WO2001053824A1 - Mouse model for rheumatoid arthritis - Google Patents
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- WO2001053824A1 WO2001053824A1 PCT/US2001/001483 US0101483W WO0153824A1 WO 2001053824 A1 WO2001053824 A1 WO 2001053824A1 US 0101483 W US0101483 W US 0101483W WO 0153824 A1 WO0153824 A1 WO 0153824A1
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5082—Supracellular entities, e.g. tissue, organisms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
- A01K67/027—New breeds of vertebrates
Definitions
- the present invention pertains to the field of medical research, particularly to the development of mammalian models of human rheumatoid arthritis
- Rheumatoid arthritis is a common autoimmune disease characterized by joint swelling, deformation and, ultimately, destruction, culminating in severe physical disability De Graaf et al , in The Epidemiology of Chronic Rheumatism. Dellgren and Ball, eds (Blackwell, Oxford, 1963), pp 446-56, Meenam et al , Arthritis Rheum , 24 544-50 (1981), Gab ⁇ el et al , J Rheumatol , 26 1269-74 (1999), James, Clin Exp Rheumatol , 17 392-93 (1999) RA is a progressive condition with well-recognized symptoms including symmetrical peripheral jomt swelling and synovial inflammation while sparing the axial skeleton, the presence of rheumatoid factor (RF) autoantibodies, increased concentrations of ⁇ nterleuk ⁇ n-6 (IL-6), interleukin-l ⁇ (IL-l ⁇ ), and granulocyte/
- nonobese diabetic or "NOD” mouse can be used to produce offspring that exhibit a physical symptomology closely matching the symptomology of hRA, including: incomplete penetrance with increased incidence in females comparable to that of hRA, disease onset later in life (5-8 months) with exacerbation or early onset due to pregnancy comparable to that of hRA, no inflammation of the spine comparable to that of hRA, and histological and serological profiles comparable to that of hRA.
- the present invention provides progeny of NOD mice useful as models of rheumatoid arthritis, such as occurs in humans, e.g., that exhibit joint and limb swelling, symmetrical enlargement of peripheral joints with sparing of axial skeleton (e.g., hips, spine); common tendon deformities, such as spontaneous rupture of extensor tendons and Boutonniere deformity; characteristic histological features, such as synovitis, leukocyte invasion, pannus formation, cartilage destruction and bone degeneration; and characteristic serological changes, such as autoantibodies specific for the Fc region of immunoglobulin G (IgG) and increases in proinflammatory cytokines, especially IL-6, in synovial fluid and serum.
- IgG immunoglobulin G
- the present invention also provides a method for preparing mouse models of human rheumatoid arthritis, and methods for using the RA mouse of the present invention, for example, to test potential therapeutics and/or treatment protocols.
- Figure 1 illustrates age- and gender-dependent prevalence of RA in F
- Figure 2 illustrates histological and skeletal abnormalities in NOD-RA mice: the hind feet skeletons of BALB/c (Fig. 2a) and NOD-RA (Fig. 2b) mice were stained with both Alizarin red and Alcian blue; radiological analysis of the hind feet of BALB/c (Fig. 2c) and NOD-RA (Fig. 2d) mice; and histological analysis by staining with hematoxylin and eosin of the ankle (Figs. 2e, i, o, & q-s), elbow (Figs. 2f, j, & p), knee (Figs.
- Figure 3 shows serological profiles, segregated by sex (M F), of BALB/c, NOD, NOD-RA, and NOD-IDDM mice (Fig. 3a); and of RA humans (Patient-RA) and non-RA humans (Healthy), and diabetic humans (Patient-IDDM) (Fig. 3b).
- Figure 4 (comprised of Figs. 4a-r) illustrates expression of pro-inflammatory cytokine's receptors in the synovial membrane of the ankle joint. Expression of IL-6R ⁇ and IL-6R ⁇ in the synovial membrane of the ankle joint of BALB/c (Figs. 4a-c), NOD-RA (Figs.
- FIG. 5 (comprised of Figs. 5a-o) Expression of NF- ⁇ Bp50, NF- ⁇ Bp65 and I ⁇ B ⁇ in the synovial membrane of the ankle joint of BALB/c (Figs. 5a-e), NOD-RA (Figs. 5f-j) and NOD-IDDM (Figs. 5k-o).
- Ankle joints of 30-week-old female mice were sectioned and stained either with H&E (Figs. 5a, f, & k) or with antibodies to NF- ⁇ Bp50 (Figs. 5b, g, & 1), antibodies to NF- ⁇ Bp65 (Figs. 5c, h, & m) and antibodies to I ⁇ B ⁇ (Figs. 5d, i, & n) or normal rabbit IgG as a negative control (Figs. 5e, j, & o).
- Figure 6 depicts the frequency of RA in Fi female mice produced by nondiabetic NOD parents from The Jackson Laboratory versus Taconic. Fj female progeny are categorized by age (months). Ankle joint thickness was caliper-measured. Individuals with an ankle joint thickness twice that of age-matched control BALB/c mice are indicated by filled symbols.
- Figure 7 illustrates the pedigrees of mice generated from nondiabetic NOD parental stock (Pi), indicating the incidence of RA expression in progeny of multiple and diverse generations.
- Fig. 7a records the incidence of RA among the offspring (up to 6 months) of NOD-RA mice bred with nondiabetic NOD mice.
- Fig. 7b records the incidence of RA among the offspring (up to 6 months) of NOD-RA mice bred with C57BL/6 mice.
- Fig. 7c records the incidence of RA among the offspring (up to 6 months) of NOD-RA mice bred with BALB/c mice.
- Figure 8 (comprised of Figs. 8a-f) illustrates gross morphology of the hind feet of a
- Figure 9 (comprised of Figs. 9a-f) provides photographic evidence of RA development and pregnancy effects on RA in NOD-RA mice.
- Gross morphology of ankle thickness of a 25-week-old BALB/c female (Fig. 9a); a 25-week-old NOD-IDDM female (Fig. 9b); a 25-week-old NOD-RA female before pregnancy (Fig. 9c), and 8 weeks after delivery and at an age of 33 weeks (Fig. 9d).
- Ankle thickness is shown before (Fig. 9e), and after (Fig. 9f) pregnancy of F 2 progeny of NOD-RA bred with C57BL/6 (NOD/C57BL-RA), Arrows indicate maximal swelling and joint abnormalities.
- Figure 10 (comprised of Figs. lOa-b) provides graphic data tracking RA development across pregnancy in Fi NOD-RA females and BALB/c females, compared to virgin Fi NOD- RA females (Fig. 10a). Also illustrated are the data for RA development in across pregnancy in F, NOD/C57BL-RA females compared to virgin F, NOD/C57BL-RA females (Fig. 10b). Data are means ( ⁇ s.e.) from five animals in each group.
- the present invention relates to a method for preparing mice that exhibit the physical characteristics (e.g., one or more symptoms) of human patients suffering from rheumatoid arthritis (RA) and thus provides a murine model of human rheumatoid arthritis.
- the mice prepared in accordance with the teachings herein are useful in studying the manifestation, penetration and progression of rheumatoid arthritis as occurs in humans, and the mice are also useful for testing new methods and products for the diagnosis and/or treatment of rheumatoid arthritis.
- the mouse model will be particularly useful for screening new drug candidates for effectiveness against RA.
- symptoms or “characteristics” of rheumatoid arthritis (RA) or RA- like disease refers to any one or more pathological manifestations of rheumatoid arthritis known in the art. Such manifestations may be overt physical characteristics (e.g., joint or limb swelling, or other physical deformities detectable upon physical examination of an individual), or clinical symptoms (e.g., radiological, histological, and serological profiles indicative of RA).
- nondiabetic nonobese diabetic mice also known in the art and referred to herein as “nondiabetic NOD mice”, “survivor NOD mice”, or “diabetes-free NOD mice”
- nondiabetic NOD mice also known in the art and referred to herein as "nondiabetic NOD mice”, “survivor NOD mice”, or “diabetes-free NOD mice”
- progeny refers to any offspring or descendents of an individual. Progeny may refer to one or more individuals, and may span several filial, or "F", generations (e.g., Fi, F 2 , F 3 , etc.) generated, either directly or by descent, from parental, or Pi, stock.
- F filial, or "F” generations
- breeding refers broadly to the propagation of individuals under controlled conditions to produce progeny.
- a preferred method for breeding physical mating (i.e., copulation) of a sexually mature male and a sexually mature female, is not an essential feature of the present invention.
- Any form, method, or mode of reproduction of an individual e.g., natural or artificial, sexual or asexual
- Methods such as artificial insemination and embryo implantation, for example, are known to practitioners in the art to provide greater control over zygote selection, to ensure successful fertilization, and to avoid possible injury to the parental stock.
- methods of asexual reproduction and/or animal cloning are known in the art and available technologies useful for breeding to produce the RA mouse model of the present invention.
- Nonobese diabetic mice are well known animal subjects for the study of diabetes and other autoimmune diseases that affect humans.
- the mice are available commercially from several sources (e.g., The Jackson Laboratory, Bar Harbor, Maine).
- NOD mice were first identified as developing spontaneous autoimmune diabetes in 1980 on the basis of cataract development that is a secondary characteristic of diabetes in humans.
- Ninety percent (90%) of female NOD mice will develop autoimmune diabetes by 20 to 30 weeks of age; and about 20% to 40% of male NOD mice develop autoimmune diabetes.
- NOD mice The diabetes that develops in NOD mice is lethal, and without insulin treatment NOD mice that become diabetic die within about 48 hours, with blood glucose concentrations of approximately 600 mg/deciliter. With insulin treatment, the diabetic mice can survive for several weeks, but the mortality rate in spite of insulin treatment is still approximately 50% at two weeks and uniformly lethal at four weeks. NOD breeding colonies are commonly maintained by paired matings initiated at 4 to 6 weeks of age and continued until the animals are 20 to 22 weeks of age. This corresponds to the period of maximum breeding potential prior to the usual onset of lethal diabetes. Surviving animals usually are killed after breeding. Pozzilli et al., Immunol. Today, 14:193- 96 (1993).
- a mouse of the present invention that exhibits one or more symptoms of rheumatoid arthritis requires breeding a nondiabetic NOD mouse to produce an arthritic progeny (i.e., a NOD-RA mouse). No incidence of RA symptoms developing in nondiabetic NOD parents has been observed.
- parental stock i.e., the parental generation, or Pi
- at least one individual must be nondiabetic NOD, that is, a NOD mouse that, although bred for the development of diabetes, fails to develop autoimmune diabetes.
- the nondiabetic NOD individual is female, more preferably both parents will be nondiabetic.
- Nondiabetic NOD parental stock should be diabetes-free, or euglycemic. Onset of diabetes in mice is signaled by marked hyperglycemia, i.e., rising and remaining above 250 mg/deciliter. Since the onset of diabetes is quickly fatal in NOD mice, the nondiabetic NOD animals useful for the purposes of the present invention are aptly refe ⁇ ed to as survivors.
- the parental mice selected be at least 12 weeks of age. Preferably the parental mice selected will be 20 weeks old or older, more preferably 22 weeks old or older, most preferably at least 24 weeks old. It is also preferred but not critical that the male and female parental stock be age- matched.
- Nondiabetic NOD Pi mice and their progeny are truly nondiabetic; that is, they are not slow-onset diabetic mice that are destined to develop the disease later but fail to exhibit onset by the typical onset age of 20-30 weeks. None of the diabetes-free Pi mice or their progeny studied in the examples that follow died or developed detectable glucosuria during an additional ten months of observation. Furthermore, histological examination of their pancreases revealed no occult disease, i.e., no lymphocytic infiltration.
- the RA mouse of the invention also referred to as NOD-RA
- NOD-RA insulin-derived NOD
- the present invention advantageously provides an alternative to destruction of nondiabetic survivors.
- maintaining NOD stock past the normal age of diabetes onset is a preferred way of isolating survivor (nondiabetic) NOD mice, it is not necessary to wait 20-30 weeks before practicing the present invention.
- nondiabetic NOD mice are, as mentioned above, born non-diabetic and will remain free of diabetes, breeding NOD mice without predetermining whether or not they are nondiabetic may be done, with the development of NOD- RA offspring confirming after the fact that at least one parental mouse was nondiabetic.
- prediabetic screening of the mice is helpful in identifying nondiabetic NOD mice useful as parental stock in the practice of the present invention. Screening for glucose levels exceeding 250 mg/dl has been mentioned above, and additional pre-onset diabetic indicators include the appearance of autoantibodies against islets or insulin, the appearance of rheumatoid factor (RF), and increasing IL-6 levels.
- RF rheumatoid factor
- lymphocytic infiltration of the pancreas is also an indicator of diabetes onset, and therefore indications that the pancreas of a NOD mouse remains free of infiltrating lymphocytes also identifies a suitable Pi mouse for the purposes of the invention.
- the Pi matings of nondiabetic NOD pairs consistently produces Fi mice that show high penetrance of RA symptomology by 20-28 weeks of age. Appearance of characteristic RA symptoms occurs much sooner in F t females that become pregnant (e.g., 10-16 weeks after pregnancy).
- the Fi mice exhibit visible bilateral swelling of the ankles and the metatarsophlangeal and proximal mterphalangeal joints of both hind feet. No swelling is typically observed at the distal mterphalangeal joints. This pattern of joint swelling mimics the pattern characteristic of human RA.
- the NOD-RA mice not only model the symptoms of human RA in overt physical characteristics, but also exhibit RA abnormalities upon clinical (e.g., radiological, histological, and serological) examination that closely resemble the symptoms observed in human RA patients.
- the penetrance of the RA-like disease in NOD mice is incomplete, as it is in humans, with identical twins of RA sufferers having less than 25% incidence lifelong of also developing RA.
- there is a marked predominance (85%) of females in a population of F t mice that develop the RA disease which is comparable to the predominance (75% females) found in human RA patients.
- Not all Fi mice will be NOD-RA mice (see Examples, infra.), and NOD-RA mice will usually begin to exhibit RA symptoms such as ankle swelling by 12 weeks of age, with peak onset at about 22-28 weeks of age.
- the NOD-RA mice according to the invention may be used in any application where a mammalian model of human RA would be advantageous.
- the NOD-RA mice prepared according to the invention will be especially useful in testing RA diagnostic reagents, such as antibodies, dyes or magnetic resonance imaging agents, or in screening potential therapeutic agents. Many applications for such NOD-RA mice will immediately suggest themselves to persons skilled in this field.
- a particularly useful application for the mouse RA model of the invention will be in drug screening.
- a method of screening utilizing NOD-RA mice according to the invention will comprise the step of administering to a NOD-RA mouse showing symptoms of RA a candidate drug for the treatment of RA and then analyzing the mouse for improvement in any of the symptoms of the disease, e.g., lowering of RA or IL-6 levels, remission or decrease in, e.g., joint swelling, abnormal joint flexion or hyperextension, etc. Any favorable change in RA symptomology in the NOD-RA mouse receiving the candidate drug will indicate that the candidate drug is useful for treating RA.
- Another particularly useful application of the mouse RA model of the invention will be in screening for preventive medicines. Since the RA-like disease in NOD-RA mice has the same penetrance and gender and age correlation as in human RA patients, a good method for testing candidate RA preventive medicines will comprise administering a candidate medicine to the progeny of a nondiabetic NOD mouse, then observing whether the expected penetrance of the disease in the progeny is altered in response to receiving the candidate medicine. If the incidence of appearance of RA in the progeny is lower than expected, if the severity of the disease is reduced, or if the onset of RA is delayed, then this indicates that the medicine has therapeutic properties.
- NOD-RA mouse according to the invention is further described in the examples that follow. These examples are illustrative of the methods and the mouse of the invention, and are not intended to limit the concept of the invention in any way.
- Example 1 Generation and physical determination of NOD-RA mice
- Fig. 1 depicts statistical analyses of prevalence of RA in Fi progeny of nondiabetic NOD parents, by compiling data on all F t progeny that were not sacrificed for histological analysis before 10 months of age. All mice were categorized by age and had ankle thickness measured using calipers. Those mice with an ankle thickness at least twice that of age- matched BALB/c controls are indicated by filled symbols (•, ⁇ ). Females are indicated with circles (O, •) and males are indicated with squares ( ⁇ , D). The onset of presumed RA was first apparent at 3 months, with a peak onset at 7 months among NOD-RA females.
- the incomplete penetrance of the murine RA-like condition resembles that of human RA; for genetically identical human twins in which RA affects one twin, the other twin has a ⁇ 25% lifelong chance of developing this condition. Furthermore, the predominantly female expression of the mouse RA-like disease (82%) is similar to that observed for human RA (83% of RA patients are female).
- Example 2 Radiological and histological analyses of NOD-RA mice Skeletal examinations were made of NOD-RA mice and BALB/c controls at 7 months of age or older to characterize joint disease occurring in the former (see Fig. 2). Hind feet skeletons of BALB/c (Fig. 2a) and NOD-RA (Fig. 2b) mice were stained with Alizarin red and Alcian blue. Comparison of the NOD-RA and BALB/c skeletal specimens shows enlargement of the peripheral synovial joints and severe joint destruction in the NOD-RA animals. Arrowheads (Fig. 2b) indicate tendon rupture secondary to joint subluxation. Radiological analysis of the hind feet of BALB/c (Fig. 2c) and NOD-RA (Fig.
- mice shows obliteration of the ankle joint space, central osseous erosion of the ankle, and fusiform swelling of soft tissue extending from the ankle down to the digits of the NOD-RA animal.
- Arrowheads indicate the locations of the radiographic deformities.
- Radiological and skeletal findings demonstrated that, in contrast to the peripheral joints, the sacroiliac and vertebral joints in NOD-RA mice were not affected.
- Histological micrographs of ankle, elbow, knee and metatarsophalangeal joints were also prepared by fixing in 4% paraformaldehyde, decalcified for 8 h in 6% nitric acid, and incubated for 8 h with 4% paraformaldehyde, and embedded in paraffin. Sections (5 ⁇ m) were prepared and stained with hematoxylin and (Figs. 2e-l). For skeletal preparations, double staining for cartilage and bone was performed with Alizarin red and Alcian blue (respectively).
- Figs. 2e-h, and q were prepared from a BALB/c mouse
- Figs. 2i-n, and r were prepared from a NOD-RA mouse
- Figures 2o, p, s and t were prepared from a NOD- IDDM mouse.
- Ankle preparations are shown in Figs. 2e, i, o, & q-s; elbow preparations in Figs. 2f, j, & p; knee preparations in Figs. 2g and k; and metatarsophalangeal joint preparations in Figs. 2h and 1.
- the joint histology of the NOD-RA animals is characterized by pannus proliferation and invasion of the articular space (green arrowhead in Figs.
- rheumatoid arthritis In human rheumatoid arthritis, onset of the disease is also characterized by serological phenomena. See, e.g., Jackson, in Clinical Laboratory Medicine. Tilton, ed. (Mosby Year Book, St. Louis, 1992), pp. 485-504. For example, about 70%-90% of RA patients produce "rheumatoid factor” (RF), which comprises autoantibodies specific for the Fc region of immunoglobulin G. In addition, markedly increased concentrations of the proinflammatory cytokine IL-6 are observed in the synovial fluid and serum of RA patients.
- RF rheumatoid factor
- RA autoimmune diseases
- anti-dsDNA antibodies to double-stranded DNA
- anti-dsDNA antibodies are usually a more sensitive marker in humans for lupus erythematosus than for RA.
- IL-6 IL-6, IL-l ⁇ , IL-lra, and GM-CSF(see Fig. 3).
- EIA549B human antibodies to rheumatoid factor IgM
- human antibodies to rheumatoid factor IgM e.g., Sigma, MO: product no.
- Human GM-CSF, IL-l ⁇ , IL-lra, IL-6 and TNF- ⁇ were also quantified using commercially available ELISA kits (e.g., R&D Systems, MN; product nos. DGM00, NFL80, DRA00, and NF60, and BD PharMingen, CA; product no. 2637KI).
- commercially available human immunoassays e.g., those from Sigma, MO. were modified to quantify murine autoantibodies to dsDNA, Scl-70 and RF.
- murine anti-dsDNA and murine anti-Scl-70 antibodies to murine IgG labeled with a horseradish peroxidase (HRP) conjugate (Santa Cruz, CA; product no. sc-2005) was used as the developing reagent.
- HRP horseradish peroxidase
- mouse IgG (Santa Cruz, CA; product no. sc-2025) was immobilized onto multi-well plates. Dilute test samples were added to the coated wells and incubated for at least 4 h at room temperature. After washing to remove unbound material, HRP conjugate anti-mouse IgM (Santa Cruz, CA; product no. sc-2064) was added to the wells.
- Murine GM-CSF, IL-l ⁇ , IL-lra, IL-6, and TNF- ⁇ was quantified using ELISA kits specific for murine cytokines (R&D Systems, MN; product nos. MGM00, MKB00, DRA00, and M6000, and BD PharMingen, CA; Product number 2673KI. Note that immunoassay kit DRA00 is useful for both human and murine IL-lra assays).
- Results are presented in Fig. 3.
- the data presented are means ( ⁇ s.e.) of values from five subjects for each group.
- Abnormally high concentrations for RF (>25 IU/ml) and anti- dsDNA (>180 IU/ml) are indicated on the graphs by dotted lines.
- RA is characterized by changes in serological parameters; about 70-90% of humans with RA produce RF as a diagnostic maker for autoimmunity, which comprises autoantibodies specific for the Fc region of immunoglobulin G. Of the mice examined, only NOD-RA animals (both male and female) produced RF at levels approaching that apparent in human RA patients.
- Antibodies to double-stranded DNA (anti-dsDNA) and antibodies to Scl-70 antigen were not detected in the serum of any of the subjects examined. Such antibodies are not a sensitive marker for diagnosis of RA in humans, being typically more specific for systemic lupus erythematosus and other autoimmune disease.
- Dysregulation of pro-inflammatory cytokines frequently tracks with clinically distinct autoimmune disease and could be causal to both murine and human disease.
- increased basal levels of pro-inflammatory cytokine TNF- ⁇ are frequently detected in the serum of diabetic NOD mice and autoimmune diabetic humans.
- the basal expression levels of TNF- ⁇ were increased 11-fold exclusively in NOD-IDDM mice; TNF- ⁇ levels were normal in NOD-RA, NOD mice without any autoimmune disease expression and BALB/c mice.
- basal TNF- ⁇ levels were exclusively elevated in diabetic humans; TNF- ⁇ levels were normal in screened RA patients
- the pro-inflammatory cytokine IL-6 was elevated in the synovial fluid and serum of humans with RA.
- NOD-RA mice exhibited high serum concentrations of IL-6 comparable to RA humans; NOD-IDDM, NOD and BALB/c mice had normal IL-6 levels.
- IL-l ⁇ is an essential inducer of IL-6 expression; high IL-l ⁇ serum levels are typical of random humans with autoimmune arthritis but not healthy controls nor diabetic patients. This remarkable trend of reciprocal cytokine expression paralleling human target organ selection was again mirrored in the tightly controlled and known genotypically identical
- NOD-RA and NOD-IDDM mice were markedly increased 100-fold in NOD-RA compared with BALB/c mice; IL-l ⁇ expression levels were up-regulated only 5- fold in NOD-IDDM compared with BALB/c.
- Clinical studies show the beneficial effect of IL-1 receptor antagonist (IL-lra), a competitive inhibitor of IL-l ⁇ , as a biological agent on the rate of joint erosion; autoimmune humans with RA more so than IDDM have suppressions of serum IL-lra.
- IL-lra"'" mice on select genetic background have high IL-l ⁇ and IL-6 levels and demonstrate autoimmune inflammation with a RA-like disease.
- IL-1RI IL-1 receptor type I
- IL-1 receptor type II IL-1 receptor type II
- Marked expression of both IL-1R subunits was apparent in association with the abnormal synovial and sub-chondrial bone inflammation membrane of only NOD-RA mice (Figs. 5k-l), whereas only a few cells expressed these subunits in the normal synovial membrane of BALB/c mice (Figs. 5h-i) or NOD-IDDM mice (Figs. 5o and r).
- NF-KB subunits, p50, p65 and I ⁇ B ⁇ are markedly expressed in the abnormal synovial and sub- chondrial bone inflammation membrane of only NOD-RA mice (Figs. 5f-j), no-expression is detected in BALB/c mice (Figs. 5a-e) or NOD-IDDM mice (Figs. 5k-o).
- Example 5 Specificity of NOD parental stock in the generation of NOD-RA mice
- experimental protocols described in Example 1 were repeated using newly acquired NOD mouse cohorts from The Jackson Laboratory (Bar Harbor, ME) and from Taconic (German town, NY) and using newly acquired BALB/c mouse cohorts (The Jackson Laboratory, Bar Harbor, ME).
- Nondiabetic NOD mice were reared for 20-22 weeks, thus selecting for nondiabetic NOD mice as parental stock (Pi).
- Nondiabetic NOD mice, as well as BALB/c mice (as a control group) were inbred to produce Fi progeny. Fi progeny were grouped into age-matched cohorts. Ankle joint thickness was measured to indicate the occurrence of RA in Fi mice. Individuals with an ankle joint thickness twice that of age-matched control BALB/c mice were identified as RA mice.
- RA developed in the Fi progeny of nondiabetic NOD mice. Twenty-four of 73 (33%) of Jackson Laboratory Fi females (J AX/NOD) and 22 of the 84 (19%) of Taconic F, females (Taconic/NOD) developed ankle swelling indicative of RA.
- Fi RA mice i.e., Fi NOD-RA mice
- Fi NOD-RA mice generated as described in Examples 1 and 5 were mated to nondiabetic NOD, C57BL/6, and BALB/c mice.
- BALB/c mice were mated to C57BL/6 mice as a control group.
- NOD-RA x NOD, NOD-RA x C57BL/6, and NOD-RA x BALB/c produced F 2 progeny exhibiting symptoms of RA by 6 months of age. RA symptoms were enhanced in female F 2 progeny of NOD-RA females. The rate of disease progression in F 2 NOD/C57BL-RA females after delivery was increased relative to that for virgin F 2 NOD/C57BL-RA females of the same age. None of the F 2 progeny developed diabetes by 30 weeks of age.
- RA was not detected among any progeny from BALB/c x C57BL/6 matings (control data not shown, but see Figs. 8 a-c), again eliminating a non-specific infection in the colony and confirming a genetic basis as a causal agent for RA among the mice.
- Fig. 8 illustrates the gross morphology of the hind feet of a 21-week-old F 2 female mouse bred from a BALB/c crossed with a C57BL/6 (Figs. 8a-c), and the hind feet of a 21- week-old F 2 female mouse bred from a NOD-RA crossed with a C57BL/6 (Figs. 8d-f).
- the F 2 NOD-RA progeny showed moderate and symmetrical peripheral fusiform swelling, as well as prominent swelling at the ankle, the metatarsophalangeal and proximal mterphalangeal joints, with sparing of the distal interphalangeal joint. Arrows and arrowheads indicate the locations of maximal swelling and joint abnormalities, respectively.
- the RA mouse of the present invention may be obtained from progeny of multiple generations descendant from nondiabetic NOD mouse (Pi) stock.
- the generation of the RA mouse of the present invention is not limited by the mating of a nondiabetic NOD mouse (or any NOD-RA progeny generated therefrom) to any particular mouse strain.
- the absence of any RA progeny from the BALB/c x C57BL/6 matings eliminate the possibility of any non-specific causal agent in the colony, and further support earlier findings that a single nondiabetic NOD mouse (of any variety), used as an ancestral parental stock, is all that is required to produce multi-generational NOD-RA progeny.
- Example 7 Pregnancy effects of RA in the NOD-RA mouse
- Fi NOD-RA females were impregnated at 4 months of age and examined weekly during pregnancy and postpartum for indications of RA (as compared to virgin NOD-RA and BALB/c females).
- F 2 females produced from these pregnancies were impregnated at 4 months and examined weekly during their pregnancy and postpartum for indications of RA (as compared to virgin F 2 females).
- Ankle thickness was measured before, during, and after pregnancy in Fi and F 2 NOD-RA females, as well as in age-matched impregnated BALB/c females and virgin Fi and F 2 NOD-RA females.
- NOD-RA mice showed grossly visible swelling of the ankles, as well as swelling at the metatarsophalangeal and proximal interphalangeal joints of both hind feet. No swelling was observed at the distal mterphalangeal joints.
- control BALB/c mice, parental (P,) NOD mice, and a cohort of 10 NOD females newly obtained from The Jackson Laboratory (with or without diabetes) exhibited normal gross morphology of the peripheral limbs, with no periarticular soft tissue swelling, when maintained under clean but not pathogen free housing conditions and aging conditions similar to those of the Fi NOD animals.
- NOD-RA mice desc ⁇ bed herein provide a novel spontaneous model that closely mimics human rheumatoid arth ⁇ tis
- the NOD-RA model exhibits clinical (e g , radiological, histological, and serological) symptoms that are typical of humans afflicted with rheumatoid arth ⁇ tis
- the disease in NOD-RA mice is spontaneous and dominant in females, with onset at older ages, incomplete penetrance in a population, lifelong exacerbation after pregnancy
- the NOD-RA mouse model may consequently be used advantageously for characte ⁇ zation of the patho
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CA002397646A CA2397646A1 (en) | 2000-01-18 | 2001-01-18 | Mouse model for rheumatoid arthritis |
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US6617171B2 (en) * | 1998-02-27 | 2003-09-09 | The General Hospital Corporation | Methods for diagnosing and treating autoimmune disease |
US6599710B1 (en) | 1999-03-10 | 2003-07-29 | The General Hospital Corporation | Treatment of autoimmune disease |
EP1340077B1 (en) * | 2000-10-17 | 2006-01-25 | Besst-Test ApS | Assay for directly detecting an inflammatory indicator in a body fluid sample |
US7582313B2 (en) * | 2002-06-27 | 2009-09-01 | The General Hospital Corporation | Methods of organ regeneration using Hox 11-expressing pluripotent cells |
US7628988B2 (en) | 2002-06-27 | 2009-12-08 | The General Hospital Corporation | Methods and compositions for treating type 1 diabetes |
WO2004045376A2 (en) * | 2002-11-15 | 2004-06-03 | The General Hospital Corporation | Screening methods to identify treatments for autoimmune disease |
ES2541683T3 (en) * | 2004-02-27 | 2015-07-23 | F. Hoffmann-La Roche Ag | Method to evaluate rheumatoid arthritis by measuring rheumatoid factor and interleukin-6 |
ATE435656T1 (en) | 2004-04-05 | 2009-07-15 | Univ California | NKG2D MODULATION |
US20080102054A1 (en) * | 2005-01-18 | 2008-05-01 | Faustman Denise L | Compositions Containing Agm Cells And Methods Of Use Thereof |
US20070148704A1 (en) * | 2005-10-06 | 2007-06-28 | Ursula Klause | Anti-CCPand antinuclear antibodies in diagnosis of rheumatoid arthritis |
PL2222706T5 (en) | 2007-12-14 | 2017-09-29 | Novo Nordisk As | Antibodies against human nkg2d and uses thereof |
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CN115043943A (en) | 2015-05-15 | 2022-09-13 | 综合医院公司 | Antagonistic anti-tumor necrosis factor receptor superfamily antibodies |
US11266730B2 (en) | 2015-09-29 | 2022-03-08 | The General Hospital Corporation | Methods of treating and diagnosing disease using biomarkers for BCG therapy |
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