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PubMed1988

Improved renal allograft survival following donor-specific transfusions. III. Kinetics of mixed lymphocyte culture responses before and after transplantation.

The essence of the clonal deletion model of the donor-specific transfusion (DST) effect is synergy between DST-priming and post-transplant immunosuppression. Using a sensitive kinetics assay of the mixed lymphocyte culture (MLC) response to donor and third-party stimulators, we compared the responses of controls (non-transfused healthy individuals) with those of patients who either had no rejection episodes in the first week posttransplant (group 1) or who had DST-type (greater than 3d onset) rejection episodes (group 2). We found that group 2 patients had normal or above-normal MLC responses after DST plus azathioprine (AZA) pretransplant treatment, but had a reduced/delayed posttransplant anti-donor MLC following reversal of early rejections (P = .05 compared with controls). Group 1 patients had a nonspecifically reduced MLC after DST + AZA treatment (P less than .02 compared with controls), while posttransplant MLC responses showed a return to normal (pretransfusion) levels. These data suggest a synergy of DST with immunosuppressive drug that induced MLC hyporesponsiveness, but only in patients who received anti-lymphoblast globulin or a sustained high dose immunosuppression in the early posttransplant period.

Azathioprine↗
PubMed2003

Relationship between molecular epidemiology and antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) in a French teaching hospital.

The objective of this study was to investigate the relationship between molecular epidemiology and antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) over a period of 4 years. The antibiotype of all MRSA isolates that were identified during a yearly period of 3 months was determined; 50 consecutive non-replicate MRSA isolates were typed each year. Susceptibility rates to gentamicin, tobramycin and ofloxacin remained stable (95, 16 and 4 %, respectively). In contrast, the proportion of MRSA isolates susceptible to erythromycin increased progressively from 10.5 to 32.5 % (P < 0.001). PFGE analysis of genomic DNA from 200 isolates revealed the presence of 15 different clones. Two epidemic clones were identified, which contained 150 (clone A) and 28 (clone C) isolates. Non-epidemic strains were more frequently susceptible to ofloxacin (31.8 versus 1.1 %) and tobramycin (45.4 versus 16.8 %) than epidemic strains; those isolates that were susceptible to all antibiotics tested belonged to sporadic clones. The increase of erythromycin susceptibility within MRSA isolates was caused by the emergence of clone C. This study suggests that when selection pressure exerted by an antibiotic is insufficient (i.e. below a threshold level), fitness advantages play a predominant role in the dissemination of MRSA clones. The balance between the selection pressure exerted by antibiotics and the disadvantage of lower replication rates of resistant strains in the absence of antibiotics complicates the biological model of clonal dissemination of epidemic MRSA strains.

Anti-Bacterial Agents↗
PubMed1996

Risk assessment of nongenotoxic carcinogens based upon cell proliferation/death rates in rodents.

Increased cell proliferation increases the opportunity for transformations of normal cells to malignant cells via intermediate cells. Nongenotoxic cytotoxic carcinogens that increase cell proliferation rates to replace necrotic cells are likely to have a threshold dose for cytotoxicity below which necrosis and hence, carcinogenesis do not occur. Thus, low dose cancer risk estimates based upon nonthreshold, linear extrapolation are inappropriate for this situation. However, a threshold dose is questionable if a nongenotoxic carcinogen acts via a cell receptor. Also, a nongenotoxic carcinogen that increases the cell proliferation rate, via the cell division rate and/or cell removal rate by apoptosis, by augmenting an existing endogenous mechanism is not likely to have a threshold dose. Whether or not a threshold dose exists for nongenotoxic carcinogens, it is of interest to study the relationship between lifetime tumor incidence and the cell proliferation rate. The Moolgavkar-Venzon-Knudson biologically based stochastic two-stage clonal expansion model is used to describe a carcinogenic process. Because the variability in cell proliferation rates among animals often makes it impossible to detect changes of less than 20% in the rate, it is shown that small changes in the cell proliferation rate, that may be obscured by the background noise in rates, can produce large changes in the lifetime tumor incidence as calculated from the Moolgavkar-Venzon-Knudson model. That is, dose response curves for cell proliferation and tumor incidence do not necessarily mimic each other. This makes the use of no observed effect levels (NOELs) for cell proliferation rates often inadmissible for establishing acceptable daily intakes (ADIs) of nongenotoxic carcinogens. In those cases where low dose linearity is not likely, a potential alternative to a NOEL is a benchmark dose corresponding to a small increase in the cell proliferation rate, e.g., 1%, to which appropriate safety (uncertainty) factors can be applied to arrive at an ADI.

Animals↗
PubMed2005

Heterogeneity of cancer risk due to stochastic effects.

Persons with exactly the same genetic background, behavior, environment, etc. may have differences in cancer risk due to a different number of cells on the way to malignancy. These differences are estimated quantitatively by using the two-stage clonal expansion model. For liver cancer the estimated relative risk for persons without intermediate cells at age 40 is less than 10% when compared to the risk of the total population, while the top 0.1% risk group has a more than 100-fold risk compared to the population. The risk of the 1% percentile in risk is more than 100-fold of the risk of the more than 95% persons without intermediate cells. The number of intermediate (premalignant) cells in the risk groups cannot be calculated from incidence data only because they depend strongly on a nonidentifiable parameter. But under plausible assumptions, less than about 1,000 intermediate cells are present at age 40 even in high-risk persons.

Adult↗
PubMed2003

Genetic diversity of Campylobacter jejuni isolates from farm animals and the farm environment.

The genetic diversity of Campylobacter jejuni isolates from farm animals and their environment was investigated by multilocus sequence typing (MLST). A total of 30 genotypes, defined by allelic profiles (assigned to sequence types [STs]), were found in 112 C. jejuni isolates originating in poultry, cattle, sheep, starlings, and slurry. All but two of these genotypes belonged to one of nine C. jejuni clonal complexes previously identified in isolates from human disease and retail food samples and one clonal complex previously associated with an environmental source. There was some evidence for the association of certain clonal complexes with particular farm animals: isolates belonging to the ST-45 complex predominated among poultry isolates but were absent among sheep isolates, while isolates belonging to the ST-61 and ST-42 complexes were predominant among sheep isolates but were absent from the poultry isolates. In contrast, ST-21 complex isolates were distributed among the different isolation sources. Comparison with MLST data from 91 human disease isolates showed small but significant genetic differentiation between the farm and human isolates; however, representatives of six clonal complexes were found in both samples. These data demonstrate that MLST and the clonal complex model can be used to identify and compare the genotypes of C. jejuni isolates from farm animals and the environment with those from retail food and human disease.

Alleles↗
PubMed2000

Diminishing returns of population size in the rate of RNA virus adaptation.

Whenever an asexual viral population evolves by adapting to new environmental conditions, beneficial mutations, the ultimate cause of adaptation, are randomly produced and then fixed in the population. The larger the population size and the higher the mutation rate, the more beneficial mutations can be produced per unit time. With the usually high mutation rate of RNA viruses and in a large enough population, several beneficial mutations could arise at the same time but in different genetic backgrounds, and if the virus is asexual, they will never be brought together through recombination. Thus, the best of these genotypes must outcompete each other on their way to fixation. This competition among beneficial mutations has the effect of slowing the overall rate of adaptation. This phenomenon is known as clonal interference. Clonal interference predicts a speed limit for adaptation as the population size increases. In the present report, by varying the size of evolving vesicular stomatitis virus populations, we found evidence clearly demonstrating this speed limit and thus indicating that clonal interference might be an important factor modulating the rate of adaptation to an in vitro cell system. Several evolutionary and epidemiological implications of the clonal interference model applied to RNA viruses are discussed.

Adaptation, Physiological↗
PubMed1989

A v-H-ras-dependent hemopoietic tumor model involving progression from a clonal stage of transformation competence to autocrine interleukin 3 production.

Autocrine interleukin 3 (IL-3)-secreting tumors were generated from an IL-3-dependent mouse mast cell line (PB-3c) after introduction of the v-H-ras oncogene. Tumor progression was characterized by four distinct phenotypes. The first corresponded to immortalized mast cells unresponsive to the oncogenic effect of v-H-ras. The second was expressed in a clonable subpopulation of PB-3c cells and was marked by the competence to form v-H-ras-dependent tumors (immortalized transformation competence). The third was a direct effect of v-H-ras expression on all PB-3c cells and was characterized in vitro by a reduced IL-3 requirement. Upon injection of v-H-ras-expressing, transformation-competent cells into mice, the final, fully malignant phenotype developed with a long latency period and was marked in vitro by independence of exogenous IL-3 and by autocrine IL-3 stimulation. Northern (RNA) blot analysis and an RNase A-T1 protection assay showed that IL-3 production was strictly associated with the tumor phenotype. Two of six tumors showed an alteration at the 5' region of the IL-3 gene. We conclude that v-H-ras required complementation by IL-3 gene rearrangement or an alternate event to generate autocrine mastocytomas.

Animals↗
PubMed2005

Multistage carcinogenesis and lung cancer mortality in three cohorts.

Experimental evidence indicates that tobacco smoke acts both as an initiator and a promoter in lung carcinogenesis. We used the two-stage clonal expansion model incorporating the ideas of initiation, promotion, and malignant conversion to analyze lung cancer mortality in three large cohorts, the British Doctors' cohort and the two American Cancer Society cohorts, to determine how smoking habits influence age-specific lung cancer rates via these mechanisms. Likelihood ratio tests indicate that smoking-related promotion is the dominant model mechanism associated with lung cancer mortality in all cohorts. Smoking-related initiation is less important than promotion but interacts synergistically with it. Although no information on ex-smokers is available in these data, the model with estimated variables can be used to project risks among ex-smokers. These projected risks are in good agreement with the risk among ex-smokers derived from other studies. We present 10-year projected risks for current and former smokers adjusted for competing causes of mortality. The importance of smoking duration on lung cancer risk in these cohorts is a direct consequence of promotion. Intervention and treatment strategies should focus on promotion as the primary etiologic mechanism in lung carcinogenesis.

Adult↗
PubMed1996

Transfer of human adenine deaminase gene into murine hematopoietic stem cells: sequential study of spleen colony-forming units from bone marrow of living mice and the requirement of the microenvironment.

Irradiated female mice were reconstituted with male hematopoietic stem cells (HSCs) retrovirally marked with human adenine deaminase (hADA) complimentary DNA. HSCs were incubated with interleukin-6 and stem cell factor before coculture with GP+E86-producing cells. Bone marrow HSCs were infused intravenously to irradiated mice and spleen colony-forming units (CFU-S) were evaluated for hADA marked clones by Southern blot analysis. 45 of 54 CFU-S were marked by the hADA gene sequence with multiple copies integrated per genome. Oligoclonal hematopoiesis evolved over time with 1-2 clones demonstrated 5-11 months after reconstitution. Comparable results were obtained with embryonic fetal liver HSCs. Incubation of bone marrow HSCs with adherent stromal cells rather than growth factors produced less efficient gene transfer, and polyclonal hematopoiesis was not observed. Donor origin was established by the Y chromosome probe. These results support the clonal succession model of hematopoiesis.

Aminohydrolases↗
PubMed2000

Leukemia relapse reconsidered from the molecular aspect.

Relapse, a major obstacle in the treatment of acute leukemia, is essentially caused by re-growth of residual leukemia cells, frequently accompanied by resistance to chemotherapy. Comparative studies of clones both at initial diagnosis and at subsequent relapse have indicated that phenotype and karyotype are frequently changed at relapse. This can be recognized as the result of negative selection by chemotherapy in a heterogeneous population. Furthermore, complex molecular alterations that include the loss of as well as the acquisition of mutations are noticed by comparing multiple genes associated with leukemia, suggesting a continuous genetic evolution. Studies on leukemia relapse have thus served as a model of clonal progression, which can be serially observed, including selection by chemotherapy, induction of resistant phenotype, and genetic alteration.

Antineoplastic Agents↗
PubMed2004

Malignant progression in meningioma: documentation of a series and analysis of cytogenetic findings.

OBJECT: The malignant progression of benign tumors is well documented in gliomas and other systemic lesions. It is also well known that some meningiomas become progressively aggressive despite their original benign status. The theory of clonal evolution is widely believed to explain malignant progression in meningioma; however, the data used to explain stepwise progression have typically been derived from the cytogenetic analysis of different types of tumors of different grades and in different patients. In this study, the authors examined the data obtained in a group of patients with meningiomas that showed clear histopathological progression toward a higher grade of malignancy and then analyzed the underlying cytogenetic findings. METHODS: Among 175 patients with recurrent meningiomas, 11 tumors showed a histopathological progression toward a higher grade that was associated with an aggressive clinical course. Six tumors progressed to malignancy and five to the atypical category over a period averaging 112 months. Tests for MIB-1 and p53 and cytogenetic studies with the fluorescence in situ hybridization (FISH) method were performed in successive specimens obtained in four patients. The MIB-1 value increased in subsequent samples of tumors. Cytogenetic analysis with FISH showed deletions of 22, 1p, and 14q. In all but one case, these aberrations were also present in the previous specimen despite its lower hispathological grade. CONCLUSIONS: The authors documented the progression of meningiomas from benign to a higher histological grade. These tumors were associated with a complex karyotype that was present ab initio in a histologically lower-grade tumor, contradicting the stepwise clonal evolution model. Although it was limited to the tested probes, the FISH method appears to be more accurate than the standard cytogenetic one in detecting these alterations. Tumors that present with complex genetic alterations, even those with a benign histological grade, are potentially aggressive and require closer follow up.

Adult↗
PubMed2026

Distributed Clonal Deletion Prevents Autoimmune Disease Progression.

Self-reactive B cells are generated during normal development and can acquire increased pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification following activation. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that clonal deletion is enforced through temporally distinct mitochondrial apoptosis (MOMP) checkpoints that differentially regulate autoreactive B cell fate and disease progression. Using conditional Bcl-2 expression to inhibit MOMP either before or after B cell activation, we find that early inhibition permits the survival and maturation of autoreactive B cells after peripheral egress, expanding the pool of cells available for activation. These cells subsequently undergo AID-dependent diversification, producing class-switched IgG autoantibodies with expanded antigen breadth that target a wider range of self-antigens and drive lethal, female-biased autoimmune disease characterized by complement activation and kidney pathology. In contrast, inhibition of MOMP only after activation allows the accumulation of germinal center, switched memory, and plasma cells and promotes autoantibody production, but results in more restricted IgG autoreactivity, limited complement activation and limited tissue damage, and normal survival. Notably, early MOMP inhibition does not expand immature bone marrow B cells, indicating that a major clonal deletion checkpoint operates in the periphery rather than during initial B cell generation. Together, these findings support a Distributed Clonal Deletion Model in which early checkpoints restrict the entry of autoreactive B cells into diversification pathways, while later checkpoints limit the persistence of diversified autoreactive clones, thereby constraining autoimmune disease progression.

Journal Article↗
PubMed1987

The role of suppressor T cells in the expression of immune response gene function.

Mechanisms underlying major histocompatibility complex (MHC)-linked immune response (Ir) gene regulation of immune responses have been the subject of considerable interest and debate in recent years. Two general mechanisms have been proposed to account for antigen-specific, Ir gene-mediated unresponsiveness. In one, defective antigen presentation resulted from the failure of processed nominal antigen and Ia antigen to associate on the antigen presenting cell membrane in a manner sufficient for helper T cell (Th cell) activation. By contrast, it has been proposed that selected Th cell clones were deleted from the repertoire during ontogeny or otherwise rendered unresponsive to the antigen-Ia complex, i.e., functionally deleted. Either of these mechanisms would account for the deficient activation of antigen-specific, Th cells observed in genetic low or nonresponder mice. In addition, the failure of mice to respond to certain antigens under Ir gene control has been attributed to the activation of specific suppressor T (Ts) cells. The latter mechanism might be considered a corollary or subset of the clonal deletion model. However, an important distinction exists. In the case of active, Ts cell-mediated Ir gene regulation, genetic low responder animals should retain the capacity for antigen-induced activation of Th cells, or Th cell activity should be demonstrable in these mice. In this communication, experiments are described which are designed to evaluate the possibility that active Ts cell-mediated regulatory mechanisms were of general importance in mediating Ir gene-related unresponsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

Predominance of autoimmune and rheumatic diseases in females.

This paper offers an explanation for the higher female incidence found in many of the autoimmune and rheumatic diseases. A list of these diseases (Table 1) shows that half of them occur in three females for each male affected. Females are genetic and hence antigenic mosaics, half their somatic cells expressing antigens derived from the paternal X, half from the maternal X (female heterochromatinization). The Burnet-Jerne theory of somatic generation of antibody diversity and forbidden clone elimination states that lymphocytes under maturation in the thymus are killed or suppressed if they recognize and hence react to a histocompatibility antigen. If this were to hold for other self antigens as well, as recent models of clonal generation and selection mechanisms predict, then lymphocytes happening to pass the crucial stage in the thymus meeting only cells expressing one of the parental X's could be released still able to react to self i.e. those somatic cells expressing the other parental X with which the lymphocyte had not been in contact. Thus, self-tolerance would be more easily broken in females than in males.

Autoimmune Diseases↗
PubMed1982

The organization of hemopoietic tissue as inferred from the effects of 5-fluorouracil.

Mouse bone marrow obtained one day after injection of 5-fluorouracil (FU) had a markedly diminished content of spleen colony forming units (CFUs) but retained its capacity to repopulate the marrow granulocyte-macrophage colony forming cell (GM-CFC) and CFUs compartments of 850 R irradiated hosts and had only a slightly reduced platelet repopulating ability (PRA). A significant correlation (r = 0.94, P less than 0.001) was observed between the content of high proliferative potential granulocyte-macrophage progenitor (HPP-GM-CFC) and the platelet and marrow GM-CFC repopulating abilities of bone marrow cell suspensions. Spleens of irradiated mice, injected with marrow from donors treated with FU between 1 and 7 days before showed an increase in colony numbers with time of sampling between 8-13 days after transplantation. In contrast, the colony counts observed in mice injected with normal bone marrow remained constant over that time interval. The colonies derived from bone marrow of FU treated mice grew faster than those from bone marrow of normal mice. Spleens obtained from irradiated mice, 10 days after injection of bone marrow derived from donors treated with FU 1 or 3 days before, showed only a few macroscopic surface colonies but when sectioned were found to contain large numbers of microscopic colonies, 80% of which were megakaryocytic. The results are interpreted on the basis of a clonal succession model of hemopoiesis with stem cells of varying proliferative potential and proliferation rates increasing as capacity for cell production decreases.

Animals↗
PubMed1995

Modulation of anti-IgM-induced B cell apoptosis by Bcl-xL and CD40 in WEHI-231 cells. Dissociation from cell cycle arrest and dependence on the avidity of the antibody-IgM receptor interaction.

The demise of B cell progenitors expressing functional IgM receptors for self appears to be the main mechanism by which B cell tolerance is accomplished. The genetic mechanisms that regulate the death process during this critical step of B cell development are still poorly understood. We have studied the regulation of apoptosis in WEHI-231 lymphoma cells after treatment with a panel of anti-IgM mAbs as an in vitro model of clonal B cell deletion. We showed that a product of bcl-x, Bcl-xL, can inhibit anti-IgM-induced apoptosis but not cell cycle arrest in a dose-dependent manner. Bcl-xL was efficient in protecting B cells from low but not high avidity anti-IgM mAbs. In contrast to that observed with Bcl-xL, CD40 stimulation was efficient in inhibiting both cell cycle arrest and apoptosis after IgM cross-linking regardless of the binding avidity of the anti-IgM Ab. Moreover, activation through IgM receptors but not CD40 induced up-regulation followed by rapid down-modulation of Bcl-xL. Thus, the capacity of Bcl-xL to modulate anti-IgM-induced apoptosis in WEHI-231 cells is highly dependent on the avidity of the Ab-IgM receptor interaction.

Animals↗