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PubMed1988

Changes in idiotypic predominance in the anti-arsonate response by priming with anti-idiotypic antibodies.

The predominant selection of CRI-A-bearing antibodies during the anti-arsonate (ARS) response of A/J mice has been used as a model to analyse the mechanism involved in the process of clonal selection and establishment of predominance. In order to assess the importance of the affinity and adaptability of CRI-A clones in this process, we tested the capability of a minor recurrent idiotype (id-1A3), present in a CRI-Aanti-ARS monoclonal antibody (65-1A3), to develop a normal anti-ARS response. Our results show that the id-1A3 predominance, established by anti-id-1A3 administration was stable during the primary and secondary anti-ARS response and that this predominance occurred concomitantly with low levels of CRI-A. Thus, a change in the idiotype predominance was achieved. In spite of the high levels of id-1A3, the anti-ARS antibody concentration, the affinity values, and the kinetics of the immune response were similar to those of the control group. All these results show that CRI-A clones are not essential in the normal development of the anti-ARS antibody response of A/J mice, and suggest that factors other than affinity could be involved in the establishment of the CRI-A predominance.

Animals↗
PubMed1996

Pancreatic islet allograft immunity and tolerance: the two-signal hypothesis revisited.

The principle assumption of this discussion is that costimulation (CoS) forms the primary stimulus that compels T cells to mount a response to their specific antigen. However, this response can be either positive or negative, depending on the developmental stage of the T cell and the microenvironment in which the antigen and CoS are received. Thus, both immunity and tolerance may represent different outcomes of a two-signal process. We would emphasize that CoS is a functional term and not a strict molecular definition. While many molecular interactions have been described as providing CoS activity, notably those involving the B-7 family of cell surface molecules, it is not yet clear what combination(s) of non-antigen-specific signals may fulfil this function. This point is important because many studies have achieved tolerance through strategies designed to inhibit specific CoS molecules. However, it may be that differential signaling through distinct CoS molecules, rather than a global inhibition of CoS per se, plays a role in the generation of active tolerance in such studies (Bluestone 1995). A corollary of this notion is that antigen (signal 1) delivery to T cells is a null event and so is not an inherently paralysing signal. Of course, if signal 1 is not itself a tolerogenic signal, then other mechanisms are necessary to explain many empirical observations of tolerance to allogeneic or self antigens. This is best illustrated by those forms of functional tolerance to either alloantigens or self antigens that do not appear to be the result of clonal deletion/inactivation. It would be relatively simple to invoke a model of tolerance whereby the relevant tissue-destructive cell is eliminated or inactivated; such a model would preclude the necessity to suggest active regulatory mechanisms of tolerance. However, in several model systems, including our own observations concerning tolerance induction to APC-depleted islet allografts, tissue-destructive T cells can persist in recipients tolerant to allogeneic or self antigens. Furthermore, there are key examples in which tolerance demonstrates a dominant phenotype; that is, tolerant cells can regulate the activity of naive, non-tolerant cells. This latter observation points to the function of an active, regulatory form of tolerance. As such, we would emphasize that tolerance should not be defined as unresponsiveness since the tolerant state is the consequence of very active immune reactions.

Animals↗
PubMed1993

Guanine arabinoside as a bone marrow-purging agent.

Arabinosylguanine (araG) is a nucleoside analogue that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate (araGTP), resulting in inhibition of DNA synthesis and selective in vitro toxicity to T lymphoblastoid cell lines as well as to freshly isolated leukemia cells from patients with T cell acute lymphoblastic leukemia (ALL). We have previously demonstrated that araG is an effective agent to use for chemoseparation of malignant T lymphoblasts from human bone marrow. When freshly isolated human T leukemia cells or T lymphoblastoid cells were treated with 100 microM araG for 18 hours, up to 6 logs of clonogenic T cells are eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We subsequently described studies in a murine model of T cell acute lymphoblastic leukemia (ALL) in which we tested whether bone marrow contaminated with malignant T cells and purged ex vivo with araG, could reconstitute both the lymphoid and myeloerythroid lineages in the absence of leukemic relapse. The model utilized 6C3HED tumor cells, derived from a Thy 1.2+ malignant murine T cell line, which were shown to cause lethal leukemia in C3H/HeN mice. Intravenous injection of 10(6) 6C3HED cells resulted in 100 percent mortality within 18 days, with autopsy revealing tumor infiltration of multiple organs. Evidence of araG's ability to purge bone marrow of malignant tumor cells without causing significant toxicity to normal marrow-derived hematopoietic progenitor cells was documented in experiments in which 75 percent of lethally irradiated mice receiving transplants of syngeneic bone marrow contaminated with 6C3HED tumor cells and treated ex vivo with 100 mM araG for 18 hours survived for 250 to > 400 days. Reconstitution of the lymphoid, myeloid, and erythroid lineages with donor cells in surviving mice was documented. The data presented indicate that araG may effectively purge bone marrow of malignant T cells without irreversible toxicity to hematopoietic stem cells. This purging regimen is recommended for consideration for clinical trials in patients with T cell malignancies undergoing autologous bone marrow transplantation and may also be a viable option for T cell depletion as a strategy to prevent graft versus host disease.

Animals↗
PubMed2003

Oral tolerance.

Autoimmune conditions caused by injurious immune responses against self-antigens can be ameliorated if the inappropriate responses to self-components that cause tissue injury can be modulated by regulatory cells or shut off via the induction of anergy or via deletion of pathogenic immune responses. Antigen encounter at the gut mucosa can lead to suppression of injurious immune responses to self-antigen via these mechanisms. This type of immunological event is termed oral tolerance. In this review, we examine the mechanisms behind the induction of oral tolerance and provide findings from its use as a form of treatment for autoimmune diseases.

Administration, Oral↗
PubMed1988

Compositional stability of artificial heterogeneous tumors in vivo: use of mitomycin C as a cytotoxic probe.

A major part of the overall response of solid cancers to cytotoxic treatments will be due to the differential sensitivities of the neoplastic cell subpopulations present. To quantitatively investigate this, artificial heterogeneous human colon xenograft tumors were constructed using two clonally related cell lines (A and D) which were mixed to create compositions of approximately 9:1 or 1:9 A:D cells. Then, the pure A, D, or admixed tumors were challenged with mitomycin C which kills A cells more efficiently than D cells by a factor of about 2.3 as determined by in vitro survival curve inactivation slopes. This difference was also exhibited in vivo by the post-mitomycin C cell survival responses determined by excision assay and by the shapes of the regrowth curves of the pure A and D or admixed tumors. By approximately 30 days after treatment, artificial heterogeneous tumors had reached a new stable cellular composition which could be quantitatively predicted based on the individual survival of A and D cells from pure clonal tumors measured 24 h after treatment. Thus, in this model system, cytotoxic treatment of heterogeneous neoplasms produced predictable and stable, albeit altered, percentage admixtures of subpopulations. This result is consistent with the observed decreased clinical responsivity of primary tumors to sequential courses of therapy due to selection of preexisting resistant subpopulations.

Animals↗
PubMed1994

Stable multilineage hematopoietic chimerism in alpha-thalassemic mice induced by a bone marrow subpopulation that excludes the majority of day-12 spleen colony-forming units.

We have investigated the contribution of highly purified day-12 spleen colony-forming units (CFU-S-12) as well as more primitive cells to sustained blood cell production using in vivo and in vitro assays that allow frequency analysis. Normal or day-6 post-5-fluorouracil light-density bone marrow (BM) was sorted on the basis of differences in rhodamine-123 (Rh123) retention or wheat germ agglutinin (WGA) affinity and tested in vivo using a recently developed alpha-thalassemic chimeric mouse model. In addition, short-term and long-term clonal activity was assessed in vitro using a limiting dilution-type long-term BM culture, the cobblestone area forming cell assay. When sublethally irradiated alpha-thalassemic mice were transplanted with as many as 281 purified WGAbright CFU-S-12, derived from a fraction containing 95% of all CFU-S-12 from day-6 post-5-fluorouracil light-density BM of wild-type mice, detectable chimerism was not observed at 6 months posttransplantation. In contrast, only three CFU-S-12 were included in the Rh123dull and WGAdim subpopulations that induced 29% to 58% and 21% to 31% stable multilineage donor-type chimerism of erythrocytes and leukocytes, respectively. The Rh123dull and WGAdim cells were up to 240-fold enriched for long-term repopulating ability (LTRA) as compared with unseparated BM. A comparable level of chimerism was found in the different hematopoietic organs and at the level of BM CFU-S-12. The frequency of the LTRA unit capable of inducing a 10% sustained level of donor-type erythrocytes was calculated to be 1 to 2 per 10(5) BM cells. Several reports have suggested that LTRA and spleen colony formation could be capacities of the same stem cell subset. However, the present results show that the majority of CFU-S-12 have only short-term repopulating ability and are physically separable from more primitive stem cells with long-term multilineage reconstituting capacities.

Animals↗
PubMed1998

Autoimmunity develops in lupus-prone NZB mice despite normal T cell tolerance.

NZB mice spontaneously develop an autoimmune disease characterized by production of anti-RBC, -lymphocyte, and -ssDNA Abs. Evidence suggests that the NZB mouse strain has all of the immunologic defects required to produce lupus nephritis but lacks an MHC locus that allows pathogenic anti-dsDNA Ab production. The capacity to produce diverse autoantibodies in these mice raises the possibility that they possess a generalized defect in self-tolerance. To determine whether this defect is found within the T cell subset, we backcrossed a transgene encoding bovine insulin (BI) onto the NZB background. In nonautoimmune BALB/c mice, the BI transgene induces a profound but incomplete state of T cell tolerance mediated predominantly by clonal anergy. Comparison of tolerance in NZB and BALB/c BI-transgenic mice clearly demonstrated that NZB T cells were at least as tolerant to BI as BALB/c T cells. NZB BI-transgenic mice did not spontaneously produce anti-BI Abs, and following antigenic challenge, BI-specific Ab production was comparably reduced in both BI-transgenic NZB and BALB/c mice. Further, in vitro BI-specific T cell proliferation and cytokine secretion were appropriately decreased for primed lymph node and splenic T cells derived from NZB BI-transgenic relative to their nontransgenic counterparts. These data indicate that a generalized T cell tolerance defect does not underlie the autoimmune disease in NZB mice. Instead, we propose that the T cell-dependent production of pathogenic IgG autoantibodies in these mice arises from abnormal activation of T cells in the setting of normal but incomplete tolerance.

Animals↗
PubMed1985

Feline glucose-6-phosphate dehydrogenase cellular mosaicism. Application to the study of retrovirus-induced pure red cell aplasia.

Neoplasms result from the uncontrolled proliferation of abnormal or transformed cells. The early stages of this process are difficult to study because of the lack of sensitive and specific markers of clonal evolution in an experimental system. We have developed a cat model using cellular mosaicism for glucose-6-phosphate dehydrogenase (G-6-PD). Our findings confirm that the structural locus for feline G-6-PD is on the X-chromosome and demonstrate that it is randomly inactivated in somatic cells. Heterozygous cats have balanced ratios of G-6-PD enzyme types in peripheral blood cells and hematopoietic progenitors that remain stable over time. In our initial studies, we used the model to analyze the events surrounding marrow failure experimentally induced by selected strains of feline leukemia virus (FeLV). Two G-6-PD heterozygous cats, one F1 male hybrid and one domestic cat were infected with FeLV (C or KT) and developed pure red cell aplasia (PRCA). Colonies arising from the more mature erythroid colony-forming cell were not detected in marrow culture of anemic animals although erythroid bursts persisted, suggesting that the differentiation of early erythroid progenitors (BFU-E) was inhibited in vivo. The ratio of G-6-PD types in hematopoietic progenitors and peripheral blood cells from the heterozygous cats did not change when the animals developed PRCA. Thus, the anemia did not result from the clonal expansion of a transformed myeloid stem cell. With this experimental approach, one may prospectively assess clonal evolution and cellular interactions in other FeLV-induced diseases.

Animals↗
PubMed2000

In vitro model of equine muscle regeneration.

Equine satellite cells are responsible for muscle healing and regeneration in the mature horse. We describe the in vitro cell culture conditions required for clonal populations of equine satellite cells to undergo both proliferation and differentiation. Our hypothesis is that these in vitro conditions model regeneration of muscle and can be used to evaluate potential therapeutics. In this study, 2 areas of satellite cell response were tested: proliferation of clones induced by growth factors, and fusion induced by culture conditions. Equine satellite cell clones showed differences in their response to growth factors as well as accumulation of cellular protein concentrations. Equine satellite cells proliferate in response to both human and bovine FGF. IGF-1, a powerful mitogen of other satellite cell culture systems, was not as effective for inducing equine satellite cell proliferation. Protein concentrations were also measured in satellite cell cultures. Clones differed in cellular protein produced depending on growth conditions. Conditions inducing differentiation into myotubes was also determined for a 96 well assay and can be used to study the final stage of functioning muscle production. This in vitro model is the first step in identifying potential therapeutics to speed wound healing and promote muscle regeneration in horses.

Animals↗
PubMed2002

Risk of myelodysplastic syndrome and acute myeloid leukemia in congenital neutropenias.

Granulocyte colony-stimulating factor (G-CSF) has had a major impact on the management of "severe chronic neutropenia" (SCN), a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia and Shwachman-Diamond syndrome (SDS) have developed myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The issue is complicated because both disorders have a propensity for MDS or AML as part of their natural history. To address this, the Severe Chronic Neutropenia International Registry (SCNIR) used its large database of chronic neutropenia patients treated with G-CSF to determine the incidence of malignant myeloid transformation in the two disorders, and its relationship to treatment and to other patient characteristics. No statistically significant relationships were found between age at onset of MDS or AML and patient gender, G-CSF dose, or duration of G-CSF therapy. What was observed, however, was the multistep acquisition of aberrant cellular genetic changes in marrow cells from patients who transformed, including activating ras oncogene mutations, clonal cytogenetic abnormalities, and G-CSF receptor mutations. In murine models, the latter produces a hyperproliferative response to G-CSF, confers resistance to apoptosis, and enhances cell survival. Since congenital neutropenia and SDS are inherited forms of bone marrow failure, G-CSF may accelerate the propensity for MDS/AML in the genetically altered stem and progenitor cells, especially in those with G-CSF receptor and ras mutations (82% and 50% of patients who transform, respectively). Alternatively, and equally plausible, G-CSF may simply be an "innocent bystander" that corrects neutropenia, prolongs patient survival, and allows time for the malignant predisposition to declare itself. In patients who transform to overt MDS or AML, hematopoietic stem cell transplantation is the only chance for cure. In those with "soft" signs of MDS, such as an isolated clonal cytogenetic change but without other evidence of MDS, or with an isolated G-CSF receptor mutation, there is room for conservative management. One option is to reduce the G-CSF dosage as much as possible, and observe the tempo of progression, if any, to more overt signs of malignancy.

Acute Disease↗
PubMed2003

Comparable in vivo efficacy of CD28/B7, ICOS/GL50, and ICOS/GL50B costimulatory pathways in murine tumor models: IFNgamma-dependent enhancement of CTL priming, effector functions, and tumor specific memory CTL.

Increasing evidence suggests that B7/CD28 interactions are important in clonal expansion and effector function of nai;ve CD4(+) T cells, whereas ICOS/GL50 interactions may optimize the responses of recently activated T(H) cells. In tumor models, it has been shown that engagement of ICOS, like CD28, by its ligands can be effective in enhancing tumor immunity. In this report, we have directly compared the in vivo efficacy of CD28 vs ICOS activation in the MethA fibrosarcoma and B16F1 melanoma tumor models. We studied the efficacy of systemic treatment of tumors with murine B7.2-IgG or GL50-IgG fusion proteins, and the therapeutic potential of B7.1 or GL50 vaccines given during various phases of the antitumor responses. In addition, we compare the efficacy of ICOS-ligand splice variants GL50 and GL50B in promoting tumor immunity. We find that each of these pathways is equally effective in promoting tumor immunity and that the efficacy of both GL50 and B7.1 vaccines is IFN-gamma but not IL-10 dependent. Our results suggest that CD28 or ICOS costimulation-based strategies may be equally efficacious as adjuvants to conventional cancer treatment.

Animals↗
PubMed2005

Estimating the number of rate limiting genomic changes for human breast cancer.

We used multistage models that incorporate the age dependent dynamics of normal breast tissue, clonal expansion of intermediate cells and mutational events to fit data for the age-specific incidence of breast cancers in the surveillance, epidemiology, and end results (SEER) registry. Our results suggest that two or three rate limiting events occurring at rates characteristic of point mutation rates for normal mammalian cells set in motion a sequence of other genomic changes that lead with high probability to breast carcinoma.

Adolescent↗
PubMed1997

A two-stage model for childhood acute lymphoblastic leukemia: application to hereditary and nonhereditary leukemogenesis.

A differential equation model is developed to represent a two-stage mutational process leading to childhood acute lymphoblastic leukemia (ALL). Leukemogenesis is modeled as transformation of target stem cells that initially grow rapidly in the embryo but plateau and then decline in postnatal childhood. Inheritance of the first of two leukemogenic mutations is allowed as a possibility in a small minority of leukemic patients who would characteristically develop leukemia at an early age. The model is shown to be capable of providing good fits to incidence data for childhood ALL; these fits allow estimation of some parameters of the model. The analysis shows that individuals inheriting one of the two mutations necessary for ALL would be likely to experience "multiclonal leukemogenesis"; that is, the parallel development of several leukemic clones arising from multiple independent leukemic events. The model suggests that between two and ten such clones would typically have developed in such individuals by the time of diagnosis. The main conclusions of the deterministic investigation were confirmed by stochastic modeling. The existence of multiclonal leukemogenesis is in principle testable by molecular biological methods (clonality analysis) that rely on the random inactivation of one of two X-chromosomes in normal female subjects. It is expected that the mathematical methods developed here will also be useful for more general (N-stage) models of malignant transformation of stem cell populations undergoing growth or decline.

Aging↗
PubMed1996

Immunodominance, competition and evolution in immunological responses to helminth parasite antigens.

The paper describes the development and analysis of a mathematical framework for the study of the within-host population dynamics of the interaction between macroparasites and the human immune system. Simple models of this interaction based on the proliferation of T cell clones specific to parasite antigen, and the impact of clonal expansion on parasite survival, capture the basic features of age-related changes in worm loads within human communities. The model is generalized to multiple epitopes on a single antigen, and reveals competitive exclusion amongst T cells, with a single clone becoming immunodominant in the absence of cross-reactive responses and genetic variation. The introduction of genetic heterogeneity and concomitant variability in the immunogenicity of specific epitopes induces additional complexity into the dynamical interaction. Most importantly, multiple epitope models with antigenic variation suggest that the immunodominant response may not necessarily be targeted at the epitope at which some strains show the greatest immunogenicity. High immunogenicity at a particular epitope can be masked by genetic variability even though many of the variants are more immunogenic at this epitope by comparison with the epitope to which the immunodominant immunological response is directed.

Animals↗
PubMed2005

Impact of clonal growth on effective population size in Hymenoxys herbacea (Asteraceae).

By influencing the proliferation of different genotypes, clonal growth can affect the maintenance of genetic variability and magnitude of genetic drift within plant populations. However, estimates of effective population size rarely incorporate the contribution of both asexual and sexual reproduction. We estimated effective size (Ne) for two populations of the clonal, self-incompatible plant, Hymenoxys herbacea, using a stage-structured demographic model for organisms with asexual and sexual recruitment and then examined the impact of reproductive strategy using an elasticity analysis. Plant rosettes monitored in two successive years had high survival rates in both populations (mean 0.94). The mean number of sexually derived recruits per initial ramet was 0.041 (SE 0.039), whereas the mean number of clonal recruits was 0.61 (SE 0.90). Effective size was 1642 and 5769 in the two populations and the Ne/N ratio averaged 0.34, comparable to values for other clonal species. Elasticity analysis indicated that increases in both clonal and sexual recruitment cause an increase in Ne while increasing the variance reduced Ne. However, Ne was more sensitive to changes in the mean and variance of asexual recruitment than sexual recruitment. These results highlight the importance of considering asexual modes of reproduction when examining the role of genetic stochasticity in populations.

Asteraceae↗
PubMed1995

The trouble with transgenic mice.

Observations on many antigen-receptor transgenic models with anti-self specificities have been interpreted as proof for clonal deletion or for mechanisms involved in clonal deletion. At the same time, there is increasing evidence that many lymphocytes that recognize self exist, are activated and produce end products, even in individuals without clinical autoimmunity. Except perhaps for the amount of anti-self activity, there is little agreement on what distinguishes immune products normally recognizing self from those associated with clinical autoimmunity. To resolve this paradox, the tendency in immunology is to accept conclusions from transgenic models as normal, while judging those from the unmanipulated state as suspect. However, transgenics have a major weakness. Transgenes encoding antigen-receptors are derived from highly selected mature lymphocytes and are expressed in developing lymphocytes that normally do not display the antigen-receptors of mature lymphocytes. Such precocious expression of antigen-receptors could have profound abnormal effects on lymphocyte development. Other transgenic models suggest that processes in lymphocyte differentiation not involving antigen-receptor binding specificity exert powerful influences on lymphocyte development; therefore, mechanisms other than classical positive and negative selection are important.

Animals↗