RESUMO
High and low antibody responder lines of mice from Selections I, III and G were assayed for two-step skin tumorigenesis using a protocol consisting in initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Concordant results were obtained in the three selections: low antibody responder mice were shown to be significantly more resistant to tumor induction than the high responder counterparts. The difference was observed for all parameters: kinetics and percentages of tumor incidence and tumor multiplicity. The three bidirectional selective breeding experiments differed in several respects namely, the origin of the foundation populations, the antigens and immunization protocols used during the selection, as well as the breeding unit environments. Therefore, the consistent results relative to tumorigenesis strongly suggest that some of the alleles relevant to multispecific 'low' antibody production could contribute to the resistance to cutaneous chemical tumorigenesis.
Assuntos
Carcinógenos/toxicidade , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/imunologia , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Formação de Anticorpos , Testes de Carcinogenicidade , Suscetibilidade a Doenças/imunologia , Camundongos , Especificidade da Espécie , Acetato de Tetradecanoilforbol/toxicidadeRESUMO
Among the differences observed between the various high (H) and low (L) antibody responder lines of mice resulting from distinct bidirectional selective breedings, one of the most puzzling is the variation in the "multispecific effect," i.e., in the modification of antibody responses to antigens unrelated to those used during the selection. The best examples are the H and L lines of selection IV, selected on the basis of responses to somatic antigen of Salmonella which do not differ in their antibody responses to sheep erythrocytes (SE). However, a wide range of variability is observed in the responses of (HIV X LIV)F2 hybrids to this antigen, and it was therefore hypothesized that distinct groups of genes might regulate antibody responses to SE and the somatic antigen. Indeed, a new selection (IV-A) for anti-SE responsiveness started from these (HIV X LIV)F2 successfully produced a high and a low anti-SE responder line. The results of selection IV-A and the variance analysis of (HIV-A X LIV-A)F2 hybrids are reported. They are roughly similar to those in selection I, also carried out for anti-SE responsiveness. In vivo attempts to identify the major regulatory mechanism which contributes to the interline difference indicate that the efficiency of macrophage accessory function has been modified in selection IV-A, as was observed in selection I, whereas this function did not differ in HIV and LIV lines. Probably in relation to the involvement of macrophage function there is a notable increase of the multispecific effect in selection IV-A when compared with selection IV. The results of selection IV-A demonstrate that responsiveness to heterologous erythrocytes and to somatic antigen of Salmonella are under separate polygenic control operating through distinct regulatory mechanisms. The choice of the selection antigen and immunization procedure is of major importance for defining the gene interaction operating in each selective breeding experiment and the extent of its multispecific effect.
Assuntos
Formação de Anticorpos , Antígenos/imunologia , Animais , Diversidade de Anticorpos , Antígenos de Bactérias/imunologia , Cruzamentos Genéticos , Eritrócitos/imunologia , Camundongos , Salmonella typhimurium/imunologia , Seleção GenéticaRESUMO
Anti-infectious immunity is the main component in host-resistance, and the basis of vaccination efficacy. The lines of mice selected for high or low (H or L) immune responsiveness, in which opposite extreme potentialities have been clearly defined, offer an appropriate model for investigating the genetic factors of resistance to infections. In fact, post-immunization antibody titers happen to be more than 200 times higher in H than in L antibody responder mice, whatever the antigen specificity. This is owing to the additive effect of genes located at about 10 loci, one of which is the MHC. Innate resistance to intracellular pathogens is higher in L than in H mice, owing to the differences in the macrophages activity within the two lines: antigen catabolism is faster in L macrophages, which also prove more efficient in controlling early bacterial growth. The fact that these two functions are under a common genetic regulation has recently been brought to light. As was expected, H mice have a stronger innate and acquired resistance to all the infections that can be cleared by means of antibody production. Differences between H and L mice for innate and acquired immunity are quantitative, that is: time- and dose-dependent. The alternative advantages of H or L phenotype are discussed, as regards efficacy of the immune system in natural populations, and may stand for the persistence of polymorphism at loci endowed with high selective value.
Assuntos
Animais , Camundongos , Imunidade Inata , Imunidade/genética , Duplicação Gênica , Metabolismo/genética , Seleção GenéticaRESUMO
The high (H) and low (L) antibody responder lines of mice produced by selective breeding are characterized by different modifications in immunocompetent cell potentialities, according to the immunization procedure used for the selection process. In selections I and II, the difference in antibody responsiveness between H and L lines was clearly shown to depend mainly on macrophage function: the more rapid catabolism of antigens in L mice was the main cause of the low antibody production. In contrast, up to now, no difference has been observed between H and L mice of selections III and IV in terms of the macrophage accessory role. The administration of silica particles has a well known impairment effect on macrophage activity. Therefore, the effect of silica injection on the kinetics of antibody responses to selection antigens was compared in H and L mice of the four selections. Silica was given either intravenously or locally in one hind footpad 6 or 24 h before immunization by the same route. Silica treatment consistently improved antibody responsiveness in the L mice of selections I and II, but had no effect in the L mice of selections III and IV. The antibody responses of the H lines of the four selections were not substantially modified by silica injections. Therefore, the silica treatment reduced the interline difference in antibody responses in selections I and II only, by interfering with the expression of the genetic modification of macrophage activity. However, a similar effect was not obtained with other substances known to affect macrophages, including dextran sulphate or carrageenan. The results reported here are in agreement with the above-mentioned statement that the genetic modification of macrophage function plays a major role in the interline difference in selections I and II and is not involved in selections III and IV.
Assuntos
Formação de Anticorpos/efeitos dos fármacos , Animais , Antígenos/administração & dosagem , Eritrócitos/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Imunização , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , CamundongosRESUMO
The selective breeding for antibody production against bovine serum albumin (BSA) and rabbit gamma-globulin (RGG) induced a large modification in responsiveness in the high (Hv) and low (Lv) responder lines at selection limit. The total response to selection (RT) was 9.0 log2 for BSA and 8.4 log2 for RGG. This gives an interline difference of 500-fold and 337-fold respectively in terms of passive agglutinin titres. For BSA responsiveness, there is, in F1 interline hybrids, an incomplete dominance effect of the low character (-0.41) and a marked maternal effect. Complete dominance effect of high character (1.08) without any maternal effect is observed for responses to RGG. The phenotypical variability of BSA responses in F2 segregants is due 60% to genetic factors and 40% to environmental effects. Such a distribution cannot be achieved for RGG responsiveness. Both responses to BSA and RGG are controlled by the additive effect of several independent loci (polygenic regulation). One of these genes is linked with the H-2 locus. The H-2 linked gene accounts for 29% of the total interline difference for response to BSA and only 11% for response to RGG. Experiments carried out to measure the reciprocal nonspecific effect of BSA and RGG responses failed to give clear-cut results. This important phenomenon will be the subject of the companion article.
Assuntos
Anticorpos/genética , Formação de Anticorpos , Camundongos/genética , Soroalbumina Bovina/imunologia , gama-Globulinas/imunologia , Animais , Cruzamento , Bovinos , Genes MHC da Classe II , Antígenos H-2/genética , Camundongos/imunologia , Coelhos , Seleção GenéticaRESUMO
In order to measure the reciprocal nonspecific effect of the genetic regulation of antibody responsiveness to bovine serum albumin (BSA) and rabbit gamma-globulin (RGG), two independent bidirectional selective breedings for responses to these two antigens were carried out: selection V/BSA and selection V/RGG respectively. The total interline separation at selection limit (RT) was 5.3 log2 for selection V/BSA and 2.6 log2 for selection V/RGG. The sum of these two values (7.9 log2) is similar to the RT in selection V carried out by alternating these two antigens in consecutive generations. In selection V/BSA, the nonspecific effect for responsiveness to RGG was 72%. In selection V/RGG, the nonspecific effect for BSA responsiveness was 135%. The F1 hybrids between homologous lines of selection V/BSA and selection V/RGG presented a larger difference in antibody response to both antigens than their parental lines. This demonstrates an additive effect of the loci controlling the two responses.
Assuntos
Anticorpos/genética , Formação de Anticorpos , Camundongos/genética , Soroalbumina Bovina/imunologia , gama-Globulinas/imunologia , Animais , Cruzamento , Bovinos , Regulação da Expressão Gênica , Genes MHC da Classe II , Camundongos/imunologia , Coelhos , Seleção GenéticaRESUMO
The intensity of delayed-type hypersensitivity (DTH) expression measured by footpad swelling was established in high and low antibody responder lines of mice produced by bidirectional selective breeding for antibody responsiveness to different antigens. These lines of mice presented a very large difference in antibody response to the antigens used in each selective breeding (selection Ags) and to several other unrelated Ags (nonspecific effect). The intensity of DTH reactivity to selection Ags and to unrelated Ags differed in the various lines investigated, but the intensity of DTH reactions was not correlated with antibody responsiveness. The results of the present article demonstrated that the expression of DTH reactivity and antibody responsiveness to the same antigens are polygenic characters subject to independent quantitative regulation.