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PubMed1987

The augmentation of tumor-specific immunity using haptenic muramyl dipeptide (MDP) derivatives. II. Establishment of tumor-specific immunotherapy models utilizing MDP hapten-reactive helper T cell activity.

Preinduction of potent haptenic muramyl dipeptide (MDP)-reactive helper T cell activity and subsequent immunization with MDP hapten-coupled syngeneic tumor cells resulted in enhanced induction of tumor-specific immunity through T-T cell collaboration between anti-MDP hapten helper T cells and tumor-specific effector T cells. The present study establishes two types of tumor-specific immunotherapy protocols utilizing helper T cells against MDP hapten cross-reactive with Bacillus Calmette Guérin (BCG). In the first model, naive normal C3H/He mice or mice in which MDP hapten-reactive helper T cells had been generated by BCG-sensitization were inoculated i.d. with syngeneic X5563 tumor cells. When both groups of mice were allowed to generate MDP hapten-modified tumor cells in the tumor mass in situ by intratumoral injection of MDP hapten, an appreciable number of growing tumors in the BCG-presensitized but not in the unsensitized group were observed to regress. In the second model, a growing X5563 tumor mass was removed by the surgical resection 9 days after the tumor implantation. Approximately 90% of C3H/He mice receiving such treatment died from tumor metastasis by about 30 days after the tumor resection. However, immunization of mice with MDP hapten-coupled X5563 tumor cells subsequent to the tumor resection resulted in an increased survival rate. Such protection from the tumor metastasis was appreciably stronger when compared to the protection obtained by immunization with MDP hapten-uncoupled tumor cells. The mice surviving in both models were also demonstrated to retain X5563 tumor-specific immunity. These results indicate that the presentation of MDP hapten-modified tumor cells to BCG-sensitized recipients results in potent tumor-specific immunity which contributes to the regression of the primary tumor or inhibition of metastatic tumor growth.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1978

Restricted helper function of F1 hybrid T cells positively selected to heterologous erythrocytes in irradiated parental strain mice. I. Failure to collaborate with B cells of the opposite parental strain not associated with active suppression.

Unprimed (CBA X C57BL/6)F1 lymph node T cells were transferred with sheep erythrocytes (SRC) into heavily irradiated F1 or parental strain mice and recovered from thoracic duct lymph or spleens of the recipients 5 days later. To study their helper function, the harvested F1 T cells were transferred with antigen into irradiated F1 mice plus B cells from either the two parental strains or from F1 mice. F1 T cells activated in F1 mice gave high IgM and IgG anti-SRC responses with all three populations of B cells. By contrast, F1 T cells activated in mice of one parental strain collaborated well with B cells of this strain, but poorly with B cells of the opposite strain. Active suppression was considered an unlikely explanation for this result since (a) good responses were found with F1 B cells, and (b) addition experiments showed that the poor response with B cells of the opposite parental strain (which was equivalent to that produced by unprimed F1 T cells) could be converted to a high response by a supplemental injection of F1 T cells activated in F1 mice. The phenomenon (a) was specific for the antigen used for activation (criss-cross experiments were performed with horse erythrocytes), (b) was reflected in levels of serum hemagglutinins as well as in numbers of splenic plaque-forming cells, (c) applied also to comparable activation of (DBA/2 X C57BL/6)F1 T cells, and (d) could be prevented by activating F1 T cells in mice of one parental strain in the presence of peritoneal exudate cells of the opposite parental strain. The hypothesis was advanced that F1 T cells contain two discrete subpopulations of antigen-reactive cells, each subject to restrictions acting at two different levels: (a) during T-macrophage interactions and (b) during T-B collaboration. It was suggested that when F1 T cells are activated to antigen in a parental strain environment, radioresistant macrophages activate only one of the two subgroups of T cells, and this subgroup is able to collaborate with B cells of the strain used for activation (and with F1 B cells) but not with B cells of the opposite parental strain. The other subgroup of T cells remains in an unprimed (nonactivated) state.

Animals↗

PubMed2005

The mouse genome.

The house mouse has been used as a privileged model organism since the early days of genetics, and the numerous experiments made with this small mammal have regularly contributed to enrich our knowledge of mammalian biology and pathology, ranging from embryonic development to metabolic disease, histocompatibility, immunology, behavior, and cancer. Over the past two decades, a number of large-scale integrated and concerted projects have been undertaken that will probably open a new era in the genetics of the species. The sequencing of the genome, which will allow researchers to make comparisons with other mammals and identify regions conserved by evolution, is probably the most important project, but many other initiatives, such as the massive production of point or chromosomal mutations associated with comprehensive and standardized phenotyping of the mutant phenotypes, will help annotation of the approximately 25,000 genes packed in the mouse genome. In the same way, and as another consequence of the sequencing, the discovery of many single nucleotide polymorphisms and the development of new tools and resources, like the Collaborative Cross, will contribute to the development of modern quantitative genetics. It is clear that mouse genetics has changed dramatically over the last 10-15 years and its future looks promising.

Animals↗

PubMed2004

CD7 and CD28 are required for murine CD4+CD25+ regulatory T cell homeostasis and prevention of thyroiditis.

CD7 and CD28 are T cell Ig superfamily molecules that share common signaling mechanisms. To determine roles CD7 and CD28 might play in peripheral lymphocyte development and function, we have generated CD7/CD28-double-deficient mice. CD7- and CD28-single-deficient and CD7/CD28-double-deficient mice had normal levels of CD4 and CD8-single-positive T cells in thymus and spleen. However, CD28-deficient mice had decreased CD4+CD25+ T cells in spleen compared with wild-type mice, and CD7/CD28-double-deficient mice had decreased numbers of CD4+CD25+ T cells in both thymus and spleen compared with both wild-type and CD28-deficient mice. Functional studies demonstrated that CD4+CD25+ T cells from CD28-deficient and CD7/CD28-double-deficient mice could mediate suppression of CD3 mAb activation of CD4+CD25- wild-type T cells, but were less potent than wild-type CD4+CD25+ T regulatory cells. Thyroiditis developed in aged CD7/CD28-double-deficient mice (>1 year) that was not seen in age-matched control mice or single CD7- or CD28-deficient mice, thus suggesting in vivo loss of T regulatory cells allowed for the development of spontaneous thyroiditis. Taken together, these data demonstrated collaborative roles for both CD7 and CD28 in determination of number and function of CD4+CD25+ T regulatory cells in the thymus and peripheral immune sites and in the development of spontaneous thyroiditis.

Aging↗

PubMed2005

NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins.

The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database (http://www.ncbi.nlm.nih.gov/RefSeq/) provides a non-redundant collection of sequences representing genomic data, transcripts and proteins. Although the goal is to provide a comprehensive dataset representing the complete sequence information for any given species, the database pragmatically includes sequence data that are currently publicly available in the archival databases. The database incorporates data from over 2400 organisms and includes over one million proteins representing significant taxonomic diversity spanning prokaryotes, eukaryotes and viruses. Nucleotide and protein sequences are explicitly linked, and the sequences are linked to other resources including the NCBI Map Viewer and Gene. Sequences are annotated to include coding regions, conserved domains, variation, references, names, database cross-references, and other features using a combined approach of collaboration and other input from the scientific community, automated annotation, propagation from GenBank and curation by NCBI staff.

Animals↗

PubMed2001

Functional association of CD9 with the Fc gamma receptors in macrophages.

CD9, a member of the tetraspan family of proteins, is highly expressed on macrophages. Although a clear function for the molecule has yet to be described, we have found that the anti-CD9 mAb activates mouse macrophages. The rat anti-CD9 mAb, KMC8.8, but not the F(ab')(2), induced tyrosine phosphorylation of proteins including syk and cbl and induced cell aggregation in the mouse macrophage cell line, J774, suggesting that co-cross-linking of CD9 and Fc gamma R was required for the signal. Co-cross-linking of CD9-Fc gamma R with KMC8.8 on macrophages from three different FcR-deficient mice, FcR gamma-chain(-/-), Fc gamma RIIB(-/-), and Fc gamma RIII(-/-), revealed that Fc gamma RIII is specific and crucial for syk phosphorylation. Although both KMC8.8 and the anti-Fc gamma RIIB/III mAb, 2.4G2, evoked similar phosphorylation patterns, only KMC8.8 induced cell aggregation. Additionally, KMC8.8 treatment led to reduce levels of TNF-alpha production and p42/44 extracellular signal-related kinase phosphorylation relative to 2.4G2 stimulation. Immunofluorescence staining showed that co-cross-linking of CD9-Fc gamma R with KMC8.8 induced filopodium extension before cell aggregation, which was followed by simultaneous colocalization of CD9, Fc gamma RIIB/III, Mac-1, ICAM-1, and F-actin at the cell-cell adhesion site. Moreover, KMC8.8 treatment of Fc gamma R-deficient macrophages revealed that the colocalization of CD9, Fc gamma RIII, Mac-1, and F-actin requires co-cross-linking of CD9-Fc gamma RIII, whereas co-cross-linking of CD9-Fc gamma RIIB induced the colocalization of only CD9 and Fc gamma RIIB. Our results demonstrate that co-cross-linking of CD9 and Fc gamma Rs activates macrophages; therefore, CD9 may collaborate with FcRs functioning in infection and inflammation on macrophages.

Actins↗

PubMed1992

Molecular and genetic analysis of liver oncogenesis in transforming growth factor alpha transgenic mice.

Overexpression of a transforming growth factor alpha (TGF-alpha) transgene induced the development of liver tumors in 69 of 93 (74%) adult male mice. To identify factors associated with oncogenesis, liver tumors from transgenic animals were characterized at the molecular level. TGF-alpha RNA transcripts were elevated in 17 of 25 (68%) liver tumors, relative to adjacent nontumorous tissue. Expression of the endogenous c-myc and insulin-like growth factor II genes was enhanced in 7 of 19 (37%) and 12 of 16 (75%) tumors, respectively. In contrast, epidermal growth factor receptor RNA levels were unchanged or reduced in all liver tumors, and mutations were not detected in either the Ha-ras or Ki-ras genes. The occurrence of liver tumors in castrated TGF-alpha transgenic mice was reduced about 7-fold, while in ovariectomized transgenic animals the incidence was increased about 6-fold. The progeny of a cross between CD1-derived TGF-alpha transgenic (MT42) and C57BL/6 mice exhibited no reduction in tumor burden (83%); however, the incidence of tumor formation in MT42 x FVB/N offspring was substantially lower (19%). We conclude that in these transgenic mice TGF-alpha promotes tumor formation and appears to play a major role in tumor progression. Moreover, other factors that may collaborate in TGF-alpha-induced hepatocarcinogenesis include c-myc, insulin-like growth factor II, sex hormones, and the genetic background upon which the transgene operates.

Animals↗

PubMed1996

Synergistic growth stimulation of mouse fibroblasts by tumor-derived adhesion factor with insulin-like growth factors and insulin.

Tumor-derived adhesion factor (TAF) has been purified as a major secretory protein with cell-adhesion activity from culture medium conditioned by human bladder carcinoma cells (K. Akaogi et al., Biochem. Biophys. Res. Commun., 198: 1046-1053, 1994). TAF is closely related or identical to a putative protein encoded by the mac25 gene (M. Murphy et al., Cell Growth & Differ., 4: 715-722, 1993) and prostacyclin-stimulating factor (T. Yamauchi et al., Biochem. J., 303: 591-598, 1994). TAF has a characteristic cysteine cluster in its NH2-terminal sequence, which is conserved in the NH2 termini of insulin-like growth factor-binding proteins. In the present study, we examined the interaction of TAF with insulin-like growth factors (IGFs) and insulin. Although in a ligand blotting assay TAF bound neither IGFs nor insulin, immunoprecipitation assay showed weak interaction of TAF with IGF-I, IGF-II, and insulin. TAF by itself stimulated the growth of BALB/c3T3 cells on the usual plastic substrates and significantly enhanced IGF- or insulin-mediated cell growth. Moreover, marked potentiation of the mitogenic activities of IGFs and insulin by TAF was found in the culture on type IV collagen substrates. The synergistic growth stimulation was completely blocked by heparin. These results suggest that TAF may regulate the growth of fibroblastic cells in collaboration with IGFs and insulin.

3T3 Cells↗

PubMed2005

Tumorigenesis in p27/p53- and p18/p53-double null mice: functional collaboration between the pRb and p53 pathways.

Mice lacking both p18(Ink4c) and p27(Kip1) develop a tumor spectrum similar to pRb(+/-) mice, and loss of p53 function accelerates tumorigenesis in pRb(+/-) mice. We hypothesized that codeletion of either p18 or p27 in conjunction with p53 deletion will also accelerate tumorigenesis. Mice lacking both p18 and p53 develop several tumors not reported in either single null genotype, including hepatocellular carcinoma, testicular choriocarcinoma, hemangiosarcoma, leiomyosarcoma, fibrosarcoma, and osteosarcoma. Mice lacking both p27 and p53 exhibit a decreased lifespan and develop unique tumors, including papillary carcinoma of the colon, hemangiosarcoma, and leiomyosarcoma. In both p18/p53 and p27/p53 double null genotypes, the incidence and spectra of tissues that develop lymphoma are also increased, as compared to the single null genotypes. The development of p27/p53 double null colon tumors correlates with secondary changes in cell-cycle protein expression and CDK (cyclin-dependent kinase) activity, perhaps contributing to the progression of colorectal cancer. We concluded that p18 and p27 can, not only functionally collaborate with one another, but also can independently collaborate with p53 to modulate the cell cycle and suppress tumorigenesis in a tissue-specific manner.

Animals↗

PubMed2025

Cathepsin Z is a conserved susceptibility factor underlying tuberculosis severity.

Tuberculosis (TB) outcomes vary widely, from asymptomatic infection to mortality, yet most animal models do not recapitulate human phenotypic and genotypic variation. The genetically diverse Collaborative Cross mouse panel models distinct facets of TB disease that occur in humans and allows identification of genomic loci underlying clinical outcomes. We previously mapped a TB susceptibility locus on mouse chromosome 2. Here, we identify cathepsin Z (Ctsz) as a lead candidate underlying this TB susceptibility and show that Ctsz ablation leads to increased bacterial burden, pulmonary inflammation and decreased survival in mice. Ctsz disturbance within murine macrophages enhances production of chemokine (C-X-C motif) ligand 1 (CXCL1), a known biomarker of TB severity. From a Ugandan household contact study, we identify significant associations between CTSZ variants and TB disease severity. Finally, we examine patient-derived TB granulomas and report CTSZ localization within granuloma-associated macrophages, placing human CTSZ at the host-pathogen interface. These findings implicate a conserved CTSZ-CXCL1 axis in humans and genetically diverse mice that mediates TB disease severity.

Animals↗

PubMed1982

Genetic control of sensitivity to moloney leukemia virus in mice. VI. Involvement of virus-specific T helper cells collaborating with B cells.

T cell responses to Moloney virus involve cytolytic and helper lymphocytes. In contrast to specific cytolytic T lymphocytes, few studies have been devoted to the characteristics of helper T cells for antibody production. The present experiments describe an assay for Moloney virus-specific help for B cells using dinitrophenylated virus. This method, using the Moloney virus as a carrier in a hapten-carrier system, allows to definition of the specific helper function of antibody responses. T helper cells were induced in murine sarcoma virus or inactivated Moloney murine leukemia virus-primed spleens or lymph nodes. T helper function was due to Thy-1.2, Lyt-1+2- cells and was macrophage-dependent. It was stimulated by whole virus of Moloney gp71 envelope protein but not Moloney p30 internal protein. Cross-reactive stimuli were obtained with other dinitrophenylated type C viruses. High and low responses were correlated respectively with resistance and susceptibility to Moloney leukemia virus. Cultures of helper T cells with preserved activity have been established and maintained for one month.

Animals↗

PubMed1988

Immunogenicity of a 92kDa component of porcine zona pellucida isolated using a monoclonal antibody (3A4-2G1) exclusively cross-reactive with porcine and human zonae pellucidae.

Three monoclonal antibodies (Mabs) to solubilized porcine zona pellucida (s-PZP) were produced. They reacted exclusively to porcine and human zonae pellucidae (ZPe) and two of them blocked sperm penetration of ZP in humans by collaborating with goat anti-mouse gamma-globulin serum as a second antibody. The antigen corresponding to one of these Mabs (Mab 3A4-2G1) was fractionated from s-PZP by immunoaffinity chromatography bound Mab 3A4-2G1. The antigen corresponding to Mab 3A4-2G1 was further fractionated by SDS-PAGE and the protein band corresponding to 92kDa was found to react to Mab 3A4-2G1, as demonstrated by Western blotting. The 92kDa fraction of s-PZP was isolated and injected into mice with complete and incomplete Freund's adjuvants to obtain an antiserum. It was shown that the antiserum to the 92kDa molecule reacted in a tissue-specific manner to human ZP and exhibited a strong inhibitory effect on sperm penetration of ZP of human oocytes.

Animals↗

PubMed1979

Cellular and genetic control of antibody responses. V. Helper T-cell recognition of H-2 determinants on accessory cells but not B cells.

Requirements for helper T-cell recognition of H-2 determinants expressed on adherent accessory cells and on B cells was individually assessed in the anti-hapten PFC responses to TNP-KLH. Complicating allogeneic effects were minimized or avoided by the use of helper T cells from normal F1 hybrids, parent leads to F1 chimeras, and F1 leads to parent chimeras. The results of both in vitro and in vivo experiments demonstrated that: (a) helper T cells are not required to recognize the identical H-2 determinants on both accessory cells and B cells; (b) helper T cells are required to recognize K or I-A region-encoded determinants expressed on accessory cells; (c) no requirement was observed in vitro or in vivo for helper T-cell recognition of B-cell-expressed H-2 determinants; and (d) no requirement was observed for H-2 homology between accessory cells and B cells. The absence of required helper T-cell recognition of the identical H-2 determinants on both accessory cells and B cells was demonstrated in two ways: (a) naive of KLH-primed (A x B)F1 hybrid helper T cells collaborated equally well with B cells from either parentA or parentB in the presence of accessory cells from either parent; (b) A leads to (A x B)F1 chimeric spleen cells depleted of accessory cells collaborated equally well with accessory cells from either parentA or parentB, even though the B cells only expressed the H-2 determinants of parentA. A requirement for helper T-cell recognition of K or I-A region-encoded H-2 determinants on accessory cells was also demonstrated in two ways: (a) (A x B)F1 leads to parentA chimeric spleen cells depleted of accessory cells collaborated with accessory cells from parentA but not parentB; and (b) (A x B)F1 leads to parentA chimeric helper T cells collaborated with normal F1 B cells only in the presence of parental or recombinant accessory cells that expressed the K or I-A region-encoded determinants of parentA. Although restricted in their ability to recognize H-2 determinants on accessory cells, it was demonstrated both in vitro and in vivo that (A x B)F1 leads to parentA chimeric helper T cells were able to collaborate with B cells from either parentA or parentB. In vitro in the presence of accessory cells from parentA, (A x B)F1 leads to parentA chimeric helper T cells collaborated equally well with B cells from either parent. In addition, the inability of (A x B)F1 leads to parentA chimeric helper T cells to collaborate with (B + accessory) cells from parentB was successfully reversed by the addition of parentA SAC as added accessory cells. In vivo, upon the addition of parentA accessory cells, (A x B)F1 leads to parentA chimeric helper T cells collaborated with parentB B cells in short-term adoptive transfer experiments.

Animals↗

PubMed1999

Cross talk between adipocytes and their precursors: relationships with adipose tissue development and blood pressure.

Adipose tissue is an important source of angiotensinogen (AT). A possible involvement of increased plasma AT has been proposed in hypertension in obese patients, but growing evidence suggests also that the local renin-angiotensinogen system (RAS), giving rise to angiotensin II (AngII), may act as a distinct system from the plasma RAS. AngII stimulates in vitro the production and release of prostacyclin from adipocytes which in turn promotes the differentiation of precursor cells into new adipocytes (Darimont et al. 1994, Endocrinology 138: 1092-1096). Cross talk between adipocytes and precursor cells has been validated ex vivo and in vivo as (1) AngII stimulates specifically prostacyclin production, (2) both carbacyclin, a stable analogue of prostacyclin, and AngII promote the formation of new fat cells, and (3) AT (-/-) mice, which have decreased blood pressure (Tanimoto et al. 1994, J. Biol. Chem. 269: 31334-31336), exhibit both hypertrophy and hypoplasia of adipose tissue compared to wild-type mice (collaboration with Prof. A. Fukamizu, Tsukuba University, Japan). Altogether the data are consistent with an autocrine/paracrine mechanism implicating AT, AngII, and prostacyclin in adipose tissue development and suggest a new role for local AngII in addition to that of systemic AngII in blood pressure. Hormonal regulation of AT production from adipose tissue is also discussed.

Adipocytes↗

PubMed1986

Functional requirements of (Phe, G)-A--L-specific T-cell clones of (H-2b X H-2k)F1 origin.

T-cell clones specific for the synthetic polypeptide antigen poly(LPhe, LGlu)-poly(DLAla)--poly(LLys) of (C57BL/6 X C3H/HeJ)F1 origin were tested for their biological activities. One group of clones was restricted in its proliferative response to the H-2b haplotype, the second to the H-2k haplotype, and the third to the F1 unique Ia determinants. All the clones which proliferated in response to antigen secreted interleukin-2 (IL-2) following stimulation. The H-2 restriction of the IL-2 secretion was the same as that of the proliferation. Two of the clones tested, C.6 and C.10, could provide help to B cells in antibody production. However, the genetic restriction profile of the helper activity was less stringent than that for the proliferative response. Thus, C.6, which proliferated in the presence of F1 antigen-presenting cells only, could help B cells and accessory cells of C3H/HeJ. C.10, which was restricted in its proliferative response to the H-2b haplotype, could collaborate with B cells and accessory cells of the H-2k haplotype as well. The antibody response of both clones was restricted to the parental or F1 strains.

Animals↗

PubMed2002

Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice.

Dual inactivation of PTEN and INK4a/ARF tumor suppressor genes is a common feature observed in a broad spectrum of human cancer types. To validate functional collaboration between these genes in tumor suppression, we examined the biological consequences of Pten and/or Ink4a/Arf deficiency in cells and mice. Relative to single mutant controls, Ink4a/Arf-/-Pten+/- mouse embryonic fibroblast cultures exhibited faster rates of growth in reduced serum, grew to higher saturation densities, produced more colonies upon low density seeding, and showed increased susceptibility to transformation by oncogenic H-Ras. Ink4a/Arf deficiency reduced tumor-free survival and shortened the latency of neoplasias associated with Pten heterozygosity, specifically pheochromocytoma, prostatic intraepithelial neoplasia, and endometrial hyperplasia. Compound mutant mice also exhibited an expanded spectrum of tumor types including melanoma and squamous cell carcinoma. Functional synergy between Ink4a/Arf and Pten manifested most prominently in the development of pheochromocytoma, prompting an analysis of genes and loci implicated in this rare human neoplasm. The classical pheochromocytoma genes Ret, Vhl, and Nf-1 remained intact, a finding consistent with the intersection of these genes with pathways engaged by Pten and Ink4a/Arf. Notably, conventional and array-comparative genomic hybridization revealed frequent loss of distal mouse chromosome 4 in a region syntenic to human chromosome 1p that is implicated in human pheochromocytoma. This study provides genetic evidence of collaboration between Pten and Ink4a/Arf in constraining the growth and oncogenic transformation of cultured cells and in suppressing a wide spectrum of tumors in vivo.

Adrenal Gland Neoplasms↗

PubMed1996

Comparative histopathologic evaluation of animal studies: murine studies with L-tryptophan and constitutents.

Following a 1994 collaborative research workshop on animal studies of the eosinophilia-myalgia syndrome (EMS), the Research Advisory Council (RAC) concluded that it would be instructive to have histopathologic slides from the different investigators and laboratories evaluated simultaneously using the same pathologist, pathologic criteria, and scoring system for cross-study comparisons of effects. The author evaluated the skin, underlying fascia and supporting tissues, and muscles, stained with hematoxylin and eosin, from 20 separate studies, representing 4 mouse strains, several protocols, and tissues from over 250 mice. The author concluded that, based on the material available, the findings are inconsistent, nonreproducible, and do not support a conclusion that L-tryptophan, case associated L-tryptophan, 1,1'-ethylidenebis(tryptophan), 3-phenylamino alanine, or a combination thereof, under the conditions of the studies, induce lesions of skin or muscle in the C57 Black, Balb/c, SJL, or B10.s strains of mice.

Alanine↗

PubMed1998

Effect of genetic modification of acute inflammatory responsiveness on tumorigenesis in the mouse.

Two distinct bidirectional selective breedings for quantitative traits were initiated from identical genetically heterogeneous mouse populations. The resulting lines are characterized by maximal or minimal acute inflammatory responsiveness (AIR): AIRmax and AIRmin lines, respectively, and by resistance or susceptibility to chemical skin tumorigenesis: Car-R and Car-S lines, respectively. The AIR response to s.c. injection of polyacrylamide microbeads, measured by cell content in the local exudate, was 10 times higher in AIRmax than in AIRmin mice. The response to selection was asymmetrical: the realized heritability was 0.26 in AIRmax and 0.008 in AIRmin, and resulted from the additive effect of 7-11 quantitative trait loci (QTL). Low responsiveness was globally dominant in F1 and 48% of F2 segregant variance was found to be due to genetic factors. These findings are the first demonstration of innate regulation of AIR by germ line genes. Susceptibility to skin tumorigenesis induced by a two-stage initiation (DMBA)-promotion (TPA) protocol was lower in AIRmax mice than in AIRmin mice, a 6-fold difference in tumor induction rate. Intense AIR was found to be associated with resistance, and low AIR with susceptibility to tumorigenesis, in F2 segregants chosen for extreme AIR phenotypes. At least some of the AIR QTLs therefore contain genes controlling tumorigenesis. Tumor phenotypes differed more in Car-R and Car-S than in AIRmax and AIRmin lines, indicating that QTLs unrelated to AIR, contribute to the host response to tumorigenesis. The extreme phenotypes/genotypes of the four selected lines and the known genetic constitution of their foundation population, offer new possibilities to discriminate the genes/mechanisms controlling two important traits: AIR and response to chemical tumorigenesis. Collaborative projects will be favorably considered. The description of tumor resistance genes in AIRmax and Car-R mice may be helpful for epidemiology and therapy of human cancer.

Acute Disease↗