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Results for “clonal modeling”

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PubMed2006

Infectious agents in mucosa-associated lymphoid tissue-type lymphomas: pathogenic role and therapeutic perspectives.

Mucosa-associated lymphoid tissue (MALT) lymphoma probably constitutes the best in vivo model showing how complex interplay between B lymphocytes and the surrounding microenvironment may lead to a neoplastic disorder. After the seminal discovery of the pathogenic association between Helicobacter pylori and gastric MALT lymphomas, evidence suggests the possible involvement of other infectious agents in the development of MALT lymphomas arising at different body sites. Although several other bacteria (Borrelia burgdorferi, Campylobacter jejuni, and Chlamydia psittaci) and viruses (Hepatitis C virus) seem to play a role in lymphomas presenting at different locations, a possible common pathogenic mechanism is emerging. Several lines of evidence suggest that different infectious agents might provide a chronic antigenic stimulation that elicits host immune responses able to promote clonal B-cell expansion. This model is also substantiated by the increasing number of patients with MALT lymphomas who exhibit objective clinical responses after antimicrobial therapy. A multidisciplinary approach is critical to better understand the complex etiopathogenesis of MALT lymphomas with the final goal to dissect the clinicopathologic heterogeneity of these disorders and design more tailored preventive and therapeutic approaches.

Anti-Infective Agents↗

PubMed2002

A mutation in an ompR-like gene on a Legionella longbeachae serogroup 1 plasmid attenuates virulence.

Examination of a panel of Legionella longbeachae serogroup 1 strains using a guinea pig model of virulence determined that this clonal species of Legionella shows a remarkable variation in symptoms and disease outcome (Doyle et al., Infect. Immun. 69, 5335-5344, 2001). The presence of plasmids was investigated, as plasmid encoded functions may contribute to the virulence of genetically similar strains. Partial sequence analysis of a large native plasmid (approximately 120 kb), designated pA5H5, from a highly virulent Australian isolate revealed a putative two-component regulatory system with inferred identity to the OmpR family of two-component transcriptional regulatory proteins and EnvZ sensor kinases. An isogenic mutant was constructed in the transcriptional regulatory gene, designated lrpR (L. longbeachae sg 1 regulatory protein) and this strain was tested in Acanthamoeba, U937 cells and in a guinea pig animal model. The mutant was reduced in intracellular multiplication within Acanthamoeba but not U937 macrophage-like cells. However, the lrpR mutant did appear reduced in invasion at the early stages of infection of U937 cells. The lrpR mutant was also attenuated for virulence in a guinea pig animal model of infection. The importance of plasmid-encoded functions for the pathogenicity of Legionella longbeachae serogroup 1 strains is discussed.

Acanthamoeba↗

PubMed2001

In situ cytokine therapy: redistribution of clonally expanded T cells.

Immunity to tumors relies on recirculating antigen-specific T cells. Whilst induction of antigen-specific T cells by immunotherapy has been convincingly proven, direct evidence for recirculation of such cells is still lacking. Here, employing a recently established in situ immunotherapy model for murine melanoma we directly demonstrate the redistribution of clonally expanded T cells. In this model IL-2 is targeted to the tumor microenvironment by means of specific antibody-IL-2 fusion proteins resulting in the expansion of T cells. The therapeutic effect of the fusion protein is not restricted to tumors expressing the targeted antigen, but extends to antigen negative variants of the tumor if present in the same animal. Analysis of the T cell infiltrate by quantitative reverse transcription-PCR revealed the presence of highly expressed TCR BV regions in both tumor variants. TCR clonotype mapping revealed that the high expressions of these regions were caused by clonal expansions and, notably, that these specific clonotypic TCR transcripts were identical in both tumors. Thus, T cell clones activated locally by targeted IL-2 therapy recirculate and mediate eradication of distant tumor sites not subjected to in situ cytokine therapy.

Amino Acid Sequence↗

PubMed1993

Clonal deletion as direct consequence of an in vivo T cell response to bacterial superantigen.

To date clonal deletion of peripheral mature T cells is restricted to in vivo model systems characterized by prolonged exposure of mice to antigens and clonal T cell expansion preceding clonal deletion. Here we describe that upon challenge of mice with the superantigen staphylococcal enterotoxin B two immediate events become imposed on ligand-reactive V beta 8+ T cells in lymph node cells draining the local site of injection. First, and within hours V beta selective clonal deletion is initiated via an apoptotic process. Second, the remaining V beta 8+ T cells first develop a profound state of ligand-specific unresponsiveness and subsequently initiate clonal in vivo growth. It is suggested that the dichotomy of events observed reflects a direct consequence of T cell receptor occupancy in the context of inappropriate signalling.

Animals↗

PubMed2003

Clonal exhaustion as a result of immune deviation.

An overwhelming virus infection that spreads within a few days throughout the host can cause deletion of the specific cytotoxic T lymphocytes (CTL). This phenomenon is known as 'clonal exhaustion'. Current explanations for this phenomenon are 'clonal', and consider either the terminal differentiation of the virus-specific CTL to an effector phenotype, or the lack of help and antigen presentation for a specific CTL clone. The virus remains controlled by some other form of immunity in the exhausted state. Candidates are innate immunity (especially NK cells and macrophages) and a T helper type 2 based immune response. Surprisingly, the role of this other form of immunity in causing exhaustion has been ignored so far. Developing a mathematical model, we here investigate the possibility that this inter-clonal immunity is responsible for exhaustion by down regulating the CTL response. The model is based on previously published exhaustion data for Lymphocytic choriomeningitis virus as an in vivo model. We demonstrate that several complicated experiments on clonal exhaustion are consistent with inter-clonal regulation. By interpreting the available data with a mathematical model, we compare this novel mechanism with the mechanisms suggested previously.

Animals↗

PubMed1995

Functional and structural interactions between osteoblastic and preosteoclastic cells in vitro.

Osteoblasts are involved in the bone resorption process by regulating osteoclast maturation and activity. In order to elucidate the mechanisms underlying osteoblast/preosteoclast cell interactions, we developed an in vitro model of co-cultured human clonal cell lines of osteoclast precursors (FLG 29.1) and osteoblastic cells (Saos-2), and evaluated the migratory, adhesive, cytochemical, morphological, and biochemical properties of the co-cultured cells. In Boyden chemotactic chambers, FLG 29.1 cells exhibited a marked migratory response toward the Saos-2 cells. Moreover, they preferentially adhered to the osteoblastic monolayer. Direct co-culture of the two cell types induced: (1) positive staining for tartrate-resistant acid phosphatase in FLG 29.1 cells; (2) a decrease of the alkaline phosphatase activity expressed by Saos-2 cells; (3) the appearance of typical ultrastructural features of mature osteoclasts in FLG 29.1 cells; (4) the release into the culture medium of granulocyte-macrophage colony stimulating factor. The addition of parathyroid hormone to the co-culture further potentiated the differentiation of the preosteoclasts, the cells tending to fuse into large multinucleated elements. These in vitro interactions between osteoblasts and osteoclast precursors offer a new model for studying the mechanisms that control osteoclastogenesis in bone tissue.

Adult↗

PubMed1996

Cytokine-dependent modulation of oral tolerance in a murine model of autoimmune uveitis.

In summary, our data suggest that oral tolerance in the mouse EAU model may occur by anergy/deletion or by suppression, depending on the feeding regimen. Tolerance involving putative regulatory cells appears to require the ability to produce both IL-4 and IL-10, whereas induction of tolerance involving anergy may not require the presence of Il-4 and IL-10. We propose that regulatory cells induced by three feedings of IRBP can be selectively enhanced through the use of cytokines. From the point of view of clinical therapy, it would be worthwhile to explore postimmunization feeding regimens involving administration of IL-4 and IL-10.

Administration, Oral↗

PubMed1988

"Tolerization" of human T-helper cell clones by chronic exposure to alloantigen: culture conditions dictate autocrine proliferative status but not acquisition of cytotoxic potential and suppressor-induction capacity.

Induction of clonal anergy in T-helper (Th) cells may have a role in regulating immune responses. A model system for studying Th cell tolerization at the clonal level in vitro could be useful for investigating the mechanisms involved. Accordingly, alloreactive helper cells were maintained in culture with interleukin 2 (IL 2) by intermittent stimulation with specific antigen. Regardless of the frequency of antigen stimulation, clones of age less than ca. 35 population doublings (PD) were found to undergo antigen-specific autocrine clonal expansion in the absence of exogenous IL 2. Such young clones (designated as phase I) could therefore not be "tolerized" by frequent exposure to antigen. In contrast, most clones of age greater than ca. 35 PD could be tolerized by frequent exposure to antigen (designated as phase II clones). Their autocrine proliferation was then blocked, although they still recognized antigen specifically as shown by their retained ability to secrete interferon-gamma (IFN-gamma) and granulocyte-macrophage colony stimulating factor (GM-CSF). The mechanism of response failure involved both an inability to upregulate IL 2 receptors in the absence of exogenous IL 2, as well as an inability to secrete IL 2. These defects were not overcome by stimulation with mitogens or calcium ionophore and phorbol esther in place of alloantigen. T-cell receptor, alpha, beta, and gamma-chain gene rearrangements remained identical in phase I and phase II clones. Tolerization of phase II clones could be avoided by increasing the period between antigen exposures. Despite this, whether or not phase II cells were capable of autocrine proliferation, they were found to have acquired the novel function of inducing suppressive activity in fresh lymphocytes. Suppressor-induction was blocked by the broadly reactive MHC class II-specific monoclonal antibody (moAb) TU39, but not by moAb preferentially reacting only with HLA-DR, DQ, or DP. Sequential immunoprecipitation on T-cell clones showed the presence of a putative non-DR, DQ, DP, TU39+ molecule on phase II clones. However, this molecule was also found on phase I clones. The nature of the TU39-blockable suppressor-inducing determinant present on phase II but not on (most) phase I clones thus remains to be clarified. In addition to suppressor-induction activity, phase II clones also acquired lytic potential as measured in a lectin approximation system. Cytotoxic (CTX) potential was also not influenced by the frequency of antigenic stimulation and could be viewed as a constitutive modulation of clonal function.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗

PubMed2025

SISTEM: simulation of tumor evolution, metastasis, and DNA-seq data under genotype-driven selection.

SUMMARY: SISTEM is a software package and mathematical framework for simulating tumor evolution and cell migrations at single-cell resolution. Unlike existing frameworks which simulate cancer cell populations under the neutral coalescent or using simple birth-death models, SISTEM simulates tumor populations under somatic clonal selection using an agent-based framework. SISTEM can generate mutation profiles, read counts, and DNA sequencing reads along with ground truth cell lineages and migration graphs under a number of easily customizable mutation and selection models. For improved realism, SISTEM allows for cell fitness to be driven by genomic events of various scales including single nucleotide variants, segmental gains and losses, whole-chromosomal and chromosome-arm aberrations, and whole-genome duplications. SISTEM also includes numerous migration models to simulate metastatic cancers, facilitating the exploration and evaluation of diverse migration patterns. AVAILABILITY AND IMPLEMENTATION: SISTEM is written in Python and is freely available open-source under GNU GPLv3 from: https://github.com/samsonweiner/sistem.

Software↗

PubMed2005

F-statistics under alternation of sexual and asexual reproduction: a model and data from schistosomes (platyhelminth parasites).

Accurate inferences on population genetics data require a sound underlying theoretical null model. Nearly nothing is known about the gene dynamics of organisms with complex life cycles precluding any biological interpretation of population genetics parameters. In this article, we used an infinite island model to derive the expectations of those parameters for the life cycle of a dioecious organism obligatorily alternating sexual and asexual reproductions as it is the case for schistosomes (plathyhelminth parasites). This model allowed us to investigate the effects of the degree of mixing among individuals coming from different subpopulations at each new generation (represented in the model by the migration rates before and after clonal reproductions) and the variance in the reproductive success of individuals during the clonal phase. We also consider the effects of different migration rates and degrees of clonal reproductive skew between male and female individuals. Results show that the variance in the reproductive success of clones is very important in shaping the distribution of the genetic variability both within and among subpopulations. Thus, higher variance in the reproductive success of clones generates heterozygous excesses within subpopulations and also increases genetic differentiation between them. Migration occurring before and after asexual reproduction has different effects on the patterns of F(IS) and F(ST). When males and females display different degrees of reproductive skew or migration rates, we observe differences in their respective population genetic structure. While results of the model apply to any organism alternating sexual and clonal reproductions (e.g. all parasitic trematodes, many plants, and all aphididae), we finally confront some of these theoretical expectations to empirical data from Schistosoma mansoni infecting Rattus rattus in Guadeloupe.

Animals↗

PubMed1996

A disease-related rheumatoid factor autoantibody is not tolerized in a normal mouse: implications for the origins of autoantibodies in autoimmune disease.

We have analyzed B cell tolerance in a rheumatoid factor (RF) transgenic mouse model. The model is based on AM14, a hybridoma, originally isolated from an autoimmune MRL/lpr mouse that has an affinity and specificity typical of disease-related RFs from this strain. AM14 binds to immunoglobulin (Ig)G2a of the "a" allotype (IgG2aa) and not to IgG2ab. Thus, by crossing the transgenes onto an IgHa (BALB/c) background or to a congenic IgHb (CB.17) background, we could study the RF-expressing B cells when they were self-specific (IgHa) or when they were not self-specific (IgHb). These features make the AM14 model unique in focusing on a true autoantibody specificity while at the same time allowing comparison of autoreactive and nonautoreactive transgenic B cells, as was possible in model autoantibody systems such as anti-hen egg lysozyme. Studies showed that AM14 RF B cells can make primary immune responses and do not downregulate sIgM, indicating that the presence of self-antigen does not induce anergy of these cells. In fact, IgHa AM14 transgenic mice have higher serum levels of transgene-encoded RF than their IgHb counterparts, suggesting that self-antigen-specific activation occurs even in the normal mouse background. Since AM14 B cells made primary responses, we had the opportunity to test for potential blocks to self-reactive cells entering the memory compartment. We did not find evidence of this, as AM14 B cells made secondary immune responses as well. These data demonstrate that a precursor of a disease-specific autoantibody can be present in the preimmune repertoire and functional even to the point of memory cell development of normal mice. Therefore, immunoregulatory mechanisms that normally prevent autoantibody production must exert their effects later in B cell development or through T cell tolerance. Conversely, the data suggest that it is not necessary to break central tolerance, even in an autoimmune mouse, to generate pathologic, disease-associated autoantibodies.

Adoptive Transfer↗

PubMed1997

Overexpressed Bcl-x(L) prevents bacterial superantigen-induced apoptosis of thymocytes in vitro.

bcl-x, a homologous gene of bcl-2, has an anti-apoptotic function and appears to play a critical role in the development of lymphoid systems. To investigate the effect of overexpressed Bcl-x(L) on the development of T lymphocytes, we established two lines of transgenic mice by using Emu-chicken bcl-x(L) (cbcl-x(L)) transgene, where the cBcl-x(L) protein was expressed mainly in lymphoid cells. Although thymocytes and splenocytes from cbcl-x(L) transgenic mice are resistant to apoptosis in vitro, clonal deletion of thymocytes, recognizing endogenous self-superantigens in the thymus, still normally proceeded and no self-reactive T cells were found in the spleen of the transgenic mice. To dissect clonal deletion, we utilized two in vitro models, thymocytes/antigen presenting cells co-culture system and fetal thymus organ culture system. In both, bacterial superantigen staphylococcus aureus enterotoxin B (SEB) induces apoptosis of T cells with Vbeta8+ T cell receptor (TCR) reacting to SEB, which mimics clonal deletion of self-reactive thymocytes in vivo. SEB-induced depletion of Vbeta8+ T cells from thymocytes when taken from the transgenic mice was effectively inhibited. The data might raise the possibility that cell death process involved in clonal deletion in the thymus is a form of apoptosis inhibited by Bcl-x(L).

Journal Article↗

PubMed1992

Retinoic acid in acute promyelocytic leukemia: a model for differentiation therapy.

Acute promyelocytic leukemia is a clonal expansion of malignant cells blocked at a specific stage of myeloid differentiation. The disease is associated with a specific translocation between chromosome 17 and chromosome 15 [t(15;17)] and with a bleeding diathesis previously attributed to disseminated intravascular coagulation, which has recently also been related to primary fibrinolysis. The high percentage of early deaths, about 20%, experienced by acute promyelocytic leukemia patients, is generally due to the hemorrhagic syndrome. A new finding is the high effectiveness of treatment with all-trans retinoic acid, a vitamin A derivative, for inducing complete remission. The induction of cellular maturation by this agent represents the first model of differentiation therapy. Furthermore, recent molecular studies revealed that the breakpoints of the t(15;17) translocation are clustered in the gene of retinoic acid receptor-alpha, generating a hybrid gene product. Gene transfection experiments disclosed the impairment of gene transactivation due to the hybrid gene products, opening new concepts for understanding leukemogenesis. Understanding the mechanisms of action of retinoic acid could extend differentiation therapy to other malignancies with aberrant gene transcription.

Carrier Proteins↗

PubMed1992

[Minimum residual leukemic cells in genetically marked brown Norway rat myelocytic leukemia model].

Different methods were used to detect minimal residual leukemic cells (LT 12 nl), which had been genetically marked with E. coli 1 acZ and neo-gene by retrovirus vector mediated gene transfer. The detection levels of flow cytometry based FDG staining and fluorophotometric method based MUG staining were 10(-3) to 10(-4) and 10(-2) to 10(-3), respectively. The method of G 418 selective agar culture was demonstrated as a 10(-4) to 10(-5) levels for the detection of LT 12 nl residual leukemic cells in bone marrow. The results indicated that the selective agar culture can be used as a sensitive method for the study of minimum residual disease in the BNML leukemia model. We have used the selective agar culture to study the distribution of clonal LT 12 nl cells in BNML during minimum residual disease (MRD). A heterogenous distribution pattern of the clonal leukemic cells was found in the genetically marked BNML leukemia model during the MRD phase.

Animals↗

PubMed1998

A caspase inhibitor protects thymocytes from diverse signal-mediated apoptosis but not from clonal deletion in fetal thymus organ culture.

A family of caspases has been implicated as an effector in various forms of apoptosis. The present study investigated whether this family of proteases is involved in the induction of intrathymic clonal deletion in comparison with apoptosis induced in the thymus by various signals. Potent apoptosis of thymocytes was induced in fetal thymus organ cultures (FTOC) when FTOC were treated with glucocorticoid, radiation, and anti-CD3 monoclonal antibody (mAb). As a model of negative selection based on apoptotic clonal deletion, the elimination of Vbeta8-expressing thymocytes was induced by inoculating Staphylococcal enterotoxin B (SEB) into FTOC. Addition of a peptide-based caspase inhibitor resulted in the protection of thymocytes from apoptosis induced by glucocorticoid, radiation, and anti-CD3 mAb. In contrast, the same treatment failed to prevent clonal deletion of Vbeta8high thymocytes. These results suggest that different pathways of cell death operate in the thymus that may be distinguished depending on the caspase/protease utilized in each pathway.

Amino Acid Chloromethyl Ketones↗

PubMed1998

Normal immunoglobulin G protects against experimental allergic encephalomyelitis by inducing transferable T cell unresponsiveness to myelin basic protein.

Normal human IgG for intravenous use (IVIg), administered intraperitoneally, protected Lewis rats against experimental allergic encephalomyelitis (EAE) induced by immunization with myelin basic protein (MBP). We demonstrate that protection was associated with an acquired unresponsiveness of lymphocytes to MBP and a decreased ability of the cells to produce IL-2, IFN-gamma and TNF-alpha and, to a lesser degree, IL-4 and IL-10, in the presence of the antigen. Lymph node (LN) cells of protected rats failed to passively transfer EAE to naive syngeneic animals. Our observations indicate that, rather than inducing selective immune deviation, IVIg induces preferential MBP unresponsiveness of Th1 cells. Whereas LN and splenic cells of IVIg-treated rats did not proliferate nor secrete IL-2 in the presence of the antigen, proliferation was restored by adding exogeneous recombinant IL-2. In contrast, LN cells of IVIg-treated rats proliferated normally and produced IL-2 in the presence of concanavalin A, indicating the selectivity for MBP of the anergy induced by IVIg when given at the time of immunization with the antigen. Treatment with IVIg also allowed a resistance to the secondary induction of EAE, indicating that IVIg protects from EAE but does not interfere with the processes that eventually lead to resistance to re-challenge. These data document the immunomodulatory effects of IVIg in T cell-dependent experimental autoimmune disease and further suggest a role for normal Ig in the selection of functional T cell repertoires.

Animals↗

PubMed1991

Isolation and molecular characterization of the B cells producing the paraprotein in a case of benign monoclonal gammapathy in C57BL mice.

Benign monoclonal gammapathy (BMG) is defined as a benign monoclonal B cell proliferative disorder characterized by the presence of a persisting component of homogenous immunoglobulins (H-Ig) in the serum. A possible role of antigenic stimulation in the development of BMG has been suggested. From a C57BL mouse, a murine model for BMG, we have isolated clonally related B cells in order to investigate the occurrence of somatic mutations in the variable heavy chain (VH) region of the genes of H-Ig-producing B cell clones. Therefore, B cells were immortalized by hybridoma technology. The hybridomas were screened for resemblance of the serum H-Ig component by Wieme agar electrophoresis, followed by immunoblotting and isoelectrofocusing. Clonal relationship was investigated by Southern blot analysis using a JH probe. In this way we isolated five hybridomas producing an IgG2a, kappa that was identical to the original serum H-Ig component according to testing with anti-idiotypic antisera. mRNA sequencing of four hybridomas showed only one base pair difference in the VH genes. This particular gene belonged to the J558 VH gene family. When compared to the most closely related known VH sequence, three base pair differences were found. The almost complete absence of base pair differences in the VH genes of the four sequenced hybridomas, compared with an independently derived hybridoma, suggests that the same germ-line VH gene has been used and that somatic mutations were infrequent in our BMG clone.

Animals↗

PubMed1996

The mechanism of UVB prevention of graft versus host disease.

We have previously demonstrated that Ultraviolet B (UVB) irradiation of Lewis donor bone marrow (BM) allografts prevents graft versus host disease (GVHD) in ACI recipients while allowing full engraftment. In a one-way GVHD model of parent to Lewis X BN (F1) rats, the site and mechanism of the action of UVB irradiation was assessed by adding nonirradiated isolated cell subsets, isolated by monoclonal antibodies (Mab) to cell surface markers, to the reconstituting UVB-irradiated bone marrow inoculum. GVHD was assessed primarily on clinical grounds by observation of posture, alopecia, skin erythema, and weight loss. The addition of nonirradiated spleen cells or non-UVB-irradiated T-cell subsets (both CD4 and CD8 positive) to the otherwise UVB-irradiated donor inoculum consistently resulted in acute GVHD. In contrast, UVB irradiation of these cells resulted in full engraftment without acute GVHD. Mixed lymphocyte culture (MLC) assays confirmed responsiveness by BM transplanted hosts to third party stimulators while coculture assays failed to show any in vitro suppressor activity in the host. We conclude that UVB acts on both the T-lymphocyte and antigen presenting cell (APC) subsets to prevent acute GVHD. We also propose a model to explain tolerance based on clonal anergy produced by modified antigen presentation by UVB-irradiated APC's or by a modified response to processed antigen.

Animals↗