associated with theoccurrence of glomerulonephritis. Granholm et al [166] demon-strated that the glomerular eluates from B/W mice contained afactor that inhibited the interaction between DNA and anti-DNA. All of these studies led to the conclusion that otherimmune complex systems besides DNA anti-DNA could play arole in the pathogenesis of lupus nephritis.

In 1981 Izui et al [165] found a correlation between thedevelopment of fatal glomerulonephritis in B/W mice, and thepresence of gp70-containing immune complexes [167]. Gp70 is aserum glycoprotein structurally related to the envelope glyco-protein of murine leukemia virus [168]. Although this virus hasa virtually ubiquitous occurrence in rodents, only lupus-proneanimals develop auto-antibodies against gp7O spontaneously[169]. Izui et al [165] concluded from these findings thatgp7O-anti-gp7O systems fulfill a pathogenic role in experimentallupus nephritis and that genes governing the production ofauto-antibodies against retroviral gp7O may be the genes mainlyresponsible for the segregation of spontaneous renal disease inB/W mice.

However Andrews et al [170] have recently questioned therole of the anti-gp7O immune response in murine SLE. Theyused a low gp7O MRL/1 cogenic mice to demonstrate thatelimination of most of the serum gp7O and virtually all of theimmune complexes containing gp7O had no observable effect onthe course or nature of the disease.

So far it can be concluded that the spontaneously occurringSLE-like disease associated with glomerulonephritis in certainmouse strains has served as a model of human SLE glomeru-lonephritis. Their study has provided several competinghypotheses of pathogenetesis [171], and further studies will beneeded before it can be ascertained which of these are pertinantto clinical SLE.

Focal and segmental glomeruloscierosisMechanisms involved in the progression of renal disease have

been studied in experimental models from the beginning of thiscentury. But during the last decade renewed interest and theuse of micropuncture and morphometry combined with phar-

macological and dietary intervention have provided enormousgain in the understanding of the factors determining the pro-gression of renal disease.

Progressive glomerulosclerosis develops in certain rat strainsspontaneously with aging [172, 173] and bears a close resem-blance to focal glomerulosclerosis in man, an entity first de-scribed by Habib et al [174]. Later it was recognized as a formof glomerular injury that can complicate various forms of renaldisease as well as systemic disease, such as hypertension anddiabetes mellitus [29]. The development of experimental pro-gressive glomerulosclerosis can be accelerated by high proteinfeeding [175], by renal ablation [1761, and by inducing systemichypertension [177] or diabetes mellitus [178]. In addition,progressive glomerulosclerosis can develop in genetic modelsof hypertension with or without unilateral nephrectomy and inmodels of obesity [179]. Finally, progressive glomeruloselerosishas been described in models of chronic glomerular epithelialcell damage induced by puromycin aminonucleoside [180] andadriamycin [181]. It has been suggested that hemodynamicfactors, and most importantly intraglomerular capillary pres-sures, play a crucial role in the pathogenesis of progressiveglomerulosclerosis [182, 183], via endothelial, mesangial andepithelial damage and glomerular hypertrophy [184]. Endothe-hal cell damage is associated with platelet aggregation andthrombosis, which may explain the beneficial effect of anti-coagulatory treatment [185, 186]. The susceptibility to developprogressive glomerulosclerosis is genetically determined [29,187] and probably depends upon the vasoactive responses to aprimary glomerular injury, such as in diabetes mellitus or inminimal change disease in man, and similarly after unilateralnephrectomy or high protein feeding in experimental models[29]. Intervention aimed at lowering capillary pressure either byprotein restriction (afferent constriction) or converting enzymeinhibition (efferent vasodilation) have been shown to be par-tially effective in preventing or retarding progressive glomeru-losclerosis in experimental models [175. 181, 183, 188—190]; itshould be remembered that these treatments have other effectsbeside those on glomerular capillaries. Similar results havebeen claimed in clinical studies but more data are needed [191—193].

The models of progressive glomeruloscierosis have providedinsight in functional abnormalities that eventually lead to end-stage renal failure, especially when the lesions closely resemblethose of human focal glomerulosclerosis. In other models, suchas experimental diabetes in rats, the lesions do not show thetypical morphological picture found in man, and here extrapo-lation seems hazardous. In addition it should be rememberedthat most male rats are prone to develop progressive glomeru-losclerosis with age and that man seems to be less susceptible.Genetic differences in susceptibility associated with vascularreactivity seem to be crucial in identifying individuals at risk.

Conclusion

In the eighty years during which experimental models ofhuman glomerulonephritis have been studied, much has beenlearned about the mechanisms by which glomerular immuneaggregates are formed, how they mediate glomerular injury,leading to an increased permeability and how progression toend-stage renal failure occurs. In recent years the emphasis ofthe studies has shifted towards the role of cellular immunity and


mediators of inflammation. Taken together, however, the stud-ies mentioned above have not resulted yet in a complete pictureof human glomerulopathy in all its variants and its pathophys-iological consequences. This is due to the fact, although be-lieved otherwise, that it is seldom possible to obtain a diseasemodel in which both etiology and pathogenesis are identical oreven similar to human disease. The study of models often iscomplicated by the fact that they are induced by methods whichdo not occur naturally or are complicated by the induction of animmune reaction in animals which is directed against thedisease-inducing antibody. Furthermore in models of glomeru-lonephritis resulting from autoimmunity, the induced autoim-mune phenomena are downregulated so that the disease re-solves spontaneously and chronic disease cannot be studied indetail.

These drawbacks however do not invalidate the observationsmade already. The study of a model frequently involves theelucidation of a detail, like participation of a mediator ofinflammation or the mechanism causing increased permeabilityof the glomerulus. The results from such studies may lead to theformulation of a working hypothesis which can be used for thestudy of human glomerulonephritis or for development ofadditional models for study. Ultimately the results from suchstudies have proved their relevance to human nephropathology,and can lead to clinical advances such as the development oftreatment modalities or even preventative measures. Until nowthough, this has hardly happened.

The reason why results from studies of experimental glomer-ulonephritis are not used more often, may be due to the fact thatmost models were developed for the studies of pathogeneticmechanisms, which in the human situation hardly appear to beaccessible for treatment. Nevertheless, the study of spontane-ously-occurring autoimmune phenomena in mice and morerecently of induced autoimmune phenomena by PBA haveopened new and exciting possibilities for the study of etiologicfactors in human glomerulopathy. Although postinfectious gb-merulonephritis has almost disappeared, additional extrinsicfactors like bacteria, viruses or drugs may prove to be impor-tant in eliciting an PBA in susceptible individuals. The recog-nition of such a mechanism then may lead to the prevention ofsome forms of glomerulonephritis.

Reprint requests to Professor P.J. Hoedemaeker, Department ofPathology, University of Leiden, P.O. Box 9603, 2300 RC Leiden, TheNetherlands

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relevance of experimental models for human nephropathology · of the glomerulonephritis models, we...

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