Genetic and pathogenic basis of autoimmune diabetes in NOD mice

Introduction

Genetic and pathogenic basis of autoimmun6

diabetes in NOD mice

David V Serreze and Edward H Leiter

The Jackson Laboratory, Bar Harbor, USA

Non-obese diabetic (NOD) mice are an excellent model of T-cell mediated autoimmune insulin-dependent diabetes in humans. Recent studies in NOD mice have shown that this disease is a result of epistatic interactions between multiple genes, both inside and outside the major histocompatibility complex (MHC), generating T cells reactive against an expanding repertoire

of autoantigens.

Current Opinion in Immunology 1994, 6:900-906

Most cases ofinsulin-dependent diabetes mellitus (IDDM) in humans appear to be attributable to T lymphocyte mediated autoimmune destruction of pancreatic b cells [l-2]. Similarly, T lymphocytes mediate autoimmune destruction of pancreatic p cells in the non-obese diabetic (NOD) mouse model of IDDM [3,4]. p cell autoreactive T cells present in diabetic NOD mice and human IDDM patients also mediate rapid rejection of islet grafts [1,5-6]. This review discusses insights the NOD mouse has provided on the immunogenetic basis of IDDM, and the pathogenic mechanisms by which autoreactive T cells mediate the initial destruction of pancreatic b cells, and then eliminate subsequently implanted islet gratis.

The H2U MHC haplotype as kkfl in NOD mice

IDDM in NOD mice is the consequence of immunoregulatory defects, since a variety of manipula- tions which promote more normal interactions between antigen-presenting cells (APC) and T cells prevent diabetes [7]. The major genetic component contributing to IDDM susceptibility in NOD mice is the strain’s unusual X%7 major histocompatibility complex (MHC) haplotype. Loci identified by genetic segregation analysis as contributing to susceptibility to insulin-dependent diabetes are provisionally referred to as fdd loci until the specific genes are elucidated. HZ?7 (Iddl) is not only the first Idd locus identified by outcrossing NOD with diabetes-resistant strains, but also the only

Idd locus for which the identity of specific susceptibility genes is actually known. NOD congenic for other MHC haplotypes remain IDDM-free despite expressing requisite susceptibility alleles at other Idd loci [8-lo]. With only rare exceptions, heterozygous expression of a protective MHC haplotype is sufficient to block IDDM development in these congenic stocks [9,10]. This sug- gests that deficiencies in immune regulation rendering the NOD strain uniquely susceptible to IDDM development are most severe when H-27 is homozygously expressed. The possibilities include a reduced ability of APC homozygously expressing HZ77 to mediate clonal deletion of autoreactive T cells, or to activate peripheral immunoregulatory mechanisms that suppress their function. Indeed, APC from NOD mice have been shown to be defective in activating each of these tolerogenic functions [ll-141.

Multiple genes within H.B7 contribute to the pathogenesis of autoimmune IDDM in NOD mice. The rare A@7MHC allele of NOD mice encodes histidine-serine residues at amino acid positions 56 and 57 instead of the proline-aspartic acid residues present in most other inbred strains. This sequence is shared by IDDM ‘high risk’ D@ alleles in humans such as DQfl 0302 [15,16]. As a result of this substitution, the I-Ad molecule binds peptides with a negatively charged carboxy terminus not bound by other MHC class II molecules [17-l. This structure-function relationship may elicit pathogenesis by altering the mosaic of p-cell autoantigens presented to CD4+ T cells. NOD mice also fail to express an I- E molecule due to a deletion within the first exon of the Ea locus [18]. IDDM is inhibited in NOD mice expressing either I-A or I-E transgenes derived from diabetes-resistant MHC haplotypes [19,20], indicating

900

Abbreviations APC-antigen-presenting cell; BCl-first backcross; DTH-delayed-type hypersensitivity; GAD-glutamic acid decarboxylase;

IDDM-insulin-dependent diabetes mellitus; MHC-major histocompatibility complex: SCID-severe combined immunodeficiency; NOD-non-obese diabetic.

0 Current Biology Ltd ISSN 0952-7915

Autoimmune diabetes in NOD mice Serreze and Leiter 901

that a major component of HZ’-linked IDDM susceptibility arises &on1 both the failure to express I-E and the homozygous expression of I-AS’. The mechanism by which transgenic expression of single class II genes from diabetes-resistant MHC haplotypes blocks IDDM development in NOD mice is poorly understood, but seems to involve the activation of peripheral immunoregulatory functions rather than inducing clonal deletion of autoreactive T cells [21-231. However, there is evidence that clonal deletion of p-cell autoreactive T cells may be induced by APC that express multiple diabetes-resistant MHC genes [14].

Although MHC class II genes clearly contribute to the immunopathogenesis of IDDM in NOD mice, the mechanism by which the relatively common class I genes (e.g. I@, 0’)) of the HZ?7 haplotype contribute to the disease process has not been clarified. Faustman et al. [24] reported that NOD mice are characterized by diminished levels of constituitive MHC class I expression on splenocytes due to a mutation within the intra-MHC encoded Tap1 peptide transporter gene. This same re- port claimed that mice with a normally resistant 129 and C57BL/6 genetic background developed autoimmune IDDM when made MHC class I deficient by ‘knock- out’ of the p2-microglobulin @&I) gene. Hence, it was proposed that MHC class I ablation, potentially elicited by a Tap gene mutation, is by itself sufficient to induce a loss of immune tolerance to B cells [25]. However, other investigators have found that while the HZ7 haplotype is indeed characterized by rare Tap alleles [26], they function in a normal manner. The NOD genomic sequence encoding the Tap1 ATP-binding domain, a critical component for proper loading of peptides onto newly syn- thesized MHC class I molecules, is identical to that of diabetes-resistant BALB/c mice [27-l. Further work has demonstrated that the affinity for ATP, the kinetics of peptide uptake and the substrate specificity of Tap transporters encoded within H2q7 do not differ from those of Tap transporters encoded within four other MHC haplotypes [28’]. That Tap gene function is normal in NOD is also supported by the finding that peptides eluted horn their H2Kd MHC class I molecules con- form to the known motifs of peptides binding to this molecule in non-autoimmune strains [17*]. The normal Tap gene function explains why several other investigators have been unable to confirm diminished levels of MHC class I expression on unstimulated macrophages and splenocytes &om NOD mice [17*,29,30*]. Indeed, rather than being accelerated, IDDM failed to develop in otherwise genetically susceptible NOD mice made deficient in MHC class I expression and CD8+ T cells by congenic transfer of a functionally disrupted f%Ztn locus [31*,32*]. Thus, in addition to the unusual class II region genes, IDDM development in NOD mice requires that the common class I gene products of H2g7 be normally expressed in order to select and target @-cell autoreactive CD8+ T cells. This pathogenic hnction appears to be dependent upon expression of particular class I alleles,

since the incidence of IDDM is reduced in NOD mice congenic for the MHC haplotype of CTS mice, sharing class II, but not the class I alleles with the H297 haplotype [33].

Polygenetic basis of IDDM in NOD mice

The H&7 MHC haplotype has been congenitally transferred to the IDDM-resistant C57BL/lOJ (Bl.0) and NON/Lt inbred mouse strains. No IDDM develops in B10.H.2~7 congenic mice and only a low (2%) incidence in NON.H~X~ congenic mice. Thus, although estimates from the genetic analyses described below indicate that 50%) or more of the genetic risk is transmitted by Zddl, a variable assortment of non-MHC linked Zdd genes is also required to mediate the pathogenesis of autoimmune IDDM. As recently reviewed by Wicker et al. [34], and summarized in Table 1, at least 14 different non-MHC Idd loci in addition to H2p7 have been identified by genetic segregation analysis. However, the particular subsets of Zdd loci that segregate with diabetes susceptibility and their relative pathogenic strengths appear to vary as a function of the diabetes-resistant strain to which NOD was outcrossed. Linkage markers for most Zdd loci have been identified in first backcross (BCl) progeny pro- duced by breeding diabetes resistant Fl hybrids with the NOD parental strain [35-41,42’,43]. Following outcross of NOD to the completely unrelated BlO strain, BCl analysis has provided evidence of 10 Zdd loci on nine different chromosomes (Table 1). However, only a subset of the Zdd loci identified in the outcross to BlO ‘segregated with IDDM in BCl progeny born an outcross of NOD with diabetes-resistant NON mice (MA MacAleer et al., unpublished data). This was correlated with a much higher incidence of disease in BCl progeny horn an outcross of NOD with NON than with BlO. NOD and NON were both derived from a common JcI:ICR progenitor, and hence may share susceptibility alleles at some Zdd loci where the BlO allele contributes to resistance. However, the sharing of certain Zdd susceptibility alleles provides only a partial explanation for the higher frequency of IDDM that is observed in BCl progeny following an outcross of NOD to NON than to BlO.

An important insight gained from the genetic analysis of IDDM susceptibility in NOD mice is that the NOD genome contains but one subset of a much larger set of potential Zdd genes providing a predisposition to autoimmune disease. When the NOD-specific diabetogenic interactions are disrupted by outcross, and then reassorted into diabetogenic combinations through intercross or backcross progeny, the same fixed set of IDDM susceptibility modifiers defining the NOD genome need not be fully reconstituted to elicit IDDM. As shown in Table 1, one of the most interesting discoveries made by outcrossing NOD with IDDM-resistant strains such

902 Autoimmunitv

rable 1. Idd loci identified in NOD mice.

.OC”S Contribution of

chromosome) NOD allele to IDDM

ddl = H2g (17) Susceptibility

‘ddi’ 19) Susceptibility

Strain/type of cross

locus segregates

MHC disparate/EC1

NON/BCl and F2

BlO/BCl

‘dd3 (3) Susceptibility NON/BCl and F2

BlO/BCl

‘dd4 111) Susceptlblllty Bl O/BCl

‘dd.5 (1) Susceptibility BlO/BCl

NOR/F2

ldd6 (6)

fdd7 (7)

ldd8 (14)

fdd9 (4)

Susceptibility

Susceptibility

Resistance

Resistance

Resistance

Resistance

Susceptibility

BlO/BCl

Mus spretudBC1

NON/BCl and F2

Bl O/BCl

NON/BCl

BlO/BCl

BlO/BCl

NON/F2

NOR/F2

fddlo (3) Susceptibility

lddll (4) Susceptibility

IddIe? (14) Susceptlbihty

Iddl3 (2) Susceptibility

ldd14 (13) Susceptibility

ldd15 (5) Susceptibility

IDDM, insulin-dependent diabetes mellitus.

Bl O/BCl

86 and SJL/BCl

B6 and SJL/BCl

NOR/F2

NON/F2

NON/F2

as B10 and NON is that the ‘normal parental strain contributes to susceptibility as well as resistance alleles (e.g. BlO-derived susceptibility alleles at Zdd7, and Zdd8, and NON-derived susceptibility alleles at Zdd6 and Zdd7, but not at Zdd8). The NON strain was, in fact, originally selected for impaired glucose homeostasis [3]. Indeed, NON/Lt mice become obese with age and exhibit impaired glucose tolerance. Accordingly, NON genes contributing to glucose intolerance apparently synergize deleteriously with the collection of NOD-derived Zdd susceptibility genes to increase the penetrance of the disease phenotype. Similarly, when NOD is outcrossed to

an inbred Mus spretus mouse, undefined M.Apretus- alleles precipitated a non-insulin dependent form of diabetes in males (M Hatteri et al., abstract, Diabetes 1992, 41:93A), emphasizing the heterogeneity not only in the genetics of diabetes, but also in its pathophysiology. In addition, the activities of certain immune mediators such as natural killer cells and lytic complement, which could possibly participate in autoimmune destruction of pancreatic p cells, are deficient in NOD, but not BlO or NON mice [ 11,441. Zdd susceptibility loci from these ‘resistant’ strains might include genes promoting more normal activation of immune responses that are defective in NOD, expanding the repertoire by which B cells may be destroyed in hybrid mice. The finding that the genome of the NOD mouse represents but one subset of a larger spectrum of potentially pathogenic gene combinations has important implications for the genetics of IDDM in human populations.

BCl analysis is well suited to identifying linkage markers for Zdd loci where the NOD-derived susceptibility allele is dominant with low penetrance, or is recessive. However, this analysis cannot be used to identify fully dominant NOD-derived Zdd susceptibility alleles, since IDDM would develop at an equal frequency in both homozygous or heterozygous segregants. These Zdd susceptibility alleles can only be identified in F2 progeny, since unlike BCl analysis, the resistance allele from the outcross partner can be fixed to homozygosity. However, since Zdd resistance alleles can be fixed to homozygosity, the frequency of affected probands is much lower in F2 than BCl progeny. This difficulty is amplified as the number of segregating Zdd loci increases. For this reason, it has not yet been possible to generate sufficient num- bers of diabetic F2 progeny from the outcross of NOD with BlO to perform Zdd linkage analysis. However, it has been possible to assess Zdd gene segregation in F2 progeny from an outcross of NOD with NON (MA MacAleer et al., personal communication). This F2 analysis did indeed reveal the presence of NOD-derived dominantly acting susceptibility alleles at two loci (Zdd14 and Zddl5), that have not yet been identified in any BCl segregation analysis. Zdd gene segregation has also been assessed in F2 progeny from an outcross of NOD with diabetes-resistant NOR mice [45]. This analysis revealed the presence of a dominantly acting NOD-derived susceptibility allele at Zdd13, a locus that did not segregate with diabetes susceptibility and resistance in BCl or F2 progeny from the outcross with NON. Similarly, the Zdd13 locus was not detected in diabetic BCl progeny from the outcross of NOD to BlO. Thus, the non-MHC genes contributing to diabetes susceptibility will vary dependent upon the resistant strain to which NOD is outcrossed. For this reason, it is not possible to specify all potential Zdd loci from outcross to a single diabetes-resistant control strain. This also provides an explanation of why it has been difficult to establish fixed patterns of inheritance of IDDM genes in humans.


Mechanisms of autdimmune b cell destruction in

NOD mice

Among the major controversies in the etiopathogene- sis of autoimmune IDDM is the question of whether T cells that initiate pancreatic P-cell destruction, and the mechanisms by which they do so, are the same as those mediating the subsequent rejection of islet grafts implanted into overtly diabetic patients. The finding that both class I and class II gene products from H2qT contribute to IDDM susceptibility in NOD mice sug- gests that autoimmune p-cell destruction is mediated by a combination of CD4+ and CDS+ T cells. Supporting this concept is the finding that both CD4+ and CD8+ T cells must be transferred from adult NOD donors to accelerate IDDM onset in neonatal or young sublethally irradiated syngeneic recipients [46,47]. Similarly, using a series of P-cell autoreactive CD4+ and CD8+ T-cell clones isolated from the insulitic lesion of adult NOD mice, Reich et al. [48] found that both T-cell subsets must be co-transferred to accelerate IDDM onset in young recipients. In contrast, other investigators have proposed that NOD APC process soluble antigens common to all p cells, and present these in the context of their rare I-AB MHC class II molecule to CD4f T cells, which then mediate autoimmune p-cell destruction in a manner analogous to a delayed-type hypersensitivity (DTH) response. This hypothesis is based on the finding that cloned lines of CD4+ T cells isolated from the spleens of diabetic NOD mice are sufficient to passively transfer IDDM and to mediate islet graft rejection [49-511. Also supporting this concept is the finding that diabetes developed at a high frequency in a transgenic stock of NOD mice in which more than 95% of the T cells expressed the rearranged TCRa and b genes from one of these CD4+ P-cell autoreactive T-cell clones [52].

Major insights into this controversy have been provided by studies in which various T-cell populations have been passively transferred into a stock of NOD mice made T- and B-lymphocyte deficient by congenic transfer of the severe combined immunodeflciency (scid) mutation [53,54-l. Since NOD&d mice lack functional T-lymphocytes, they remain diabetes-free. The obvi- ous advantage of using T cell deficient NOD-scid mice as recipients for passive transfer studies is that it is not possible for the transferred T-cell population to activate effecters endogenous to the host. When CD4+ T cells isolated from the spleens of overtly diabetic NOD donors are transferred into NOD-scid recipients, both insulitis and overt IDDM develops within 3-4 weeks [54-l. Similarly, cloned lines of islet-reactive CD4+ T cells isolated f%om the spleens of overtly diabetic NOD mice also transfer IDDM to NOD&d recipients [55]. These results support the hypothesis that I-As7 restricted CD4+ T cells are sufficient to mediate autoimmune destruction of pancreatic B cells in NOD mice by a DTH-like mechanism. However, passive transfer studies using NOD-stid recipients have provided evidence that while populations

of CD4+ T cells present in diabetic NOD mice are sufficient to transfer IDDM, these effecters are only generated after B-cell necrosis has been initiated by a process dependent upon MHC class I restricted CD8+ T cells. This was demonstrated by the finding that while CD4+ T cells isolated from young prediabetic NOD donors can ‘home to NOD-scid islets, they cannot initiate IDDM in the absence of CD8+ T cells [54*]. P-cell necrosis in NOD mice initiated by a process requiring MHC class I restricted CD8+ T cells apparently results in the release of previously sequestered antigens, which subsequently activate and amplify many additional effector T-cell populations. Some of these additional T-cell populations ac- tivated during the later stages of P-cell destruction may be able to passively transfer IDDM and mediate islet graft destruction, but the antigens to which they respond, and the mechanisms by which they mediate B-cell cytotoxicity, will not accurately reflect the cytotoxicity of the T cells that actually initiate autoimmune P-cell destruction in young prediabetic NOD mice.

While the NOD T-cell repertoire that initiates autoimmune B-cell destruction is much less diverse than that accumulated in overtly diabetic mice, it does not appear that these initiating effecters are monoclonal in nature. This is supported by two separate studies in which reverse-transcription polymerase chain reaction analysis was used to demonstrate that T cells inflltrat- ing the islets of 3-week-old NOD mice use TCR genes in a polyclonal fashion [56,57]. Although unlikely to represent the sole antigen to which p-cell autoimmunity is initiated in NOD mice, the 65 and 67 kDa isoforms of glutamic acid decarboxylase (GAD) appear to represent key early b-celI autoantigens in this process. Their potential role as primary b-cell autoantigens is supported by two recent reports that very young (3- to 4-week-old) prediabetic NOD mice develop a spontaneous CD4+ T-cell response directed against epitopes at the carboxyl terminus of GAD [58*,59*]. In older NOD mice with more pronounced insulitic lesions, CD4+ T- cell reactivity was found to have spread to other epitopes within the GAD molecule 158.1, as well as to secondary P-cell autoantigens, including heat-shock proteins, pe- ripherin and carboxypeptidase H. The failure of NOD mice to establish T-cell tolerance to GAD was overrid- den by intrathymic [59*] or intravenous injection [58*] of large quantities of recombinant GAD into 3- to 4- week-old recipients. These treatments blocked not only the development of primary NOD T-cell responses to GAD but also the spread of T-cell reactivity to secondary g cell autoantigens and, most importantly, inhibited the development of IDDM. However, given that the GAD isoforms are solely intracellular proteins [60], they are likely to be immunologically presented by MHC class I molecules and thus predominantly elicit a CD8+ T-cell response. Therefore, it is possible that a CD4+ T- cell response to GAD is elicited only after p-cell lysis is initiated by T cells responding to other antigens. Indeed, NOD T cells reportedly exhibit spontaneous reactivity

904 Autoimmunity

against g-cell extracts before developing GAD reactivity [61]. However, even if GAD is not the sole p-cell autoantigen for which tolerance is initially lost, the appear- ance of a CD4+ T-cell response to the carboxyl terminus of GAD marks a key turning point in the development of IDDM in NOD mice. Interestingly, an autoimmune response to GAD is also one of the earliest preclinical markers of IDDM development in humans [62].

Conclusion

Studies in the NOD mouse have shown that the pathogenesis of autoimmune IDDM is the result of complex epistatic interactions between multiple Zdd susceptibility genes. To date, the only known Idd genes reside within the H2g7 MHC haplotype. Thus, major future research efforts will have to be directed at determining the identity and biological function of non-MHC associated Zdd genes. While autoimmune IDDM is polygenically con- trolled, these epistatic interactions can be disrupted by the presence of APC in transgenic NOD mice expressing only a single class II gene fi-om a diabetes-resistant MHC haplotype. This is significant as it indi- cates that autoimmune diabetes may be preventable by gene therapy protocols designed to induce expression of single diabetes-resistant MHC genes on hematopoieti- tally derived APC. It may also be possible to develop a similar protocol that will enable a person who has al- ready developed overt IDDM to regenerate a new T-cell repertoire that is tolerant to islet grafts. An increased un- derstanding of the p-cell antigens to which autoimmune responses are initiated is a step towards the achievement of this long-term goal.

Acknowledgements

Work cited from the authors’ laboratories was supported by National Institutes of Health grants DK46166 (DVS), and DK27721 and DK36175 (EHL), and by grants from the Ju- venile Diabetes Foundation International and Cancer Center Support (CORE) CA34196.

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906 Autoimmunity

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57. Waters SH, O’Neil JJ, Melican DT, Appel MC: Multiple TCR VP gene usage by infiltrates of young NOD mouse islets of Langer- hans: a polymerase chain reaction analysis. Diaberes 1992, 41:308-312.

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59. Tisch R, Yang X-D, Singer SM, Liblau RS, Fugger L, McDevitt . HO: Immune response to glutamic acid decarboxylase corre-

lates with insulitis in non-obese diabetic mice. Nature 1993, 366:72-75.

While unlikely to be the sole antigen 10 which p-cell autoimmunity is initiated in NOD mice, these two studies [58*,59*] that CAD represents a key early autoantigen for CD4+ T cells.

60. Aguilar-Diosdado M, Parkinson D, Corbett JA, Kwon G, Mar- shall CA, Cingerich RL, Santiago JV, McDaniel ML: Potential autoantigens in IDDM: expression of carboxypeptidase-Ii and insulin but not glutamate decarboxylase on the &cell surface. Diabefes 1994, 43:418-425.

61. Celber C, Paborsky L, Singer S, McAteer D, Tisch R, Jolicoeur C, Beulow R, McDevitt H, Fathman CC: Isolation of nonobese diabetic mouse T-lymphocytes that recognize novel autoantigens involved in the early events of diabetes. Diabetes 1994, 43:33-39.

62. Eaekkeskov S, Aanstoot H-J, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P: Identifi- cation of the 64k autoantigen in insulin-dependent diabetes as the CABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990, 347:151-l 56.

IN Serreze and EH Leiter, The Jackson Laboaratory, 600 Main Street, Bar Harbor, Maine 04609, USA.

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Genetic and pathogenic basis of autoimmune diabetes in NOD mice