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Spontaneous autoimmune thyroiditis in the BUF rat.

The inbred BUF rat develops autoimmune thyroiditis spontaneously. The incidence is related to the age of the animal and is increased by neonatal thymectomy and by treatment with methylcholanthrene. Autoantibodies to thyroglobulin can be demonstrated by indirect immunofluorescence and hemagglutination, but skin tests are negative. The "spontaneous" autoimmune disease may be due to the conjunction of an unusually vigorous immunological response to thyroglobulin and the loss of thymic suppressor function.

Animals

Effect of inhibitory and stimulatory agents on protein synthesis in hepatomas and host livers of rats.

Female inbred BUF rats bearing intrahepatically transplanted hepatomas (5123 or 19) were subjected to acute exposure to a variety of hepatotoxic agents (actinomycin D, aflatoxin B1, CCl4, dimethylnitrosamine, ethionine, puromycin, or sparsomycin) or of stimulatory agents (hydrocortisone, phenobarbital, or whole-body X-ray). The responses in terms of changes in polyribosomes and protein synthesis (in vitro and in vivo) of host liver and hepatoma were evaluated. The responses of the host livers and hepatomas to the different agents varied. In general, the host livers responded much more than did the hepatomas. Of the two hepatomas, hepatoma 19 responded less (particularly in terms of polyribosome changes) than did hepatoma 5123. In a few experiments, different doses of actinomycin D, ethionine, or sparsomycin were used and in all instances the host livers responded more than did the hepatomas.

Animals

Cellular components of allograft rejection: identity, specificity, and cytotoxic function of cells infiltrating acutely rejecting allografts.

Functioning mononuclear cells have been harvested from heterotopic rat cardiac allografts during maximal transplant cellular infiltration. T cells, identified by a T cell-specific absorbed rabbit anti-rat brain serum, constituted two-thirds of the total cells recovered. Approximately 20% of the infiltrating cells bear and synthesize surface immunoglobulin. Macrophages, identified by latex ingestion and morphologic and cytochemical techniques, comprise 9% of the graft infiltrate. Donor-specific cytotoxic T lymphocytes are concentrated within the graft. A separate population of Fc receptor-positive recovered cells mediate antibody-dependent LMC (Ab-LMC). Neither effector cell was adherent or phagocytic. These studies have conclusively established that cytotoxic T lymphocytes accumulate within rejecting allografts; however, the enriched presence of cytotoxic T cells within the grafts is not fully dependent upon antigen recognition per se, since Lew animals grafted with both BN and BUF hearts have Lew anti-BN and Lew anti-BUF killer cells in each graft.

Animals

Spontaneous and methylcholanthrene-enhanced thyroiditis in BUF rats. II. Induction of experimental autoimmune thyroiditis without completed Freund's adjuvant.

The immunization of Buffalo strain (BUF) rats with rat thyroid extract and Bordetella pertussis vaccine without complete Freund's adjuvant resulted in experimental autoimmune thyroiditis (EAT) in 90% of the rats by the 10th day after immunization. The treatment did not elicit thyroiditis in Lewis strain (LEW) rats. This susceptibility to the induction of EAT without the use of complete Freund's adjuvant was inherited by F1 hybrids of BUF and LEW. Neither histamine sensitizing factor from B. pertussus nor Escherichia coli vaccine substitute for whole pertussis vaccine.

Animals

A new common marker for premalignant and malignant hepatocytes induced in the rat by chemical carcinogens.

A new common antigen, preneoplastic (PN), was found in every early and late hyperplastic nodule and in every primary hepatoma induced by N-2-fluorenylacetamide, ethionine, 3-methyl-4-dimethylaminoazobenzene, dimethylnitrosamine, or diethylnitrosamine in three strains of rats (CFN, F344, and BUF). It so far has not been found in normal adult rat liver, liver surrounding nodules or cancer, fetal liver, amniotic fluid, adult rat serum, sera from rats with hyperplastic nodules or primary hepatomas, or various normal rat tissues. Immunofluorescent staining indicated the PN antigen was present in the cytoplasm of hepatocytes in hyperplastic nodules and in primary hepatomas.

Animals

Comparison of the haplotypes of the major histocompatibility complex in the rat. III. Two difficult haplotypes: H-1h (Ag-B12) in the HW strain and Ag-B13 (H-1m) in the MNR/N strain.

Two haplotypes which posed difficult problems in serological identification, those of the HW and MNR/N strains, were studied. The HW strain was originally described as a unique haplotype (H-1h), but breeding difficulties precluded its detailed serological analysis. The red blood cells of the HW strain agglutinate weakly and cross-react with antisera to the Ag-B8 group. Anti-HW antisera cross-react strongly with LEW, ACI and WKA, but absorption with these strains did not produce an adequate typing serum. By judicious selection of recipients, however, an appropriate typing reagent could be made; a particularly useful one was (BUF X MR)F1 anti-HW absorbed with WKA red blood cells. The HW haplotype segregated appropriately in a (DA X HW)F2 population. The HW strain is a low responder to poly(Glu52Lys33Tyr15). The H-1h haplotype of this strain was designated Ag-B12. The MNR/N strain had not previously been studied serologically, although its MLR type had been defined as H-1c (MLR-5). Antisera to MNR/N cross-reacted strongly with the H-1a,b,d,f haplotypes, but MNR/N red blood cells agglutinated only weakly with many antisera. An operationally monospecific reagent antiserum to the MNR/N haplotype could not be made. The uniqueness of the MNR/N haplotype was shown by F1 tests with LEW.1A, LEW.1D and LEW.1F, by various serological analyses, including production of antisera against MNR/N and in the MR strain; by segregation studies with (LEW X LEW.1D)N5 and (DA X DA.MNR)N4 segregating back-cross populations, and by grafting skin from (DA X DA.MNR)N4 homozygous and heterozygous animals to DA recipients. The MNR/N strain is a high-responder to poly(Glu52Lys33Tyr15). The MNR/N haplotype of this strain was designated Ag-B13 (H-1m). The data led to the working hypothesis that the MNR/N strain may be a recombination between the A region of H-1d and the B region of H-1c. In addition, the H-1d private specificity at the A region was probably lost by a deletion mutation which left the main complex of public specificities intact.

Animals

The induction of specific resistance in F1 hybrid rats to local graft-vs.-host reactions: nature of the eliciting cell.

A specific state of resistance to local graft-vs.-host (GVH) reactions can be induced in F1 hybrid rats, derived from Ag-B incompatible matings, as a consequence of inoculation with low numbers of parental strain lymphocytes. The magnitude of GVH resistance is markedly and directly dependent upon the number of parental strain lymphocytes used in the pretreatment regimen. The relevant constituents of the resistance-inducing parental cell population are thymus-derived (T) lymphocytes possessing immunologic competence for host alloantigens. B cells, themselves incapable of inducing GVH resistance, adversely effect the induction or display of this effect by T cells.

Animals

Skin and heart allograft prolongation in tilorone-treated rats.

Tilorone is a synthetic amino-alkoxyfluorenone with demonstrated antiviral and antitumor properties. This study gives evidence for immunosuppressive properties of the substance as well. Buffalo rats (AgB6) received skin grafts from rats of the Fischer (AgB1) strain. Control animals rejected in 9.9 +/- 1.1 days, compared to 13.7 +/- 2.3 days for recipients treated with Tilorone. Steroids when combined with Tilorone further prolonged skin allografts to 16.7 +/- 2.6 days. Heart allografts from Fischer (AgB1) and Brown-Norway (AgB3) to Lewis (AgB1) also were performed. In the Fischer to Lewis combination, allograft survival was prolonged from 14.7 +/- 1.0 to 31.0 +/- 3.8 days. In the Brown-Norway to Lewis combination, treated rats rejected in 10.2 +/- 1.4 days versus 6.6 +/- 1.1 days for controls. Increased levels of cytotoxic antibody specific to lymphocytes of the donor strain were noted in Tilorone-treated animals. The mechanism by which Tilorone prolongs allografts may well involve a combination of interferon production and specific suppression of thymus-derived lymphocytes.

Animals

Prolongation of rat heart allograft survival by a synthetic progestogen (melengestrol acetate) and ara-cytidine acylates.

Immunosuppressive effects of newly developed synthetic progestins, melengestrol acetate (MGA), and three pyrimidine analogs, ara-cytidine (Ara-C), Ara-C 5'-benzoate and octanoate, were investigated on the heart allograft survival in the rat. MGA at the dose of 25 mg/kg given every 3rd day starting 1 day before the grafting through day 20 prolonged the graft survival significantly without toxic effects (80.2 +/- 40.2 days versus control 7.0 +/- 0.1 days). The high dose (50 mg/kg/day) was more effective (137.4 +/- 26.6 days) but a high incidence of multiple abscesses (37%) was also noted. The other three agents were either highly toxic or not immunosuppressive.

Animals

Mixed leucocyte interaction suppression generated after alloimmunization.

Utilizing a bone marrow cell immunization protocol designed to actively enhance renal or cardiac allografts, the in vitro mixed lymphocyte interaction has been studied. After immunization with allogeneic cells over a wide dose (10(5) to 10(8)) and time range, the mixed lymphocyte interaction using peripheral blood lymphocytes is reduced, and this reduction is shown in mixing experiments to be attributable to a circulating suppressor cell that has adherence characteristics of T lymphocytes. Specificity for in vivo generation of these circulating cells as well as specificity in the in vitro reaction was shown, although a nonspecific suppression background was observed. Allogeneic thymocytes, splenocytes, and platelets were effective in immunizing to generate these cells also. There was no general correlation with the ability to generate these cells and to actively enhance cardiac allografts, since suppression was seen after alloimmunization in strain combination that cannot be actively enhanced.

Animals

Studies on skin-reacting transplantation antibodies.

Evidence is presented that skin-reacting transplantation antibodies (SRTA) can be elicited not only by skin allografts, but also by injection of dispersed allogeneic lymphoid cells. Two mechanisms of action of SRTA, which are not mutually exclusive, are compatible with the experimental results. (1) SRTA may act as homocytotropic antibodies, producing skin reactions by fixing to the skin of the test animal and combining with circulating antigens brought to the test site. (2) SRTA may produce skin reactions by combining directly with "sessile" antigens in the skin. Genetic studies showed that the antigens combining with SRTA are inherited as simple Mendelian traits. Furthermore, it was shown that these antigens are not related to the major rat histocompatibility antigens, Ag-B, nor are they related to any other described rat alloantigen system. Thus, the antigens responsible for SRTA belong to a new antigenic system.

Animals

Modulation of mixed lymphocyte culture reactivity following alloimmunization between H-1 (Ag-B)-histocompatible rat strains.

H-1 (Ag-B)-histocompatible rats were cross-immunized to study the effects of presensitization on the mixed lymphocyte culture (MLC) reactivity in normally nonresponsive MLC interactions. Lewis (LEW) rats, H-1 (Ag-B), were given s.c. injections of Fischer (F), H-1 (Ag-B), lymhocytes at weekly intervals for 3 weeks. Immunized LEW (Lew-iF) and F lymphocytes showed increased proliferative responses in MLC after the third immunization. The augmented proliferative responses in the MLC between these H-1 (Ag-B)-histocompatible rat strains following immunization may reflect minor histocompatibility antigenic differences. On the other hand, decreased proliferative responses in MLC between Lew-iF and Ag-B (H-1)-disparate rat strains were demonstrated. Alloimmunization across minor histocompatibility differences led to different types of regulatory effects on the MLC interactions. With low MLC responses, e.g., minor histocompatibility differences, the regulation tends to be positive; whereas for strong MLC responses, e.g., major H-1 (Ag-B) differences, the regulation tends to be negative or suppression.

Animals

Processing of streptococcal cell walls by rat macrophages and human monocytes in vitro.

Phagocytosis and degradation of cell walls by peritoneal macrophages obtained from Fischer 344 or Buffalo rats was measured in tissue culture. Group A cell wall antigen, detected by immunofluorescence, persisted in cultured rat macrophages for at least 40 days, whereas group D cell wall material was eliminated by 6 to 8 days. This same pattern of persistence of group A cell walls and elimination of group D cell walls was observed in cultures of human monocytes followed for 24 days in culture. Group A streptococcal cell walls labeled with either [14C]alanine or [14C]glucose were handled in a similar manner by macrophages from either Fischer 344 or Buffalo rats. In contrast, [14C]glucose-labeled group D cell walls were degraded at a much faster rate. Buffalo macrophages were more efficient than Fischer 344 macrophages in degrading group D cell walls. The inability of macrophages to degrade group A cell walls was not due to a failure of lysosomes to fuse with phagosomes. Neither serum lysozyme in the culture medium nor cell wall-associated autolysin contributed to the degradation of group D cell walls by macrophages. Neither immune serum nor macrophages obtained from specifically immunized rats influenced phagocytosis or persistence of group A cell walls.

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