Effects of housing conditions on the development of wet skin lesions in the NOA mouse.

The effects of housing on the onset time and prevalence of wet skin lesions were investigated in NOA mice, which spontaneously develop these lesions at a high rate. Wet skin lesions developed earliest in mice that were housed individually. For mice that were housed in groups, the lesions developed earlier in mice with non-littermate group housing than in mice with littermate group housing. The prevalence of lesions was in the following order: individual housing > non-littermate group housing > littermate group housing. These results suggest that socio-psychological factors are involved in the etiology of wet skin lesions in the NOA mouse. Under individual housing conditions, two other novel characters of the NOA mouse were also observed, specifically, development of dry skin and wet skin lesions at the tail root. These characteristics developed early and with high prevalence and were easily observed on external examination. Therefore, these novel characteristics observed in NOA mice are potential markers of the psychological state of the animals.     

The effect of prednisolone trimethylacetate on the pathogenicity of dermatophilus congolensis to white mice

Albino mice were successfully infected intravenously, subcutaneously, intraperitoneally and on the intact and scarified skin with Dermatophilus congolensis. Various gross lesions were observed. Large subcutaneous nodules were produced in mice that were injected subcutaneously. Lesions involving the internal organs were obtained in mice that had been injected intravenously and intraperitoneally in addition to microabsessation and scab formation on the tails of those that were injected intravenously. The application of D. congolensis on scarified skin resulted in scab formation covering the whole area while its application on non-scarified skin produced isolated lesions. The organism was isolated in pure culture from exudate, pus and scab material obtained from lesions. Severe histopathological changes were noted in sections prepared from the lesions. Premedication of mice with prednisolone trimethylacetate increased the severity of the experimentally induced lesions.     

IL-18 mediates the formation of stress-induced, histamine-dependent gastric lesions

A role of IL-18 in the induction of gastric lesions by water immersion and restraint stress (WRS) was investigated. When wild-type BALB/c mice were exposed to WRS, levels of IL-18 in the serum and stomach increased rapidly with the development of acute gastric lesions. In IL-18-deficient mice [IL-18 knockout (KO) mice] similarly exposed to WRS, no gastric lesions were observed, but the administration of IL-18 before exposure to WRS resulted in the induction of WRS-induced gastric lesions. WRS enhanced gastric histidine decarboxylase (HDC) activity with concomitant increases in gastric histamine content. In IL-18 KO mice, the WRS-induced elevation of gastric HDC activity and histamine levels was much less than that in wild-type mice, but it was augmented by prior administration of IL-18. Treatment of wild-type mice with cimetidine, a histamine H2 receptor antagonist, inhibited the formation of WRS-induced gastric lesions with no effect on the induction of gastric IL-18 by WRS. Levels of corticosterone, one of the stress indicators, were lower in IL-18 KO mice than in wild-type mice. The glucocorticoid receptor antagonist mifepristone had no effect on gastric IL-18 and histamine levels but aggravated the stress-induced gastric lesions, indicating that corticosterone was not involved in the IL-18-mediated formation of stress-induced gastric lesions. These results indicate that IL-18 is involved in the induction of gastric lesions by WRS through augmentation of HDC activity and production of histamine in the stomach.     

Elimination of macrophage-specific apolipoprotein E reduces diet-induced atherosclerosis in C57BL/6J male mice

Apolipoprotein (apo)E is synthesized in atherosclerotic lesions by macrophages, however, its role in lesions is not known. Whereas apoE could exacerbate atherosclerosis by promoting macrophage uptake of cholesterol-rich lipoproteins or modulating protective inflammatory responses, it could also restrict lesion formation by facilitating cholesterol efflux out of lesions. The role of apoE was examined in lethally irradiated male C57BL/6J wild-type (WT) mice that were repopulated with bone marrow cells (BMT) from either identical C57BL/6J mice (WT+WT BMT) or C57BL/6J apoE-deficient mice (WT+E-/- BMT). This enabled us to compare normal mice with mice possessing macrophages that did not express apoE. The participation of macrophage-derived apoE in atherosclerosis was assessed by placing the mice on an atherogenic diet. Male WT+E-/- BMT mice had significantly reduced lesion area in the aortic valves (P < 0.01) compared with male WT+WT BMT mice ( approximately 22,000 vs. approximately 49,000 microm2/section, respectively). Further evaluation revealed that plasma cholesterol, lipoprotein cholesterol distribution, and plasma apoE were similar between the two groups, indicating that these known risk factors did not account for the differences in lesion area. However, the two groups were distinguished by the amount of apoE found in the lesions. ApoE antigen was expressed abundantly in WT+WT BMT lesions, whereas WT+E-/- BMT lesions contained little apoE. These findings indicate that the majority of apoE in lesions is synthesized locally by resident macrophages, and suggest that locally produced apoE can promote diet-induced atherosclerosis in male wild-type mice.     

Experimental autoimmune thyroiditis in mice chronically treated from birth with anti-IgM antibodies

The role of T lymphocytes in the pathogenesis of experimental autoimmune thyroiditis in mice is well established while the role of B lymphocytes is unclear. Mice with thyroid lesions have thyroglobulin antibodies whereas these antibodies can occur in mice immunized with Tg that do not develop thyroid lesions. To determine whether thyroglobulin antibodies are necessary for the development of the thyroid infiltrates with mononuclear cells, which are characteristic for experimental autoimmune thyroiditis, AKR mice chronically treated from birth with goat anti-mouse IgM antibodies were immunized with mouse thyroglobulin in Freund's complete adjuvant when they were 7 weeks old. Control mice, similarly immunized, were chronically injected from birth with normal goat gamma-globulin. Three weeks after immunization, all mice were sacrificed, thyroglobulin antibodies in the serum were measured by hemagglutination assay and enzyme-linked immunosorbent assay, and thyroid pathology was assessed. The serum concentration of IgG and IgM, the percentage of B and T lymphocytes in the spleen (flow cytometry), and the in vitro proliferative response of spleen lymphocytes to stimulation by PHA, LPS, and Tg were also measured. All mice treated with anti-IgM antibodies did not have detectable thyroglobulin antibodies but 63% of these mice and 88% of control mice (all of which had thyroglobulin antibodies) had thyroid lesions. Mice treated with anti-IgM antibodies that did not have thyroid lesions had a more pronounced depression of B lymphocytes than similarly treated mice that had thyroid lesions. These experiments suggest that thyroglobulin antibodies are not necessary for the development of thyroid infiltrates with mononuclear cells. B lymphocytes could still participate in the production of experimental autoimmune thyroiditis by presenting thyroglobulin to helper T lymphocytes.     

Leishmania amazonensis infection in nude mice.

Leishmania amazonensis is an intracellular protozoan parasite of macrophages. Cutaneous leishmaniasis in an immunocompetent host begins as papules or nodules followed by ulceration at the site of promastigote inoculation. In this study, the pathological changes of cutaneous leishmaniasis lesions in T cell deficient nude mice were examined. When infected with L. amazonensis promastigotes, nude mice developed non-ulcerative cutaneous nodules. By histological examination of cutaneous lesions, massive accumulation of vacuolated histiocytes containing amastigotes was observed in all the nude mice. Although infiltration of mononuclear and polymorphonuclear cells was seen in the lesions of immunocompetent mice, few such cells were observed in the lesions of nude mice. These results indicate the importance of T cells on the ulcer formation in cutaneous leishmaniasis.     

Bystander activation involving T lymphocytes in herpetic stromal keratitis

Herpes simplex virus infection of mouse corneas can lead to the development of an immunopathological lesion, termed herpetic stromal keratitis (HSK). Such lesions also occur in TCR-transgenic mice backcrossed to SCID (TgSCID) that are unable to mount detectable HSV-specific immune responses. The present study demonstrates that lesion expression in such mice depends on continuous viral replication, whereas in immunocompetent mice, lesions occurred even if virus replication was terminated at 4 days after infection. The continuous replication in TgSCID mice was considered necessary to produce an activating stimulus to CD4(+) T cells that invade the cornea. Lesions in TgSCID were resistant to control by cyclosporin A, but were inhibited by treatment with rapamycin. This result was interpreted to indicate that T cell activation involved a non-TCR-mediated cytokine-driven bystander mechanism. Bystander activation was also shown to play a role in HSK lesions in immunocompetent mice. Accordingly, in immunocompetent DO11.10 mice, lesions were dominated by KJ1.26(+) OVA-specific CD4(+) T cells that were unreactive with HSV. In addition, KJ1.26(+) HSV nonimmune cells parked in ocularly infected BALB/c mice were demonstrable in HSK lesions. These results provide insight for the choice of new strategies to manage HSK, an important cause of human blindness.     

Cryptosporidium parvum-induced inflammatory bowel disease of TCR-beta- x TCR-delta-deficient mice

Experimental inoculation of neonatal immunocompetent strains of mice with Cryptosporidium parvum results in a transient, noninflammatory enteric infection. In the present study, we show that inoculation of mice deficient in alphabeta and gammadelta T cells (TCR-beta- x TCR-delta-deficient mice) with C. parvum results in persistent infection and severe inflammatory bowel disease-like lesions. The most severe lesions in these mice were in the cecum with similar yet less severe lesions in the ileum and proximal colon. The most notable aspect of the histopathology was glandular hyperplasia with abscess formation, extensive fibrosis of the lamina propria with infiltrates of predominately polymorphonuclear cells and macrophages, and a few small aggregates of B cells. Persistently infected mice also developed extensive hepatic periportal fibrosis in association with C. parvum colonization of bile ducts. Lesions observed in TCR-beta- x TCR-delta-deficient mice were markedly different than previously described lesions detected in C. parvum-infected TCR-alpha-deficient mice. Cryptosporidium parvum-infected TCR-alpha-deficient mice have extensive infiltrations of B cells, whereas TCR-beta- x TCR-delta-deficient mice had only a few small aggregates of B cells. These findings indicate that although gammadelta T cells are not necessary for induction of intestinal inflammation in C. parvum-infected alphabeta T-cell-deficient mice, their presence does alter the morphology of the ensuing lesion.     

cyclinA1基因变异诱导小鼠发生头颈部皮肤病变

目的研究cyclinA1基因变异对活体小鼠动物模型可能产生的影响。方法饲养46只cyclinA1基因变异的小鼠与25只同龄野生型小鼠9～24个月,进行比较观察。对发现病变部位的组织切片和对照标本采用HE染色和免疫组织化学染色方法检查。结果cyclinA1基因变异鼠中,约有24％（11／46）在头颈部发生了深溃疡状的皮肤病变,HE染色结果显示病变及病变周围皮肤过度角化,皮脂腺增生明显。而25只野生型鼠中未见类似改变。以cyclinA1特异性抗体进行免疫组织化学染色结果显示,野生型小鼠的皮脂腺内可以观察到明显的染色,而cyclinA1基因变异小鼠标本中没有染色。结论cyclinA1基因变异是导致本实验中观察到的小鼠发生头颈部皮肤病变的直接或间接原因。     

Microbial Adjuvant and Autoimmunity

Definite lesions in the exocrine pancreas were produced when SMA mice were immunized eight times at intervals of 30 days with a mixture of extract of pooled pancreas from syngeneic mice and the capsular polysaccharide of Klebsiella pneumoniae type 1 Kasuya strain (CPS-K), whereas no pancreatic lesions were produced in mice given CPS-K alone or pancreatic extract alone. The typical histological changes were characterized by infiltration with lymphocytes, plasma cells, and other mononuclear cells, degeneration and lysis of the acinar cells, destruction of the lobular architecture, and replacement by fatty tissue and fibrous connective tissue. The endocrine islets were well preserved. No specific histological changes were produced in the organs other than the pancreas in these mice. Most of mice immunized with pancreatic extract mixed with CPS-K produced serum precipitins to syngeneic pancreatic antigens. However, severe pancreatic lesions were also produced in mice showing no definite precipitin production.     

Role of interleukin 1 in experimental pulmonary granuloma in mice

Pulmonary granulomas were induced in immunized BALB/c mice by the intratracheal injection of antigen-coated and plain agarose beads. Prominent lesions developed within 24 hr, reached peak intensity within 3 days, and gradually declined in size thereafter. The hypersensitivity granulomas induced in sensitized mice by antigen-coated beads were much larger than the lesions induced by plain beads. Minimal inflammation was produced in unsensitized mice injected with antigen-coated or plain beads. Aqueous extracts prepared from pulmonary granuloma lesions induced in sensitized mice by antigen-coated beads contained high levels of interleukin 1 (IL 1) and migration inhibition factor (MIF) activities. The kinetics of appearance of these mediators were similar. Lower but detectable activity of both mediators was detected in extracts prepared from sensitized mice injected with plain beads. Neither interleukin 2 (IL 2) nor IL 2 neutralizing activities were detected in the extracts. The presence of IL 1 and MIF in extracts prepared from early and peak pulmonary granulomatous lesions suggests that these soluble factors are produced by cells within the lesions, and that they are involved in mediating the expression and/or maintenance of the granulomas.     

Variation in virulence of Coxsackie virus B3 in the heart of mice, II. Pathological comparison

Histopathological analysis of the heart in adult mice inoculated with Coxsackie virus B3 (CB3) strains revealed that strain SK-74 isolated from a patient suffering from severe diarrhea and fever produced severe myocarditis but strain T-70 isolated from a healthy child induced no lesion in the hearts of mice tested, and that intensities of myocardial lesions in mice inoculated with strain PMH were higher than those in mice inoculated with prototype strain Nancy. The results support the conclusion in the preceding paper that strain SK-74 is virulent but strain T-70 is avirulent in mice. The results also partially indicated that the virulence of prototype strain Nancy in the heart of mice is enhanced by passages of the strain in the heart of mice. All four strains of CB3 produced lesions in the pancreas although lesions induced by strain T-70 were less marked than those induced by the remaining three strains.     

TNF receptor p55 is required for elimination of inflammatory cells following control of intracellular pathogens.

The elimination of lymphocytes within inflammatory lesions is a critical component in the resolution of disease once pathogens have been cleared. We report here that signaling through the TNF receptor p55 (TNFRp55) is required to eliminate lymphocytes from lesions associated with intracellular pathogens. Thus, TNFRp55-/- mice, but not Fas-deficient mice, maintained inflammatory lesions associated with either Leishmania major or Rhodococcus equi infection, although they developed a Th1 response and controlled the pathogens. Inflammatory cells from either L. major- or R. equi-infected C57BL/6 mice were sensitive to TNF-induced apoptosis, and conversely the number of apoptotic cells in the lesions from TNFRp55-/- mice was dramatically reduced compared with wild-type mice. Furthermore, in vivo depletion of TNF in wild-type mice blocked lesion regression following R. equi infection. Taken together, our results suggest that signaling through the TNFRp55, but not Fas, is required to induce apoptosis of T cells within inflammatory lesions once pathogens are eliminated, and that in its absence lesions fail to regress.     

Susceptibility of Germ-free Mice to Infectious Megaenteron

Germ-free (GF)-ICR mice were shown to be less susceptible to oral inoculation with a pathogenic strain of Escherichia coli (E. coli 0115a, c: K(B)) than GF-CF#1 mice. In GF-CF#1 mice a large number of organisms were recovered from the intestinal wall from the cecum to the rectum 3 to 7 days after inoculation. Unlike those in GF-CF#1 mice, lesions in GF-ICR mice were localized in a part of the cecum and organisms were recovered only from the cecal wall and rarely from organs other than those of the alimentary tract. In both strains of mice, however, organisms were recovered in large number from the intestinal contents. Histopathology and immunofluorescence revealed organisms closely attached to the surface of the cecum, colon and rectal epithelia in GF-CF#1 mice but only in a part of the cecal epithelium in GF-ICR mice. After being in contact with conventional CF#1 mice for 21 days and then inoculated orally with the pathogenic E. coli, ex-GF-CF#1 mice died within 14 days with severe intestinal lesions, but ex-GF-ICR mice survived without lesions.     

Behavioral characteristics in mice with brain lesions induced by hypertonic saline

Behavioral and histopathological characteristics were studied in mice treated repeatedly with hypertonic saline. In passive avoidance response using a step-through-type shuttle box, the mice treated with hypertonic saline showed shorter latency than control mice. No changes were observed in active avoidance response using a two-way-type shuttle box, spontaneous motor activity or motor function. Histopathological examination revealed marked and frequent degeneration and loss of neurons in the hippocampus as compared with animals after single treatment. The animals with severe hippocampal lesions showed impairment of passive avoidance response. The present brain lesions resulting from repeated treatment with hypertonic saline in mice are considered to be a possible model for memory disorders caused by hippocampal lesions in humans.     

Experimental murine model for autoimmune enterocolitis using Klebsiella pneumoniae O3 lipopolysaccharide as a potent immunological adjuvant

An experimental model for autoimmune enterocolitis was produced in mice by repeated immunization of homologous colon extract together with Klebsiella 03 lipopolysaccharide (KO3 LPS) as an immunological adjuvant. Histological changes in the intestinal lesions were characterized by infiltration with polymorphonuclear leukocytes in the lamina propria, muscularis mucosae and submucosa of repeatedly immunized mice. No such intestinal lesions were produced in mice receiving injections of colon extract alone or KO3 LPS alone. Development of the autoantibody and delayed-type hypersensitivity against colon extract were found in mice immunized with the mixture of colon extract and KO3 LPS. Distinct positive staining was detected specifically on the columnar epithelium of villi. Sera from hyperimmunized mice defined organ-specific antigens present in the intestine. Therefore, it was suggested that the intestinal lesions might be caused by an autoimmune mechanism.     

Renal thrombotic microangiopathy in a genetic model of hypertension in mice

Our goal was to develop a model of accelerated hypertension with renal microangiopathy. Transgenic mice that are hypertensive because of overexpression of human renin (R+ mice) and human angiotensin (A+ mice) genes were studied. To increase arterial pressure to levels comparable to those that may be seen in malignant hypertension, high salt was added to the diet and/or the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methylester (L-NAME), was added to the drinking water. Renal lesions, decline in renal function, and proteinuria developed within 10 weeks in R+/A+ mice given both L-NAME and a high-salt diet, and within 24 weeks in mice given either L-NAME or a high-salt diet. Renal morphology showed features of severe thrombotic microangiopathy, with extensive vascular and glomerular lesions in all R+/A+ mice on high salt, L-NAME, or high salt plus L-NAME. Vascular lesions included fibrin thrombi and onion skinning of the vessel walls, whereas glomerular lesions included segmental sclerosis, mesangiolysis, fibrin thrombi within glomerular capillaries, and double-contour formation of glomerular capillary walls. Renal morphology was normal in control mice fed high salt and/or L-NAME. No R+/A+ mice fed a normal diet developed vascular lesions, whereas a few mice developed mild focal glomerular lesions. In summary, these studies characterize vascular and glomerular lesions in R+/A+ mice fed high salt, L-NAME, or both high salt and L-NAME, and provide a murine model of malignant hypertension with renal thrombotic microangiopathy.     

IL-17 is involved in bone resorption in mouse periapical lesions

Periapical lesions are induced by bacterial infection of the dental pulp and result in destruction of the surrounding alveolar bone. Although various immunological studies concerning periapical bone resorption have been reported, the role of cytokines in the formation of periapical lesions remains unclear. In this study, the role of IL-17A in periapical lesions in mice was investigated. Normal C57BL/6, IFN-γ^−/−, TNF-α^−/−, and IL-17A^−/− mice were subjected to pulp exposure and infected with Prevotella intermedia (ATCC25611) and Porphyromonas gingivalis (ATCC33277) in the mandibular first molar. Periapical lesions were determined by μCT on day 21 after infection, and 3D visual construction was performed using 3D picture quantification software. The expression of IL-17A mRNA in periapical lesions was determined by the RT-PCR and real-time RT-PCR method. Periapical lesions developed in wild-type, IFN-γ^−/−, and TNF-α^−/− mice after infection with P. intermedia and P. gingivalis . However, periapical lesions were not observed in IL-17A^−/− mice. The expression of IL-17A mRNA was significantly induced in periapical lesions of wild-type mice after infection. These results suggest that IL-17A, but not IFN-γ or TNF-α, plays an important role in the formation of periapical lesions.     

Naturally occurring mouse hepatitis virus infection in the nude mouse.

A group of athymic nude mice developed an unusual chronic wasting disease within 1-3 months after their arrival into the laboratory. Affected nude mice had severe, acute-to-chronic, active hepatitis with multinucleated giant hepatocytes and fibrosis. Vascular and central nervous system lesions were frequently present, giant cell peritonitis, ascites, and multinucleated giant cells in the intestinal epithelial villi were less frequently observed. Mouse hepatitis virus was isolated from the livers of three mice with lesions. The virus, when inoculated into nude mice, produced lesions similar to those observed in the natural outbreak.     

Microbial adjuvant and autoimmunity. II. Production of lesions in mice immunized with syngeneic tissue extracts together with the capsular polysaccharide of Klebsiella pneumoniae.

The target organs of mice immunized with the respective syngeneic tissue extracts together with the capsular polysaccharide of Klebsiella pneumoniae (CPS-K) as a powerful adjuvant were examined for production of lesions. In 15 out of 24 mice injected three times or more with syngeneic eyeball extracts and CPS-K adjuvant at intervals approximately 30 days, severe eyeball lesions developed in which the normal structure was almost completely lost. A large part of the eyeball tissue of these mice was replaced by infiltration with cells such as lymphocytes, plasma cells and other mononuclear cells and by connective tissue. No definite eye lesions developed in mice injected with CPS-K alone, eyeball extracts alone or eyeball extracts emulsified in complete Freund's adjuvant (CFA). In all of mice injected four times with thyroid gland extracts and CPS-K at intervals of approximately 30 days, definite thyroid gland lesions were produced. In three out of five mice of this group, the thyroid lesions were so severe that the normal thyroid follicular structure was almost completely lost, and a large part of the thyroid gland was replaced by infiltration with lymphocytes, plasma cells and other mononuclear cells and in part by connective tissue. In only one out of five mice injected with thyroid gland extracts emulsified in CFA, definite but milder thyroid gland lesions developed. No definite thyroid lesions developed in the remaining four mice of this group and also in any of the mice injected with thyroid gland extracts alone or CPS-K alone. Repeated injections of lymphoid tissue extracts and CPS-K also induced pathological changes in the spleen and lymph nodes, although less marked than those in the cases of the eyes and thyroid gland. The most remarkable change was a decrease in numbers of small lymphocytes at the areas surrounding the central arterioles in the white pulp of the spleen and the post-capillary venules in the cortex of the lymph nodes. From these results it has been concluded that our system can provide new and useful models for autoimmune diseases in man.