Foreign serum-induced bile duct lesion (BDL) in athymic BALB/c nude mice

To investigate a role of cellular immunity in foreign serum-induced bile duct lesion (BDL) in mice, athymic BALB/c nude (nu/nu) mice were intraperitoneally injected with swine serum (SS) twice a week up to 8 weeks and were compared with euthymic BALB/c heterozygote (nu/+) and wild-type (+/+) mice treated with SS in the same way for 4 weeks. All immunized nu/+ and +/+ mice developed marked BDL, and their sera showed high anti-SS IgE and IgG1 antibody titers, whereas no immunized nu/nu mice developed lesions, and their sera showed no elevation of antibody titers. Next, nu/nu mice were reconstituted with splenocytes derived from nu/+ mice, and then were intraperitoneally injected with SS twice a week for 3 weeks. Most of the reconstituted nu/nu mice developed BDL, and their sera showed the elevation of anti-SS IgE and IgG antibody titers. These results suggest that cellular immunity may play a pivotal role in the pathogenesis of swine serum-induced BDL.     

Cells with natural killer activity in the cerebrospinal fluid of normal mice and athymic nude mice with acute Sindbis virus encephalitis

Sindbis virus causes an acute, nonfatal inflammatory encephalitis in weanling BALB/c mice. Mononuclear inflammatory cells are present in the cerebrospinal fluid (CSF) as well as in the parenchyma of the brain. Both aspects of this inflammatory response were eliminated by treatment with cyclophosphamide. Athymic nude (nu/nu) mice developed no inflammation in the brain, but did develop a CSF pleocytosis that peaked on day 2 after infection. The time course of the appearance of cells in the CSF was earlier in nu/nu mice than their heterozygote (nu/+) littermates. The pleocytosis in nu/nu mice reached a peak on day 2, whereas in nu/+ mice the peak was on day 4, as it is in normal BALB/c mice. To determine whether some of the CSF cells in nu/nu mice may be natural killer (NK) cells, NK activity was measured in a 4-hr assay by using a YAC-1 target cell. NK cell activity in the spleen and peripheral blood was induced by infection with Sindbis virus in nu/nu mice with a similar time course to that of nu/+ mice (peak 1 day after infection). CSF from nu/nu mice had NK activity present 2 days after infection that was greater than that present in either the peripheral blood or spleen. BALB/c and nu/+ mice had insufficient cells present for assay at day 2, but BALB/c mice had NK activity present in the CSF 3 and 5 days after infection that exceeded that in the peripheral blood or spleen. Brain interferon was detectable on day 1 in nu/nu mice, but not until day 2 in nu/+ mice even though the amounts of brain virus were the same in the two groups at all time points. It is concluded that cells with NK activity contribute to the CSF pleocytosis induced by acute Sindbis virus encephalitis.     

Carrageenan-induced decline of natural killer activity: II. Inhibition of cytolysis by adherent non-T Ia-negative suppressor cells activated in vivo

The intravenous injection of 1 to 2 mg of ι-carrageenan (CAR) into (C57BL/6 × C3H)F₁ or BALB/c mice causes a prompt and substantial decline of splenic natural killer (NK) activity against YAC-1 lymphoma targets lasting approximately 1 week in F₁ mice. During this time, NK activity can be enhanced by administration of the interferon inducer polyinosinic-polycytidilic acid. The in vivo effect of CAR requires neither an intact thymus nor unimpaired proliferative capacity of lymphomyeloid cells, according to experiments in congenitally athymic BALB/c.nu/nu mice and in preirradiated (700 rad of γ-rays) F₁ hybrids. The splenic cytotoxic activity lowered in vivo by CAR can be restored in vitro by removing subpopulations of cells that adhere to glass wool or carbonyl iron particles, but not to Sephadex G-10. Thus, the lytic function of mature NK cells is reversibly inhibited in the spleens of CAR-treated animals; differentiation and maturation of NK precursors are not inhibited, as judged by the enhancing effect on NK activity of the interferon inducer. Splenocytes of CAR-treated donors suppress cytotoxic effectors of untreated mice in cell mixing experiments. Athymic and preirradiated animals given CAR are fully competent donors of suppressor cells. Suppressor function is insensitive to irradiation (2000 rad of γ-rays in vitro) and to anti Thy-1 or anti-Ia antibody plus complement. Inhibition of NK cytolysis is not restricted by the major histocompatibility complex and can also be mediated by cell-free supernatants in which suppressor cells were incubated. This model of reversible inhibition of NK activity suggests that activation of thymus-independent suppressor cells is one of the regulatory mechanisms of natural cytotoxic activity in vivo.     

The efficacy of biological response modifiers against murine cytomegalovirus infection in normal and immunodeficient mice

The host-mediated antiviral effect of two biological response modifiers (BRM), OK-432 and PS-K, against murine cytomegalovirus (MCMV) was evaluated in normal and immunologically deficient mice of the same litters. In normal littermate mice, BALB/c (nu/+) or C57BL/6 (bg/+), the BRM-induced resistance against MCMV infection was evidenced by increase in fifty percent lethal doses, decrease in titers of viruses replicated in the target organs and augmentation of natural killer (NK) cell activity of the spleen cells. In T cell-deficient, athymic nude mice, BALB/c (nu/nu), the protective effect was manifested by prolongation of the survival, decrease in the virus titers, and increase in the NK-cell activity, but without decrease in mortality. In NK cell-deficient, beige mutant mice, C57BL/6 (bg/bg), the BRM-induced protection was nullified or minimized, and there was little difference in those parameters between BRM-treated and untreated mice. However, with higher doses of OK-432, but not PS-K, or with sublethal doses of MCMV, the NK cell activity was slightly augmented in the beige mutant mice. Thus both NK cell and T cell activity are essential for mice to overcome acute MCMV infection and it is likely that the protective effect of BRM manifests itself fully, at least in immunologically intact mice.     

Induction of B-Cell Lymphoma in BALB/c Nude Mice with an Ecotropic, B-Tropic Helper Virus Present in the Murine AIDS Virus Stock

The pathogenicities of the murine AIDS (MAIDS) virus complex (LP-BM5) and ecotropic helper virus (BM5eco) isolated from the complex to BALB/c nude mice were studied to elucidate the possible role of replication-competent helper virus in inducing the monoclonal outgrowth of lymphoid cells. Neither LP-BM5 nor BM5eco was pathogenic in adult BALB/c nude mice. However, B-cell lymphoma developed with a very high frequency when either virus was inoculated into newborn BALB/c nude (nu/nu) mice. The cells from the B-cell lymphoma were easily transplanted into nude mice. These results suggested that ecotropic helper virus in the MAIDS virus complex plays an important role in inducing the monoclonal outgrowth of lymphoid cells under immunodeficient conditions caused by defective virus.     

Gastrointestinal microecology of BALB/c nude mice.

The aerobic, facultative, and anaerobic microorganisms cultivable from the stomachs, ilea, ceca, and colons of BALB/c athymic (nu/nu) mice (normal and wasting), thymus-implanted normal nude mice, and their heterozygous (nu/+) littermates were investigated. Ninety-one species representing 23 genera of bacteria and yeasts were isolated from the 27 mice. The wasting nude mice showed significantly lower numbers of lactobacilli in their stomach microbiota than did mice from the other three groups. The littermate animals appeared unique among the four groups in having corynebacteria as a major constituent of their stomach and ileal flora. The normal nude mice appeared to have a more diverse anaerobic stomach flora than their heterozygous littermates. These minor differences are discussed with respect to possible immunological, physiological, and environmental factors as their cause. Because the gastrointestinal microfloras of the mice from the four groups were not radically divergent from each other, it was concluded that loss of T-cell function does not dramatically alter the makeup of the cultivable gastrointestinal microflora in these mice.     

Partially restorative role of T cells for low interleukin 2 dependent growth of NK cell progenitors from nude mice

The frequency of cells in the spleens of nude mice which could be grown in conditioned medium containing interleukin 2 and of those which developed natural killer (NK)-like activity was evaluated. Although BALB/c nu/nu spleen cells have higher spontaneous NK activity than euthymic mice, they showed a substantially lower frequency of proliferating and cytotoxic cells as compared to BALB/c nu/+ littermates. This defect in cells of nu/nu mice was reversed in part by culturing nu/nu responder cells in the presence of irradiated (3,000 R) splenic or thymic feeder cells that included T cells. In contrast to the dissociation of NK activity and progenitor frequencies in nude mice, the results of parallel studies with spleen cells from euthymic mice indicated that the limiting dilution assay correlated well with previously described features of NK activity. High-NK-reactive CBA/J mice were found to have a considerably higher frequency of interleukin 2 dependent NK cell progenitors than low-NK-reactive strains of mice when assessed against NK-susceptible YAC-1 targets. The frequency of progenitors of cells cytotoxic against YAC-1 was higher in spleens of high-NK-reactive mice than that of cells reactive against the NK-insensitive target P-815. Furthermore, the phenotype of the progenitor cells and of the cultured effector cells was consistent with that of NK cells rather than cytotoxic T cells in that the cells expressed asialo GM1, some Thy-1, but no detectable Lyt-1 or Lyt-2 antigens. Thus, the present observations suggest that the subpopulation of NK cell progenitors in nude mice which can grow and develop cytotoxic reactivity in vitro in the presence of interleukin 2 is small, that it can be increased appreciably in the presence of T cells, but that this does not represent the major pathway for development of NK cells in athymic individuals.     

Regulation of the anti-alpha(1----3) dextran IgG antibody response of BALB/c mice by idiotype-specific T suppressor lymphocytes.

The immune response of BALB/c mice against the so-called thymus-independent bacterial Ag alpha(1----3) dextran (Dex) is restricted to the expression of few major idiotypes (Id). It is furthermore under the control of T lymphocytes which regulate the isotype expression in such a way that they prevent anti-Dex IgG antibody production upon immunization. At the same time these T cells are part of a regulatory system for Dex-specific B cell memory formation. The underlying Ts cell activity has previously been analyzed by using euthymic and athymic congenic animals. Now we have isolated CD4-positive Id-specific T cell lines and clones which by several criteria are representatives of the above Ts cells. They inhibit in vitro proliferation and antibody secretion of Dex-specific hybridoma B cells. They prevent Id-restricted in vivo IgG anti-Dex antibody formation in T cell-reconstituted BALB/c nu/nu mice. At the same time they enforce, again Id-specific, accumulation of Dex-specific B memory cells. As has been shown previously under the influence of splenic Ts cells, these B memory cells are arrested in the original host but can be expanded and activated for anti-Dex IgG antibody formation upon adoptive transfer into X-irradiated allotype congenic nonresponder BALB.Ighb mice. The data show that the regulatory influence of T cells on the anti-Dex response is Id specific. It can now be studied by means of cloned Ts cells.     

Interleukin-4 production in BALB/c mice immunized with Anisakis simplex.

We investigated the interleukin (IL-4) levels in BALB/c mice immunized with Anisakis extract in single or multiple doses and in mice orally infected with a larva. From animals immunized maximum responses were obtained with the multiple doses with an only IL-4 peak. Conversely, in the mice inoculated with a larva per os, the IL-4 levels showed two peaks of different rates.     

Variation in adenovirus transgene expression between BALB/c and C57BL/6 mice is associated with differences in interleukin-12 and gamma interferon production and NK cell activation

The innate immune response against replication-defective adenoviruses (Ad) is poorly defined. We and others have previously observed striking differences in the rate at which the Ad vector itself or the virus encoding a variety of transgenes is eliminated in different mouse strains. Here, we report that Ad infection of BALB/ mice is associated with sixfold-higher levels of serum alanine aminotransferase and that Ad transgenes induce two- to threefold-higher levels of intrahepatic NK cells and NK activity compared to C57BL/6 mice. The increase in NK activation in BALB/c mice was associated with approximately 4-fold higher level of mRNA expression of a newly described NKG2 receptor activator, H-60, as well as increased expression of interleukin-12 and gamma interferon mRNAs in BALB/c mice compared to C57BL/6 mice. NK depletion in BALB/c mice or defective NK function in C3H beige mice extended transgene expression compared to their appropriate controls, and attenuation of NK together with CD8 T-cell function had a synergistic effect. These findings indicate that there are intrinsic differences in the innate immune responses of different mouse strains to Ad and Ad transgenes and that NK cells, in cooperation with CD8 T cells, play a pivotal role in the early extinction of transgene expression in BALB/c mice.     

Underdevelopment of fetal thyroid follicular cells in athymic nude mouse (BALB/cAnNCrj-nu/nu) observed by electron microscopic morphometry.

Fetal thyroid follicular cells of congenitally athymic nude mouse (BALB/cAnNCrj-nu/nu) were studied with an electron microscope. The area of the entire cell, nucleus and mitochondrion were measured and compared in athymic and euthymic fetal nude mice (BALB/cAnNCrj-nu/+) at 18 days of gestation. The mean area of cytoplasm was significantly smaller in homozygous athymic nude mice than in heterozygous euthymic ones. The mean area of the mitochondrion was also smaller in homozygous athymic nude mice, but the difference was not statistically significant. There was no significant difference between the two groups in the area of the nucleus. These findings suggest that the thyroid gland of athymic nude mice is still underdeveloped at the end of gestation as compared to that of their euthymic littermates.     

Enhanced human tumor cell transplantability in a new congenic immunodeficient mouse; KSN-BNX

We introduced two mutant genes (beige; bg that induces the deficiency of natural killer (NK) activity andxid that decreases the production of immunoglobulin) into KSN nude mice with high reproductive performances. We produced KSNbg/bg(nu/nu) (KSN-bg), KSN-xid/xid(nu/nn) (KSN-xid), KSNxid/xid;bg/bg(nu/nu) (KSN-BNX) and KSN-nu/+ (KS) mice by backcross (cross-intercross method). All strains showed as high a reproductivity rate as the parental KSN mice. KSN-xid and KSN-BNX mice had a reduced percentage of B220 positive cells in the spleens compared to KSN and KSN-bg mice, but they showed increased percentages, of Thy-1 and asialo GM1 positive cells. The serum immunoglobulin concentrations of KSN-BNX were as low as KSN-xid. Both KSN-bg and KSN-BNX mice showed deficient NK activity in spleens, whereas KSN-xid mice showed an elevated NK activity. Compared to nude mice, the growth of both human tumor cell TCO-1 and BxPc-3 transplanted subcutaneously was enhanced in KSN-BNX mice. However Panc-1 cells that was rejected in nude mice was not accepted in KSN-BNX mice. Liver metastasis of human pancreatic tumor cells; Capan-1, BxPc-3 and MIAPaCa-2 were studied. No significant difference was observed in the percentage of metastasis formed mice between nude and KSN-BNX mice.     

Eradication of a large MOPC-315 tumor in athymic nude mice by chemoimmunotherapy with Lyt2+ splenic T cells from melphalan-treated BALB/c mice bearing a large MOPC-315 tumor

Summary We have previously shown that spleen cells from BALB/c mice that are in the process of eradicating a large MOPC-315 tumor following low-dose (2.5 mg/kg) melphalan (l-phenylalanine mustard) therapy are effective in preventing tumor progression upon adoptive transfer into BALB/c mice bearing a barely palpable tumor that had been treated with a subcurative dose of melphalan [Mokyr et al. (1989) Cancer Res 49: 4597]. Here we show that such spleen cells in conjunction with a subcurative dose of drug (adoptive chemoimmunotherapy, ACIT) can cause the complete regression of a large (15–20 mm) s.c. MOPC-315 tumor in a large percentage of T-cell-deficient (athymic nude) tumor-bearing mice. Spleen cells that were effective in ACIT of athymic nude mice displayed in vitro a substantial direct lytic activity against MOPC-315 tumor cells, and the lytic activity was greatly enhanced when the spleen cells were cultured for 5 days with or without mitomycin-C-treated MOPC-315 stimulator tumor cells. The cells responsible for the therapeutic effectiveness of the spleen cells in ACIT of athymic nude mice, as well as the cells responsible for the direct in vitro anti-MOPC-315 lytic activity of the spleen cells, were of the Lyt 2 and not the L3T4 phenotype. Most of the athymic nude mice that completely eradicated a large MOPC-315 tumor as a consequence of ACIT were capable of rejecting a challenge with 30–100 times the minimal lethal tumor dose for 100% of normal BALB/c mice administered more than 1 month after the ACIT. The ability of these athymic nude mice to resist the tumor challenge was associated with the presence of a greatly elevated percentage of cells expressing T cell surface markers in their spleens. Thus, it is conceivable that splenic Lyt 2⁺ T cells from melphalan-treated BALB/c mice bearing a large MOPC-315 tumor mediate their therapeutic effectiveness in ACIT of athymic nude mice bearing a large MOPC-315 tumor, at least in part, through direct cytotoxicity for MOPC-315 tumor cells. In addition, eradication of a large MOPC-315 tumor through cooperation between antitumor immunity and melphalan toxicity endues the athymic nude mice with an elevated percentage of T cells in their secondary lymphoid organs, and these T cells are probably responsible for the long-lasting protective antitumor immunity exhibited by these mice.Supported by research grant IM-435A from the American Cancer Society and research grant B-8806 from the Bane EstateIn partial fulfillment of the requirements for the Doctor of Philosophy DegreeRecipient of Career Development Award CA-01350 from the National Cancer Institute     

The Influence of the Athymic Mutation Nude on the Components of the Orcadian Rhythm of Activity in Mice

The mutation known as nude brings about the lack of a thymus gland in mice. This immuno-deficiency makes it possible to graft normally unaccepted, human cancerous tumors onto the mouse. Consequently, this animal is frequently used as a model for evaluating anti-cancer therapies. The effect of this mutation on biological rhythms constitutes a necessary step before using this model for cancer chronotherapy research. We evaluated the circadian and ultradian components of the restactivity cycle in the following strains of mice: CS7BL/6 with homozygous nu/nu, heterozygous nu/+, thymectomised +/+, and sham-operated +/+. The amount of activity was reduced in nu/nu as compared to the other groups. Nonetheless, neither the nude mutation nor thymectomy yielded any notable change in the circadian rhythm of activity.     

Murine Mammary Tumor Virus Expression During Mammary Tumorigenesis in BALB/c Mice

Steady-state levels of murine mammary tumor virus (MuMTV) RNA were quantitated during mammary tumorigenesis in BALB/c mice by molecular hybridization with a representative MuMTV complementary DNA (cDNA) probe. Hyperplastic alveolar nodule (HAN) lines are preneoplastic mammary lesions that were induced in BALB/c mice by hormones alone or in combination with 7,12-dimethylbenz(a)anthracene and give rise to mammary tumors. The hormone-induced HAN lines D1 and D2 contained detectable amounts of hybridizable MuMTV sequences. MuMTV RNA sequences were also observed in five of the six transplanted BALB/c mammary tumors that were examined. Similar levels of hybridizable MuMTV RNA were observed between the D1 or D2 HAN line and mammary tumors derived from each HAN line. The D2 HAN line as well as D2, C4, and CD8 mammary tumors accumulated RNA that was apparently homologous to most of the MuMTV genome. Thermal denaturation of hybrids indicated extensive sequence homology between the MuMTV cDNA and hybridizable RNA in the BALB/c HAN lines and mammary tumors. A low level of type C viral RNA was observed in the BALB/c HAN lines and most mammary tumors by molecular hybridization with a cDNA to Moloney murine leukemia virus. These data demonstrate that MuMTV sequences are frequently expressed in hormone-induced BALB/c HAN lines and mammary tumors derived from HAN lines or ductal hyperplasias induced in BALB/c mice by hormones and/or a chemical carcinogen. The transition from the preneoplastic to the neoplastic state in BALB/c mice does not appear to be due to a change in the steady-state levels of MuMTV RNA since the hormone-induced HAN lines and mammary tumors had similar levels of hybridizable MuMTV RNA.     

Spontaneous heart failure in BALB/c mice

The hearts of BALB/c mice are known to acquire pronounced greyish white spots (cardiac white spots). BALB/c male mice were examined for the relationship between the incidence of cardiac white spots and weekly age, and compared with DDY male mice. During the observation period of 0.4-30 weeks, cardiac white spots on the right ventricle of BALB/c mice were first detected at three weeks (6 of 20 mice; 30%), and the maximal incidence of cardiac white spots was obtained at nine weeks (39 of 44 mice; 88%). In contrast, DDY mice were completely devoid of cardiac spots. Histopathologically, the cardiac spots were dystrophic calcinosis. There were significant increases in the relative organ weights of the heart and kidney of BALB/c mice compared with those of DDY mice. However, there was no significant difference between BALB/c and DDY mice in serum calcium concentration or histological characteristics of the parathyroid gland or bone marrow. The cardiac white spots of BALB/c mice were considered to be controlled by genetic susceptibility that occurred spontaneously with aging. The results described here suggest that BALB/c mice are adequate experimental animals for the study of myocardial disease that occurs spontaneously.     

Brush border enzyme activities in the small intestine after long-term gliadin feeding in animal models of human cœliac disease

Cœliac disease is a human, genetically linked, disorder which develops in gluten-sensitive persons. The aim of this study was to investigate the effect of prolonged feeding of gliadin, a major fraction of gluten, on enzyme activities of enterocyte brush border membrane enzymes in rats, mice and pigs. Brush-border membranes were isolated from mucosal scrapings of the small intestine of 21-d-old rat pups hand-fed with formula milk diet, two-month-old nu/nu and +/+BALB/c mice and two-month-old piglets fed three times a week starting at birth with high doses of gliadin. Activities of lactase, sucrase and dipeptidyl peptidase IV (DPP IV) were determined. Individual animal models differed in their response to gliadin feeding. In comparison with albumin fed controls the activities of DPP IV and lactase were decreased in rat pups, nu/nu BALB/c mice and piglets. DPP IV activity was mostly affected in the ileum of rats and piglets fed with gliadin starting at birth. On the other hand, lactase and sucrase activities of nu/nu BALB/c mice and piglets decreased to the largest extent in jejunum.     

Extrathymic clonal deletion of self-reactive cells in athymic mice

The repertoire of T cells present in congenitally athymic mice was studied by flow cytometric analysis on populations of T cells expanded polyclonally in vitro. Athymic (BALB/c x C57BL/6)F1 mice have levels of potentially autoreactive V beta 3- and V beta 11-bearing T cells that are significantly higher than those of euthymic CB6F1 mice. Examination of potentially autoreactive cells in athymic AKR mice, however, yielded contrasting results. V beta 6+ cells, which are deleted intrathymically in normal AKR mice, are present in the repertoire of young (less than 6-wk-old) AKR nu/nu mice. Isolation of a cloned CD4+V beta 6+ cell line with Mls-1a reactivity from young AKR nu/nu mice indicates that the correlation between TCR usage and specificity is consistent with that described in euthymic mice and that this population contains autoreactive T cells that are not anergic. By 6 mo of age, however, cells expressing V beta 6 are no longer detectable. Inability to detect these cells is not simply caused by failure to expand these cells in culture, because freshly isolated populations from old nude mice exhibit the same selective absence of V beta 6-bearing cells. The data strongly suggest that extrathymic deletion, rather than clonal anergy, accounts for the apparent absence of autoreactive V beta 6-bearing cells in aged AKR nu/nu mice.     

Pubertally Initiated High-Fat Diet Promotes Mammary Tumorigenesis in Obesity-Prone FVB Mice Similarly to Obesity-Resistant BALB/c Mice

Premenopausal breast cancer is associated with increased animal fat consumption among normal-weight but not overweight women. Our previous findings in obesity-resistant BALB/c mice showed that a diet high in saturated animal fat (HFD) promotes mammary tumorigenesis in both DMBA carcinogenesis and Trp53-null transplant models. Having made these observations in BALB/c mice, which have very modest HFD weight gain, we determined the effects of HFD in FVB mice, which gain significant weight on HFD. Three-week-old FVB mice fed a low-fat diet or HFD were subjected to 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. Like BALB/c mice, HFD promoted mammary tumorigenesis. Development of tumors largely occurred prior to mice becoming obese, indicating the role of animal-derived HFD rather than resulting obesity in tumor promotion. Also similar to BALB/c mice, early-occurring adenosquamous mammary tumors were abundant among HFD-fed FVB mice. Tumors from HFD mice also had increased intra-tumor M2 macrophages. Prior to tumor development, HFD accelerated normal mammary gland development and increased mammary M2 macrophages, similarly to BALB/c mice. The promotional effects of puberty-initiated HFD on carcinogen-induced mammary cancer are thus largely weight gain-independent. Like BALB/c mice, HFD promoted adenosquamous tumors, suggesting a role for early age HFD in promoting this subtype of triple negative mammary cancer. M2 macrophage recruitment was common to both mouse strains. We speculate that a similar effect of HFD on immune function may contribute to epidemiological findings of increased breast cancer risk in young, premenopausal, normal-weight women who consume a diet high in saturated animal fat.     

Thymus-independent induction and antigen-dependent recovery of idiotype-specific suppression

BALB/c nude (nu/nu) mice and euthymic (nu/+) littermates were treated as neonates with anti-T15 antibody and challenged at various ages with either a thymus-independent, PC-Brucella abortus (PC-BA), or thymus-dependent, PC-keyhole limpet hemocyanin (PC-KLH), form of phosphorylcholine (PC). Nu/nu mice challenged with PC-KLH received KLH-primed splenic T cells prior to immunization. Neither neonatally anti-idiotype-treated nu/+ nor nu/nu mice responded with the production of T15-positive anti-PC antibodies after challenge with either form of PC antigen. It is concluded that neither induction nor maintenance of a state of T15-specific suppression requires thymus-matured T cells. Recovery of anti-PC responsiveness in suppressed nu/+ or nu/nu mice was similar and was found to be related to the form of antigen used to elicit the response. Immunization with PC-KLH revealed a long-lasting unresponsiveness (up to 16 weeks). In contrast, immunization with PC-BA elicited a full anti-PC response as early as at 6.5 weeks of age.