LEW

Inbr. F?+96.

Colour: Albino

Genet: a, h, c.

Origin: Dr. Margaret Lewis from Wistar stock, to Aptekman and Bogden 1954 at F20, to Silvers in 1958 at F31. Subsequently distributed by Silvers. Used as the inbred partner for a number of congenic strains at the major histocompatibility complex (Stark and Kren 1969). A substrain with congenital hydrocephalus due to primary aqueductal stenosis has been described by Yamada et al, (1992)

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Characteristics

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Anatomy

Low relative heart weight in 10-week old males (4/23) (Tanase et al 1982).

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Behaviour

Docile. High response to operant morphine-reinforced behaviour (1/4) (Ambrosio et al 1995). Has a weak 24-hr. rhythm in wheel running activity when compared with ACI (Siebert and Wollnik 1991). Can be triggered into paradoxical sleep by dark pulse stimulation (ie. turning off the lights), in contrast with BN (Leung et al, 1992). Develops larger acoustic and tactile startle response than strain F344, which may be associated with strain differences in hypothalmic-pituitary-adrenal activation (Glowa et al,1992).

Lifespan and spontaneous disease

Survival 26% at 2 years (Lindsey et al 1968). In a study involving 305 female and 324 male rats of the LEW/Han substrain, mean lifespan in females was 27.7_5.1 months, in males 32.5_6.6 months. In both sexes the lifespan was mainly determined by the occurrence of neoplasms. Of the large spectrum of 52 histologically different types of tumours, the highest incidence was observed for adenomas of the pituitary and adenomas/adenocarcinomas of the adrenal cortex in both sexes, mammary gland tumours and endometrial carcinomas (45%) in females, and C-cell adenomas/adenocarcinomas of the thyroid gland and tumours of the haemopoietic system (28%) in males (Baum et al, 1995).

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Immunology

Sensitive to the development of a number of experimental autoimmune conditions including experimental allergic encephalomyelitis after challenge with guinea pig myelin basic protein (McFarlin et al 1975a, b, Hughes and Stedronska 1973, Perlik and Zidek 1974, Gasser et al 1975, Willenborg 1979), induced autoimmune myocarditis (Friedman et al 1970), autologous immune complex glomerulonephritis (linked to the MHC) (Stenglein et al 1975, Watson and Dixon 1966, Kelchner et al 1976), adjuvent-induced arthritis (Perlik and Zidek 1974, Koga et al 1973), streptococcal and Lactobacillus casei cell wall induced arthritis (Cromartie et al 1977, Clark et al 1979, Wilder et al 1982, 1983, 1987, Lehman et al 1983), reactive arthritis induced by Yersinia enterocolitica (Hill and Yu 1987), allergic orchitis (Levine and Sowinski 1970), autoallergic sialadenitis (a model of Sjogren's disease) (Cutler et al 1987), and experimental autoimmune myesthenia gravis (Lennon et al 1975, Biesecker and Koffler 1988 (7/9)). Response may be modified by microflora (Kallen and Logdberg 1982). Epitope specificities of collagen-induced arthritis studied by Cremer et al (1992). DA is sensitive whereas LEW are relatively resistant to oil-induced arthritis using Freund's incomplete adjuvent (Holmdahl et al, 1992, 1994). Following lethal irradiation and re-constitution with syngeneic bone marrow and given cyclosporin A for several weeks these rats will develop cyclosporin-induced autoimmunity after withdrawal of the cyclosporin. The condition resembles graft-versus host disease in terms of acute dermatitis and chronic scleroderma. BN rats do not develop this disease (Wodzig et al, 1993). Highly susceptible to the induction of experimental autoimmune uveoretinitis (EAU) and endotoxin-induced uveitis which appears to be associated with the production of tumour necrosis factor (TNF) by retinal Muller glia and retinal pigmented epithelium. Strain BN is resistant (Dekozak et al, 1994). Susceptible to the induction of EAU by interphotoreceptor retinol-binding protein (cf WKAH, W/M, LEJ and BUF, but in contrast with TO) (Sasamoto et al, 1994).

Moderately sensitive to the development of experimental glomerulonephritis following injection of nephritogenic antigen from bovine renal basement membrane (2/10) (Naito et al, 1991)

Susceptible to the induction of proteinuria following treatment with the monoclonal antibody 5-6-1, like BN and outbred Wistar, but unlike resistant outbred Sprague-Dawley rats which were also resistant to glomerular damage (Gollner et al, 1995).

A substrain (initially designated Le-R, but now re-named strain LER), resistant to the development of experimental allergic encephalomyelitis but which is still histocompatible with LEW has been described by Waxman et al (1981) and Driscoll et al (1985). Gasser et al (1983) suggested that the resistance is probably due to a non-MHC-linked mutation. However, it now seems that resistance is due to genetic contamination by BUF strain rats (Goldmuntz et al, 1993, see strain LER).

About half of females sensitised against H-Y antigen accept skin grafts from neonatal sygeneic males, and about half of these will subsequently accept skin from adult males (Silvers and Collins 1979). High antibody response to concanavalin A and phytohaemagglutinin (Williams et al 1973). Interferon production in response to polyriboinosinic-polyribocytodilic acid 20-40 fold higher than that observed in six other inbred strains. The effect is due to more than one gene, and is not associated with the MHC (Davis et al 1984). Resident macrophages (ramified microglea) of the central nervous system are not constitutively major histocompatibility complex class-II positive, in contrast with BN (Sedgwick et al, 1993). Mercury (HgCl₂) stimulates peritoneal polymorphonuclear leukocytes and macrophages to produce hydrogen peroxide, in contrast with strain BN (Contrino et al, 1992). Resistant to the development of autoimmunity from skin-injected HgCl₂ , in contrast to BN (Warfvinge and Larsson, 1994). Poor (5/5) antibody response to a synthetic 20 amino acid peptide derived from the alpha helical region of the RT1-D-u beta chain (Murphy et al, 1994). Although DA and LEW are both highly susceptible to the development of EAE, there are marked differences in the array of myelin epitopes capable of inducing the disease as well as MHC restriction of these epitopes between the two strains (Stepaniak et al, 1995).

Highly susceptible to inflammatory disease due to deficient glucocorticoid counter-regulation of the immune response resulting from deficient corticotropin-releasing hormone responsiveness. Have significantly more benzodiazepine binding sites than F344, though there was no difference in affinities (Smith et al, 1992 see also Oitzl et al, 1995). No differences between LEW and F344 in the sensitivity of target tissues to exogenous glucocorticoids which could be associated with differences in susceptibility to inflammatory disease (Karalis et al, 1995).

Biochemistry and Physiology

High fertility. High serum thyroxine, insulin and growth hormone levels (1/5 in each case) (Esber et al 1974). Becomes obese on a high fat diet (rank 2/7)(Schemmel et al 1970). High hepatic metabolism of ethylmorphine in females (3/10) (Page and Vesell 1969). Short gestation period (3/8) (Peters 1986). Low blood pressure (22/23), reaching 119_2.0 (SEM) mmHg at 10 weeks of age (Tanase et al 1982). Liver gangliosides are of the a-type (cf ACI, LEA, & BUF) (Kasai et al 1993). Rapid metaboliser of MPPB (F344 is slow) (Takahara et al 1993). Have substantially lower levels of diurnal and stress related corticosterone levels with higher levels of corticosteroid-binding globulin in plasma, spleen and thymus than F344 rats (Dhabhar et al, 1993). Lower concentrations of cortical and hippocampal 5-HT1A receptors compared with F344 and outbred Spargue-Dalwey rats (Burnet et al, 1994).

Hackbarth et al (1981) report on kidney function in this and other strains. Hackbarth et al (1983) report on haematological parameters in relation to several other strains.

Drugs and chemicals

Long pentobarbitone sleeping time in males (3/10) but short time in females (10/10) (Vieregge et al 1987). High serum ceruloplasmin levels (Stolc 1984). Compared with F344, LEW rats show a much higher preference for several classes of drugs of abuse. This may be associated with lower levels of neurofilament proteins in the ventral tegmental area of the brain (Guitart et al, 1992). Duration of morphine-induced EEG slow-wave bursts and associated behavioural stupor was greater in LEW than F344 rats (Myomichelson and Young, 1993). LEW rats self-administer more morphine and drugs of abuse than F344 rats (Gosnell and Krahn, 1993, Glowa et al, 1994, Ambrosio et al, 1995). Duration of EEG slow-wave bursts and behavioural stupor also longer in LEW than F344 following administration of ethylketocyclazocine, suggesting differences in opioid-related receptor populations between these strains (Mayomichelson and Young, 1993). Cocaine conditioned place preference was greater in LEW than F344 rats (Kosten et al, 1994). Susceptible to the induction of glandular stomach adenocarcinomas following treatment with catechol (contrast WKY) (Tanaka et al, 1995)

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Infection

Young animals susceptible to Borrelia burgdorferi-induced arthritic lesions resembling those found in human Lyme disease (Barthold et al 1988). Susceptible to the induction of encephalitis by coronavirus, with a much longer delay in lymphocyte proliferation following infection than in the resistant BN strain (Imrich et al, 1994). Susceptible (1/4) to ocular infection with herpes simplex virus with death following 4 x 10⁴ plaque forming units (pfu). PVG was relatively resistant (Nicholls et al, 1994).

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Cutler L. S., Bullis D., and Greiner D. L. (1987) Experimental autoallergic sialadenitis in the LEW rat: A reproducible animal model of Sjogren's syndrome. Transplant. Proc. 19, 3196-3198.

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INBRED STRAINS OF RATS
Updated 9 Apr. 1998
Michael FW Festing
MRC Toxicology Unit, Hodgkin Building,
University of Leicester, UK