Responses In Mouse Strains Research Articles

Differential lung gene expression changes in C57BL/6 and DBA/2 mice carrying an identical functional Mx1 gene reveals crucial differences in the host response

BackgroundInfluenza virus infections represent a major global health problem. The dynamin-like GTPase MX1 is an interferon-dependent antiviral host protein that confers resistance to influenza virus infections. Infection models in mice are an important experimental system to understand the host response and susceptibility to developing severe disease following influenza infections. However, almost all laboratory mouse strains carry a non-functional Mx1 gene whereas humans have a functional MX1 gene. Most studies in mice have been performed with strains carrying a non-functional Mx1 gene. It is therefore very important to investigate the host response in mouse strains with a functional Mx1 gene.ResultsHere, we analyzed the host response to influenza virus infections in two congenic mouse strains carrying the functional Mx1 gene from the A2G strain. B6.A2G-Mx1r/r(B6-Mx1r/r) mice are highly resistant to influenza A virus (IAV) H1N1 infections. On the other hand, D2(B6).A2G-Mx1r/r(D2-Mx1r/r) mice, although carrying a functional Mx1 gene, were highly susceptible, exhibited rapid weight loss, and died. We performed gene expression analysis using RNAseq from infected lungs at days 3 and 5 post-infection (p.i.) of both mouse strains to identify genes and pathways that were differentially expressed between the two mouse strains. The susceptible D2-Mx1r/r mice showed a high viral replication already at day 3 p.i. and exhibited a much higher number of differentially expressed genes (DEGs) and many DEGs had elevated expression levels compared to B6-Mx1r/r mice. On the other hand, some DEGs were specifically up-regulated only in B6-Mx1r/r mice at day 3 p.i., many of which were related to host immune response functions.ConclusionsFrom these results, we conclude that at early times of infection, D2-Mx1r/r mice showed a very high and rapid replication of the virus, which resulted in lung damage and a hyperinflammatory response leading to death. We hypothesize that the activation of certain immune response genes was missing and that others, especially Mx1, were expressed at a time in D2-Mx1r/r mice when the virus had already massively spread in the lung and were thus not able anymore to protect them from severe disease. Our study represents an important addition to previously published studies in mouse models and contributes to a better understanding of the molecular pathways and genes that protect against severe influenza disease.

T1BT* structural study of an anti-plasmodial peptide through NMR and molecular dynamics

BackgroundT1BT* is a peptide construct containing the T1 and B epitopes located in the 5’ minor repeat and the 3’ major repeat of the central repeat region of the Plasmodium falciparum circumsporozoite protein (CSP), respectively, and the universal T* epitope located in the C-terminus of the same protein. This peptide construct, with B = (NANP)3, has been found to elicit antisporozoite antibodies and gamma-interferon-screening T-cell responses in inbred strains of mice and in outbred nonhuman primates. On the other hand, NMR and CD spectroscopies have identified the peptide B’ = (NPNA)3 as the structural unit of the major repeat in the CSP, rather than the more commonly quoted NANP. With the goal of assessing the structural impact of the NPNA cadence on a proven anti-plasmodial peptide, the solution structures of T1BT* and T1B’T* were determined in this work.MethodsNMR spectroscopy and molecular dynamics calculations were used to determine the solution structures of T1BT* and T1B’T*. These structures were compared to determine the main differences and similarities between them.ResultsBoth peptides exhibit radically different structures, with the T1B’T* showing strong helical tendencies. NMR and CD data, in conjunction with molecular modelling, provide additional information about the topologies of T1BT* and T1B’T*. Knowing the peptide structures required to elicit the proper immunogenic response can help in the design of more effective, conformationally defined malaria vaccine candidates. If peptides derived from the CSP are required to have helical structures to interact efficiently with their corresponding antibodies, a vaccine based on the T1B’T* construct should show higher efficiency as a pre-erythrocyte vaccine that would prevent infection of hepatocytes by sporozoites.

Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility.

High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, <10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p = 0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer.

Quantitative Differences in Immune Responses in Mouse Strains that Differ in their Susceptibility to Trypanosoma brucei brucei Infection

We compared the relative resistance and soluble variant surface glycoprotein (VSG)-specific responses in (C57BL/6 x BALB/c)-F1 (B6B-F1) and C3H mice during infection with Trypanosoma brucei brucei, the hemoprotozoan parasite causing a debilitating disease in man and livestock. We demonstrated that C3H mice are relatively more trypanosusceptible, as evidenced by their reduced ability to control parasitemia and shorter survival time, than B6B-F1 mice. Quantitative differences in the pattern of cytokine and antibody (Ab) production were observed between the 2 mouse strains following infection with T. b. brucei. Thus, although both mouse strains recorded detectable levels of IFN-gamma, TNF-alpha, NO and IL-10 in plasma and lymph nodes, as well as plasma IgM, IgG1, IgG2a, IgG2b and IgG3 Abs against VSG, the susceptible C3H mice only exhibited trace levels of Abs of all isotypes and yet produced elevated levels of IFN-gamma, TNF-alpha and NO, compared to the relatively trypanotolerant B6B-F1 mice. In aggregate, these data strongly suggest that trypanosome-infected C3H mice have an immunological defect, manifested not only by suppression at the B cell clonal level, but also at the level of protective T cell and macrophage phenotypes.

Exposure to mercuric chloride during the induction phase and after the onset of collagen‐induced arthritis enhances immune/autoimmune responses and exacerbates the disease in DBA/1 mice

In susceptible mice, mercuric chloride induces a systemic autoimmune response that is characterized by elevated serum levels of immunoglobulin G1 (IgG1) and immunoglobulin E (IgE), production of anti-nucleolar antibodies (ANolAs) and the formation of renal IgG deposits. We have previously shown that mercury can also enhance immune/autoimmune responses in mouse strains genetically prone to develop spontaneous autoimmune disease. Here, we investigated whether mercury can enhance the severity of murine collagen-induced arthritis (CIA), an inducible (acquired) autoimmune disease that cannot be induced by mercury itself. While mercury administered prior to the induction phase of CIA exerted little, if any, influence, administration of mercury during the induction phase and following onset aggravated the symptoms of this disease and increased the serum levels of IgE and IgG2a antibodies directed against collagen type II (CII). Furthermore, while animals injected with mercury alone exhibited a significant decrease in the ratio of the levels of interferon-gamma (IFN-gamma) to interleukin-4 (IL-4) mRNA in their spleens, this ratio was increased in mice with CIA, with or without administration of mercury. Finally, the production of anti-nuclear antibodies, a hallmark of autoimmunity in response to mercury, was observed in all mice with CIA treated with this heavy metal. Our findings suggest that exposure to mercury during the development of CIA may influence immunological factors in such a way as to synergistically promote disease development.

The TGF-beta response to Leishmania chagasi in the absence of IL-12.

Cure of leishmaniasis requires a type 1 immune response characterized by IFN-gamma production. Leishmania major infection leads to a type 2 response suppressing cure of susceptible BALB/c mice, and L. major causes an exacerbated type 2 response in mouse strains with a gene knockout (KO) such that they lack IL-12p40 (IL-12KO mice). In contrast, type 1 responses are inhibited by TGF-beta without Th2 cell expansion in BALB/c mice infected with L. chagasi. We questioned whether the type 2 or the TGF-beta response would dominate during L. chagasi infection of IL-12KO mice. C57BL/6 mice developed self-resolving L. chagasi infection with abundant IFN-gamma. In contrast, L. chagasi disease was exacerbated and IFN-gamma was low in IL-12KO mice. Total TGF-beta was significantly higher in IL-12KO than control C57BL/6 mice, but IL-4 and IL-10 levels were similar. TGF-beta was further augmented in IL-12/IFN-gamma double-KO mice. Thus, in contrast to L. major, the TGF-beta response was exacerbated whereas type 2 cells were not expanded during L. chagasi infection of IL-12KO mice. We conclude that L. chagasi has an inherent propensity to elicit a prominent TGF-beta response that either suppresses, or is suppressed by, a type 1 response. We propose this be termed a "type 3" immune response, which can antagonize a type 1 response.

The need for IgG2c specific antiserum when isotyping antibodies from C57BL/6 and NOD mice

Isotyping and quantitation of murine IgG2a antibodies are widely performed with commercial monoclonal and polyclonal antisera raised against BALB/c IgG2a myeloma proteins. Recently it became evident that inbred mouse strains with the Igh1-b allele do not have the gene for IgG2a and instead express the IgG2c isotype. We show that commercial anti-IgG2a sera cross-react inadequately against IgG2c in immunoblot and ELISA and hence, are not suitable to detect and measure this subclass in mouse strains such as C57BL/6, C57BL/10 and NOD. We have used DNA immunization to generate polyclonal anti-IgG2c serum and demonstrated that it is essential to use IgG2c-specific antiserum to quantify accurately isotypic responses in mouse strains with the Igh1-b allele.

Inflammatory and Epithelial Responses in Mouse Strains That Differ in Sensitivity to Hyperoxic Injury

The pulmonary response to various toxicants including bleomycin, ozone, ionizing radiation, and hyperoxia is highly variable among mouse strains. The current study tests the hypothesis that at a similar stage of injury, regardless of strain, expression of inflammatory cytokine and epithelial marker genes would be similar, indicating a common pathway of injury progression. Three strains of mice, C57B1/6J, 129/J, and C3H/HeJ, ranging from sensitive to resistant, were exposed to >95% O2 for varying times. Ribonuclease protection was used to quantify changes in cytokine mRNA. Despite differences in the kinetics, each strain demonstrated similar hyperoxia-induced changes in the abundance of interleukin (IL)-6, IL-4β, IL-3, and tumor neucrosis factor (TNF)-α. For each strain, death was accompanied by similar increases in cytokine mRNAs above steady-state control levels. Other inflammatory cytokines, including IL-lα, IL-4, and interferon (IFN)-γ, were unaltered in all strains at all times. In situ hybridization analysis of the epithelial markers, surfactant protein B (SPB), and clara cell secretory protein (CCSP) at the time of proinflammatory induction showed a similar pattern of expression in all strains. Increased SPB was detected in bronchiolar epithelium, while the number of type II cells expressing this message declined. Both the number of cells expressing CCSP as well as abundance per cell declined. These results suggest that although differences in acute sensitivity to hyperoxia exist between mouse strains, once initiated, acute epithelial cell injury and associated inflammatory changes follow the same, pattern in all strains.

Oral vaccination against coccidiosis: responses in strains of mice that differ in susceptibility to infection with Eimeria vermiformis.

Four strains of mice with different susceptibilities to Eimeria vermiformis were orally dosed with a crude antigen prepared from sporulated oocysts of the parasite, with or without cholera toxin as adjuvant. The effect on subsequent challenge infections depended on the resistance and susceptibility phenotypes of the host: oocyst production was reduced in susceptible C57BL/6 and NIH mice but increased in resistant BALB/c and C3H mice. Despite this contrast, no fundamental differences were detected between the immune responses of BALB/c and C57BL/6 mice, either to vaccination or after superimposed infection, but the suppressing and enhancing effects of vaccination were transmissible to naive recipients via suspensions of mesenteric lymph node cells. The results obtained are compared with those previously reported for parenterally immunized BALB/c and C57BL/6 mice.

Humoral immune responses to systemic Candida albicans infection in inbred mouse strains

The protective role of humoral antibodies in the resolution of systemic candidiasis remains controversial. Investigation of the humoral immune responses in mouse strains of varying susceptibility to infection may demonstrate a link between mouse strain susceptibility, antibody production and specificity, and the ability to resolve an infection. The antibody response in five different strains of mice during primary immune response to systemic infection with Candida albicans was investigated. Immune sera were fractionated by protein A affinity chromatography to yield fractions containing IgG1, IgG2a and IgG2b immunoglobulins. BALB/c mice of low susceptibility to the infection and DBA/2J mice of high susceptibility produced increased levels of the IgG1 isotype and decreased levels of the IgG2a isotype. AKR, CBA/H and C57B1/6J mice of moderate susceptibility produced antibodies predominantly of the IgG2a isotype. The patterns of antigen recognition by antibodies in immune sera and in fractions obtained after protein A chromatography of immune sera were investigated by western blotting and immunostaining. Antibodies from AKR(H-2K) and CBA/H (H-2k) mice reacted strongly after immunoblotting with antigens of 87 and 96 kDa. In contrast, immune sera from both the highly susceptible DBA/2J (H-2d) mice and the resistant BALB/c (H-2d) mice reacted strongly with an antigen of 48 kDa. C57B1/6J (H-2b) mice produced variable antibody reactivity to antigens of 48, 65, 66 and 79 kDa depending on the IgG subclass tested. The IgG subclass responses and the patterns of antigen recognition in these mice suggest that humoral responses to C. albicans may be restricted by H-2 haplotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of peptide binding patterns in different major histocompatibility complex/T cell receptor complexes using pigeon cytochrome c-specific T cell hybridomas. Evidence that a single peptide binds major histocompatibility complex in different conformations.

The interaction of TCR, antigen, and MHC complex has been analyzed using synthetic peptide antigens and a series of single amino acid-substituted analogues. Two similar antigens, mouse cytochrome c (mcyt c) and pigeon cytochrome c (pcyt c), elicit T cell responses in strains of mice bearing MHC class II Ek beta Ek alpha (B10.A), Eb beta Ek alpha [B10.A(5R)], and Es beta Ek alpha [B10.S(9R)]. The immunogenic regions of these antigens are located in the peptide sequence p88-104 for pcyt c and m88-103 for mcyt c. The limited T cell repertoire for these antigens is comprised of four groups of T cell phenotypes that have very few differences in their TCR gene make up. In this paper, we examine the diversity in their fine specificity for each of the antigens, m88-103 and p88-104, complexed with each of the I-Ek haplotypes. Epitopes, i.e., residues that interact with the TCR, and agretopes, i.e., residues in the MHC-binding site, were assigned for the two peptide antigens in the presence of APC bearing E beta kEk alpha, Eb beta Ek alpha, or Eb beta Ek alpha using T cell hybridomas of the phenotypes I, IIIa, and IV. From our results, we conclude that first, the substitution of any residue between 95 and 104 of the cytochrome c peptide changed the antigenic potency of the peptide for at least one of the hybridomas. Second, each T cell type has a different recognition pattern of epitopes and agretopes for a particular antigen-MHC complex, thus, ruling out a static model of T cell recognition, which assigns certain, invariant agretopic residues to the peptide by which it interacts with the MHC molecule independently of the TCR. Third, the same T cell hybridoma responded to the antigens differently when presented on various MHC molecules, implying that overall changes in the MHC groove, as displayed by the three haplotypes, may affect the efficiency in binding the peptide. Fourth, since most of the residues are used as epitopes by at least one of the T cell specificities, the peptide appears to be recognized in a different conformation by each T cell hybridoma phenotype; and, finally, the epitopic and agretopic residues do not segregate, for any one of the T cell specificities, in such a way that suggests they are recognized in a helical conformation. In summary, our results suggest that a single peptide may generate diversity in the T cell response by virtue of its conformational flexibility within the TCR-MHC-antigen complex.

The Effect of Cyclosporin on Major Histocompatibility Complex-linked Resistance to Murine Cytomegalovirus

The ability of mice to survive infection with murine cytomegalovirus (MCMV) is known to be influenced by genes of the major histocompatibility complex (MHC). One hypothesis to account for this association is that MHC-linked resistance to MCMV is an 'immune response' gene effect, caused by differences in the strength of the MHC-restricted T cell response of mouse strains with different MHC haplotypes. Therefore, removal of T cell responses in mouse strains differing only at the MHC should render them equally susceptible to the virus infection. To test this hypothesis, the immunosuppressive drug cyclosporin (CsA) was used to reduce T cell responses in inbred congenic mouse strains carrying either a resistant or susceptible MHC haplotype. CsA reduced the delayed-type hypersensitivity (DTH) response to MCMV in both resistant and susceptible mouse strains to background levels, equivalent to control uninfected mice. CsA treatment had little effect on the susceptibility of C57BL/10 and B10. BR mice to the virus and the differences in susceptibility between these strains remained. In contrast, CsA increased the susceptibility of the genetically susceptible BALB/c mice (H-2d) by 100-fold and increased the susceptibility of resistant BALB.K mice (H-2k) by 15-fold. Thus the H-2-determined difference in susceptibility between these strains was increased after CsA treatment. The results obtained with congenic strains show that MHC-linked resistance patterns to MCMV are not eliminated by CsA and suggest therefore that T cells are not responsible for this phenomenon. Interestingly, the mean time to death was delayed for CsA-treated BALB/c mice compared with untreated mice given equivalent virus doses. In addition, although CsA prevented DTH responses in both genetically susceptible A/J (H-2a) and resistant CBA (H-2k) mice, CsA treatment markedly increased the susceptibility of A/J mice (32-fold) but had little effect on the susceptibility of CBA mice to the virus.

Divergence of the Role of Acute Phase Protein Responses in Autoimmune Strains of Mice

Divergence of the Role of Acute Phase Protein Responses in Autoimmune Strains of Mice

Induction of protective immunity against Schistosoma mansoni by a nonliving vaccine. II. Response of mouse strains with selective immune defects.

The efficacy of a new vaccination procedure against Schistosoma mansoni, involving intradermal injection of nonliving antigen combined with the bacterial adjuvant Mycobacterium bovis strain bacillus Calmette Guérin, was tested in several strains of mice. Development of protection against subsequent infection was compared with in vivo skin test reactivity and in vitro humoral reactivity to soluble and surface-associated schistosome antigens. Significant levels of resistance and immune response were displayed by many inbred mouse strains, including C57BL/6J, C3H/HeN, and CBA/J, as well as outbred Swiss-Webster mice. However, no definite correlation was observed between the level of any particular immune response and the level of resistance to challenge S. mansoni infection. Development of protective immunity was also examined in mice with various immune defects, to determine whether these responses are relevant to resistance in this model. Animals with defective specific immediate hypersensitivity response due to deficiencies in IgE (SJL/J) or mast cell (W/Wv) production displayed strong resistance as a result of immunization. Likewise, mice bearing the lpsd (C3H/HeJ) or xid (CBA/N) mutations, affecting cellular or humoral response to certain thymus-independent antigens, developed significant levels of resistance after immunization. A/J mice, with defects in cellular recognition of bacterial endotoxin as well as deficiencies in natural killer cell activity and complement function, also showed significant protective immunity. Thus, these reactivities do not appear to be essential to the resistance against S. mansoni induced by the nonliving vaccine. Two nonresponder strains were identified, P and BALB/c. P mice were defective in specific delayed hypersensitivity response as well as resistance to infection. However, BALB/c mice showed no obvious immune deficiencies at the time of challenge. These results agreed with previous findings in mice immunized by exposure to radiation-attenuated cercariae with one exception; BALB/c mice were protected by vaccination with irradiated cercariae but not by the nonliving vaccine. Thus, further examination of immune response in mice identified in this study as high and low responder strains should allow characterization of critical immune resistance mechanisms induced by the nonliving vaccine, as well as immune mechanisms operating in common between these two models of resistance to S. mansoni.

Regulation of allotype-linked NPb idiotype by an idiotype-positive soluble factor derived from a T cell hybridoma. Coupling of the circuit regulation to the network concept.

We reported in this paper genetic requirements for the suppression of anti-4-hydroxy-3-nitrophenylacetyl (NP) antibody response induced by an NP-specific, Igh-1 linked idiotype (NPb) positive T suppressor factor (NPb-TsF) derived from a T cell hybridoma 7C3-13 of B10.BR (Igh-1b, H-2k) mouse origin. NPb-TsF could suppress the responses mounted by primed spleen cells of all IgVH compatible strains regardless of their H-2 haplotypes. The majority of the anti-NP antibody response suppressed by NPb-TsF was idiotype positive (Id+). NPb-TsF was also capable of suppressing the responses of H-2 compatible but Igh incompatible strains where responding cells do not produce NPb idiotype. NPb-TsF was incapable of suppressing the responses of mouse strains who are incompatible both in IgVH and H-2 loci, indicating that the identity in either IgVH or H-2 genes between NPb-TsF and responding cells was necessary for the initiation of the suppression by NPb-TsF. It was further found that the NPb-TsF utilizes anti-idiotypic Lyt-1+2+3+ T cells (transducer cells), which are present only in IgVH compatible strains, to ultimately suppress the Id+ antibody production by B cells. These results indicate that there exists a pathway where an idiotypic NPb-TsF activates a suppressor circuit mediated via the idiotype-antiidiotype interactions apart from the previously described carrier-specific and H-2 restricted suppressor circuit. Both pathways involve the 'transduction' step utilizing Lyt-1+2+3+ intermediary T cells. Our experiments provide important clues for coupling the two major immunological concepts, network and circuit.

Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae : I. Analysis of antibody and T-lymphocyte responses in mouse strains developing differing levels of immunity

The kinetics of cellular and humoral responses directed against schistosomula were examined in mice of three inbred strains which demonstrate differences in the degree of resistance induced by immunization with irradiated cercariae. T-Cell reactivity was observed during the first 4 weeks after vaccination but declined to control levels thereafter. Anti-schistosomulum antibody was first detected 2 weeks after vaccination, peaked by 6 weeks, and persisted as late as 15 weeks. In sera obtained at 6 weeks, antibody activity was detected in affinity chromatography-purified fractions containing IgM, IgA, IgG 1, IgG 2a, and IgG 3 immunoglobulins. In general, the cellular and humoral responses observed in C57B1/6J mice, which consistently developed a high level of immunity after vaccination, were not significantly different from those observed in C3H/HeJ or CBA/J mice, which achieved only low to moderate levels of immunity. Thus, although antibody production appears to correlate more closely than T lymphocyte responsiveness with the typical long-term resistance pattern observed in this model, the absence of striking differences in parasite-specific antibody levels between mice of these different strains suggests that additional mechanisms may be involved in the development of immunity after vaccination.

Genetic control of phytohemagglutinin responsiveness by murine spleen cells and correlation between the release of lymphotoxins and DNA synthesis.

AbstractResponse to phytohemagglutinin was investigated in adult mouse spleen cells of congenic strains which differ only at the H‐2 locus. The stimulation of spleen cells was assessed by release of lymphotoxins and DNA synthesis.The results obtained show that the response to PHA markedly varied according to the genetic origin of spleen cells. Cells with H‐2a and H‐2b specificities responded better to PHA than those with H‐2f and H‐2s specificities. Furthermore, there was good correlation between the amount of released lymphotoxins and the level of DNA synthetic response.These results are discussed on the basis of an H‐2 linked genetic control of PHA response in mouse strains.

A cellular basis for genetically controlled immunologic unresponsiveness in mice: tolerance induction in T-cells.

H-2(q) mice (DBA/1) do not make an antibody response to a synthetic aminoacid polymer, (Glu, Ala,Tyr(10)), after an immunizing regimen that produces a good antibody response in mouse strains with other H-2 alleles. Their thymocytes, however, show evidence of recognizing this antigen since they synthesize DNA when they meet the antigen in the spleen. This recognition event does not lead to memory production, as it does in genetic responders, since the thymocytes fail to respond to a second immunization with (Glu,Ala,Tyr(10)). Nonresponder mice do make antibody to (Glu,Ala,Tyr(10)) when they are immunized with it complexed to an immunogenic carrier, but previous treatment with free polymer can temporarily abolish this response. Thus, we suggest that the basis for the unresponsiveness of these mice is that their T-cells (thymus-processed lymphocytes) have an inordinate propensity to become (or to induce other cells to become) immunologically tolerant.

Differences in antibody responses of mouse strains to enterobacterial common antigen.

SummaryThe genetic influence of various mouse strains on antibody response to the common antigen (CA) of Enterobacteriaceae was determined. Four strains of mice, three inbred and one random-bred, were injected ip with CA of E. coli 014 or 0111, with or without incomplete Freund's adjuvant. CA antibody titers, determined by hemagglutination tests, revealed the following: CBA/St and C57BL/6Ha mice responsed significantly better than did DBA/2Jax and Swiss albino mice; ethanol-soluble CA from E. coli 0111 was a better immunogen than was CA from E: cold 014; adjuvant did not enhance immunogenicity of CA in responding mice; highest titers were noted 5 days after the third injection of CA, persisted for 2 weeks, and declined by the end of 2 months; and a subsequent injection of CA failed to elicit a secondary response.