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T N Fredrickson

Publications and source records attributed to T N Fredrickson.

At least 19 recordsLinked to original sources
PubMed2001

Cells of the marginal zone--origins, function and neoplasia.

Splenic marginal zone B cells of humans and mice are anatomically positioned with specialized macrophages, dendritic and endothelial cells. Together, they function as the first line of defense against blood borne pathogens with a low triggering threshold for B cells providing a rapid proliferative and antibody response to infections. In humans, B cells with similar cytology and physical relations to follicles are found in lymph nodes and Peyer's patches. However, they also develop in mucosa-associated lymphoid tissue (MALT) and other sites, such as the thyroid and salivary gland, that normally lack organized lymphoid tissue. Chronic antigenic stimulation at these sites or in response to infection with Hepatitis C provides the milieu for mutations at FAS, API2/ML, TP53 and INK4a/p19ARF and the development of marginal zone lymphomas (MZL) in node, spleen and MALT. Only splenic MZL are seen in mice. A reduced threshold for triggering to proliferation may predispose the marginal zone B cell to neoplasia with mutations in genes regulating apoptosis playing a leading role.

Animals↗
PubMed2001

Combined histologic and molecular features reveal previously unappreciated subsets of lymphoma in AKXD recombinant inbred mice.

Hematopoietic neoplasms developing in AKXD recombinant inbred, NFS.V(+) and ICSBP knockout mice were assessed using morphologic, cytologic and molecular criteria that relate these disorders to human lymphoma and leukemia. Lymphoma types included precursor T-cell and B-cell lymphoblastic, small lymphocytic, splenic marginal zone, follicular, and diffuse large cell (DLCL). In addition to previously defined subtypes of DLCL composed of centroblasts or immunoblasts, two additional subtypes are defined here: lymphoblastic lymphoma like (LL) and lymphoma characterized by a histiocytic reaction (HS). DLCL(HS) were distinguished from true histiocytic lymphomas by the presence of clonal Ig gene rearrangements.

Animals↗
PubMed2000

Accelerated appearance of multiple B cell lymphoma types in NFS/N mice congenic for ecotropic murine leukemia viruses.

Spontaneous lymphomas occur at high frequency in NFS x V+ mice, strains congenic for ecotropic murine leukemia virus (MuLV) proviral genes and expressing virus at high titer. In the present study, a total of 703 NFS x V+ lymphomas were studied by histopathology, immunophenotypic analysis, immunoglobulin heavy chain or T cell receptor beta chain rearrangements, and somatic ecotropic MuLV integrations; 90% of the lymphomas tested were of B cell lineage. Low-grade tumors included small lymphocytic, follicular, and splenic marginal zone lymphomas, while high-grade tumors comprised diffuse large-cell (centroblastic and immunoblastic types), splenic marginal zone, and lymphoblastic lymphomas. Comparison of mice of similar genetic background except for presence (NFS x V+) or absence (NFS x V-) of functional ecotropic MuLV genomes showed that NFS x V-clonal lymphomas developed at about one-half the rate of those occurring in NFS x V+ mice, and most were low-grade B cell lymphomas with extended latent periods. In NFS x V+ mice, clonal outgrowth, defined by Ig gene rearrangements, was associated with acquisition of somatic ecotropic proviral integrations, suggesting that, although generation of B cell clones can be virus independent, ecotropic virus may act to increase the rate of generation of clones and speed their evolution to lymphoma. The mechanism remains undefined, because only rare rearrangements were detected in several cellular loci previously associated with MuLV insertional mutagenesis.

Animals↗
PubMed1999

Splenic marginal zone lymphomas of mice.

Splenic marginal zone lymphomas (MZLs) have been found to occur at a high frequency in NFS.N mice congenic for high-expressing ecotropic murine leukemia virus (MuLV) genes from AKR and C58 mice. Based on morphological, immunological, and molecular studies of these mice, MZL is clearly recognizable as a distinct disease with a characteristic clinical behavior. MZL was staged according to the degree of accumulation and morphological change of cells within the splenic marginal zone, as follows: 1) a moderate increase in normal-looking MZ cells, judged to be prelymphomatous, and 2) MZL in three variants: i) distinct enlargement of MZ by normal-looking cells (MZL), ii) distinct enlargement of MZ by basophilic centroblast-like cells (MZL+), and iii) extensive splenic involvement by centroblast-like cells (MZL++). The rate of mitosis and apoptosis increases with lymphoma grade. In most cases, emergence of a dominant IgH clonal pattern in paired splenic biopsy and necropsy samples was correlated with progression. MZLs were transplantable and homed to the spleen. MZL may constitute a commonly occurring lymphoma type unrecognized, in part, because of the centroblastic morphology of high-grade MZL and possible overgrowth of lower-grade MZL by more aggressive follicular lymphomas.

Animals↗
PubMed1998

Spontaneous development of plasmacytoid tumors in mice with defective Fas-Fas ligand interactions.

B cell malignancies arise with increased frequency in aging individuals and in patients with genetic or acquired immunodeficiency (e.g., AIDS) or autoimmune diseases. The mechanisms of lymphomagenesis in these individuals are poorly understood. In this report we investigated the possibility that mutations at the Fas (lpr) and Fasl (gld) loci, which prevent Fas-mediated apoptosis and cause an early onset benign lymphoid hyperplasia and autoimmunity, also predispose mice to malignant lymphomas later in life. Up to 6 mo of age, hyperplasia in lpr and gld mice results from the predominant accumulation of polyclonal T cell subsets and smaller numbers of polyclonal B cells and plasma cells. Here, we examined C3H-lpr, C3H-gld, and BALB-gld mice 6-15 mo of age for the emergence of clonal T and B cell populations and found that a significant proportion of aging mice exclusively developed B cell malignancies with many of the hallmarks of immunodeficiency-associated B lymphomas. By 1 yr of age, approximately 60% of BALB-gld and 30% of C3H-gld mice had monoclonal B cell populations that grew and metastasized in scid recipients but in most cases were rejected by immunocompetent mice. The tumors developed in a milieu greatly enriched for plasma cells, CD23- B cells and immunodeficient memory T cells and variably depleted of B220+ DN T cells. Growth factor-independent cell lines were established from five of the tumors. The majority of the tumors were CD23- and IgH isotype switched and a high proportion was CD5+ and dull Mac-1+. Considering their Ig secretion and morphology in vivo, most tumors were classified as malignant plasmacytoid lymphomas. The delayed development of the gld tumors indicated that genetic defects in addition to the Fas/Fasl mutations were necessary for malignant transformation. Interestingly, none of the tumors showed changes in the genomic organization of c-Myc but many had one or more somatically-acquired MuLV proviral integrations that were transmitted in scid passages and cell lines. Therefore, insertional mutagenesis may be a mechanism for transformation in gld B cells. Our panel of in vivo passaged and in vitro adapted gld lymphomas will be a valuable tool for the future identification of genetic abnormalities associated with B cell transformation in aging and autoimmune mice.

Aging↗
PubMed1998

Murine cytomegalovirus infection-induced polyclonal B cell activation is independent of CD4+ T cells and CD40.

The results of this study demonstrate that murine cytomegalovirus (MCMV) induces polyclonal B cell activation in mice during the acute phase of primary infection. First flow cytometric analysis revealed that surface expression of CD45R, IgM, and IgK by splenocytes from MCMV-infected mice was significantly reduced with a concomitant increase in the frequency of surface IgG-expressing cells. Second, ELIspot assays demonstrated that the changes revealed by flow cytometry were paralleled by increases in the numbers of IgG-producing cells, especially those secreting IgG2a. Third, the IgG antibodies from MCMV-infected animals reacted against a variety of self and foreign antigens. MCMV-induced B cell activation was independent of CD4+ T-cell-mediated help and CD40, since activation was observed in two models of mice deficient for this T cell subset and in mice deficient for CD40. Reverse transcription-polymerase chain reaction analysis showed that mRNA transcripts for the cytokines IL-6, IL-10, and IFN-gamma were rapidly induced following infection with MCMV, but only IL-6 and IFN-gamma proteins were detectable by ELISA. In addition, the numbers of cells producing IL-6 and IFN-gamma were significantly increased in the spleen. The magnitude of the polyclonal B cell activation response was diminished by 50% in IL-6-deficient mice but not in mice lacking IFN-gamma. In the absence of IFN-gamma, surface expression and serum levels of IgG2a were reduced while IgG1 expression was increased.

3T3 Cells↗
PubMed1998

Expression of cyclin D1 in mouse B cell lymphomas of different histologic types and differentiation stages.

The G1 cyclin, cyclin D1, has been implicated in the development of human and mouse tumors. Here we describe immunohistochemical analyses of cyclin D1 for a large panel of mouse B cell tumors. In addition, we characterize cyclin D1 expression in a series of cultured cell lines that represent transformed B cells at different stages of development. Immunohistochemical analysis showed that for low-grade lymphomas, cyclin D1 was expressed by 83% of centroblastic centrocytic (CBCC) and 14% of small lymphocytic lymphomas (SLL). For high-grade tumors, 28% of B lymphoblastic and 23% of centroblastic tumors expressed cyclin D1, while all immunoblastic lymphomas were negative. Studies of RNA and protein prepared from cultured B lineage tumors showed that cyclin D1 was expressed by all pre-B and most B cell tumors but not by cell lines representative of late B cell differentiation or by plasma cells. Expression of cyclin D1 in the lymphomas was not associated with alterations in the genomic structure of the Fis-1 (Bcl-1) common proviral integration site or cyclin D1 itself or with cell growth activity as assessed by expression of proliferating cell nuclear antigen (PCNA).

Animals↗
PubMed1997

Control of immunodeficiency and lymphoproliferation in mouse AIDS: studies of mice deficient in CD8+ T cells or perforin.

CD8+ T cells were previously shown to be important in preventing lymphoproliferation and immunodeficiency following infection of murine AIDS (MAIDS)-resistant mice with the LP-BM5 mixture of murine leukemia viruses. To further evaluate the mechanisms contributing to MAIDS resistance, we studied mice lacking CD8+ T cells or deficient in perforin due to knockout of the beta2-microglobulin (beta2M) or perforin gene, respectively. In contrast to wild-type, MAIDS-resistant controls, B10.A mice homozygous for the beta2M mutation and B10.D2 mice homozygous for the perforin mutation were diagnosed as having MAIDS by 5 to 8 weeks after infection by the criteria of lymphoproliferation, impaired proliferative responses to mitogens, and changes in cell populations as judged by histopathology and flow cytometry. Unexpectedly, there was no progression of lymphoproliferation through 24 weeks, even though immune functions were severely compromised. Expression of the defective virus responsible for MAIDS was enhanced in spleens of the knockouts in comparison with wild-type mice. These results demonstrate that perforin-dependent functions of CD8+ T cells contribute to MAIDS resistance but that other, non-CD8-dependent mechanisms are of equal or greater importance.

Animals↗
PubMed1997

Charlotte Friend Memorial Lecture: murine leukemia virus (MuLV) tumorigenesis.

Recent analysis of over 500 lymphomas occurring in NFS.V mice, congenic for Akv-type ecotropic MuLV structural genes, has revealed that about 90% are of B cell lineage as determined by demonstration of clonal rearrangements of Ig heavy chain genes, phenotyping by immunocytochemistry or cytofluorometric analysis, and by site and morphology of tumor. At least 40% of the B cell lymphomas were found to have their origin in the splenic marginal zone, a site only once before described for mouse lymphomas. Clonal somatic integrations of ecotropic MuLV occurred in 85% of tumors.

Animals↗
PubMed1997

Immunologic havoc induced by the 60 kD Gag protein of the MAIDS defective virus.

The mechanisms responsible for development of profound immunodeficiency and extensive lymphoproliferation that characterize infection of different species with retroviruses are only partially understood. In mice, it has been shown the activities of an unusual Gag protein are necessary and sufficient to induce these abnormalities in a syndrome designated mouse AIDS (MAIDS). Current studies suggest that complex, antigen-driven interactions between T cells and B cells result in polyclonal activation of both types of lymphocytes, aberrant cytokine production and late lymphomas.

Animals↗
PubMed1996

Endogenous Mtv-encoded superantigens are not required for development of murine AIDS.

Immune activation in murine AIDS (MAIDS) has been suggested to involve a superantigen (SAG). The possibility that SAGs encoded by mammary tumor virus (MTV) might be the source of stimulation was studied by using Mtv mice. Mtv- mice developed typical MAIDS, excluding a requirement for Mtv-encoded SAGs in the pathogenesis of this disorder.

Animals↗
PubMed1994

Influence of H-2 class II antigens on the development of murine AIDS.

Inbred strains of mice differ markedly in their relative susceptibility to the development of lymphoproliferation and immunodeficiency, a syndrome termed mouse AIDS (MAIDS), after infection with the LP-BM5 mixture of murine leukemia viruses (MuLV). The etiologic virus in this mixture is replication defective (BM5def) and encodes only a variant gag protein. Genetic determinants of resistance and susceptibility to induction of MAIDS reside both within and outside the MHC. In strains with C57BL background genes, the MHC haplotypes associated with resistance to disease include d and a, whereas haplotypes b, s, and q are associated with sensitivity. Previous studies showed that MHC class I genes (H-2Dd, H-2Ld) mapping in the D end of H-2 and other genes mapping proximal to the D end determine resistance to MAIDS. This paper examines the nature of these non-D end MHC genes using assays of MHC recombinant and transgenic mice. We demonstrate that expression of E alpha d confers significant resistance to MAIDS, even in mice that do not express H-2Dd/H-2Ld. Unexpectedly, we found that E alpha polymorphisms can significantly influence resistance, with H-2b mice bearing E alpha d as a transgene having greater resistance to MAIDS than mice bearing an E alpha k transgene. E alpha d-mediated resistance to MAIDS was associated with decreased levels of the BM5def genome in splenic DNA, suggesting that E alpha genes exert their effect by enhancing antiviral activity.

Animals↗
PubMed1993

Effects of immunization with the p12 proteins of LP-BM5 defective and ecotropic viruses on development of MAIDS.

Among murine leukemia viruses (MuLV) present in the LP-BM5 virus mixture, the agent etiologic for an acquired immunodeficiency syndrome (MAIDS) is replication defective, containing only a single open reading frame which includes all of gag. The Gag polyprotein encoded by the defective virus, termed BM5def, differs most in p12 from that of nonpathogenic ecotropic virus (BM5eco). As one approach to examining the role of p12 in disease, the ecotropic and defective virus forms of the protein, synthesized in bacteria, were used to immunize three strains of mice differing in their sensitivity to MAIDS. In each strain, both proteins elicited substantial antibody responses that were cross-reactive with either p12 and recognized the proteins as part of intact viral Gag polyproteins. Immunization with either p12 before infection with LP-BM5 viruses had no effect on the sensitivity or resistance of mice to MAIDS or on the extent of helper virus spread. The variant p12 of BM5def, when presented on its own, is thus not a crucial antigenic determinant of disease. Alternative mechanisms by which BM5def may contribute to MAIDS are discussed.

Amino Acid Sequence↗
PubMed1993

Importance of interferons in recovery from mousepox.

Gamma interferon is shown to be critical in recovery of C57BL/6 mice from mousepox. Anti-gamma interferon treatment of mice infected in the footpad with ectromelia virus resulted in enhanced spread to and efficient virus replication in the spleen, lungs, ovaries, and, especially, liver. All treated, infected mice died within a mean of 7 days, 2.5 days earlier than mice with severe combined immunodeficiency that were given a comparable infection. On the other hand, alpha interferon appeared not to have a major role in controlling virus replication in tissues examined, and beta interferon was important for virus clearance in the liver and ovaries but not the spleen. Either anti-alpha, beta interferon or anti-beta interferon antibody therapy resulted in only 25% mortality. Infected control mice survived but showed persistence of ectromelia virus at the site of infection (the footpad) and transient presence of the virus in the spleen, liver, lungs, and ovaries and in the fibroreticular but not lymphoid cells of the draining popliteal lymph node. Depletion of gamma interferon but not alpha and/or beta interferon resulted in a significant reduction in the numbers of splenic T (especially gamma delta-TCR+), B, and Mac-1+ cells, although the proportion of Mac-1+ cells in the spleen increased compared with control values. Depletion of alpha, beta, or gamma interferons did not severely affect the generation of virus-specific cytotoxic T-lymphocyte responses or natural killer cell cytolytic activity. This study, in which a natural virus disease model was used, underscores the crucial importance of gamma interferon in virus clearance at all stages of infection and in all tissues tested except the primary site of infection, where virus clearance appears to be delayed.

Animals↗
PubMed1993

Retrovirus-induced lymphoproliferation as a model for developing diagnostic criteria for malignant lymphoma in mice.

Several methods for evaluating lymphoproliferative lesions in mice were compared. The model systems included spontaneous lymphomas arising in CWD mice and NFS mice congenic for ecotropic murine leukemia virus (MuLV) induction loci and a series of transplants in mice with severe combined immunodeficiency disease mutation of cells derived from mice infected with LP-BM5 MuLV. Primary lymphomas and donor tissues and transplants were examined using histopathology, flow cytometry, and Southern blot analysis of DNA for rearrangements of immunoglobulin and T-cell receptor genes and for viral integrations. The use of flow cytometric analysis, to establish cell lineage and define population size, and DNA analysis, for cell lineage and clonality determination, allowed the identification of malignant lymphoproliferations. Histologic evaluation did not define clonal populations of particular lineage but did provide other indications of malignancy such as invasiveness and presence of a dominant morphologic cell type. Thus, the precision of diagnosis of mouse lymphomas can be considerably enhanced by augmenting histopathologic examination with antigenic and molecular characterizations that can define malignant populations.

Animals↗