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PubMed1999

gamma delta+ T cells regulate major histocompatibility complex class II(IA and IE)-dependent susceptibility to coxsackievirus B3-induced autoimmune myocarditis.

Coxsackievirus B3 (CVB3) infection induces myocardial inflammation and myocyte necrosis in some, but not all, strains of mice. C57BL/6 mice, which inherently lack major histocompatibility complex (MHC) class II IE antigen, develop minimal cardiac lesions despite high levels of virus in the heart. The present experiments evaluate the relative roles of class II IA and IE expression on myocarditis susceptibility in four transgenic C57BL/6 mouse strains differing in MHC class II antigen expression. Animals lacking MHC class II IE antigen (C57BL/6 [IA+ IE-] and ABo [IA- IE-]) developed minimal cardiac lesions subsequent to infection despite high concentrations of virus in the heart. In contrast, strains expressing IE (ABo Ealpha [IA- IE+] and Bl.Tg.Ealpha [IA+ IE+]) had substantial cardiac injury. Myocarditis susceptibility correlated to a Th1 (gamma interferon-positive) cell response in the spleen, while disease resistance correlated to a preferential Th2 (interleukin-4-positive) phenotype. Vgamma/Vdelta analysis indicates that distinct subpopulations of gamma delta+ T cells are activated after CVB3 infection of C57BL/6 and Bl.Tg.Ealpha mice. Depletion of gamma delta+ T cells abrogated myocarditis susceptibility in IE+ animals and resulted in a Th1-->Th2 phenotype shift. These studies indicate that the MHC class II antigen haplotype controls myocarditis susceptibility, that this control is most likely mediated through the type of gamma delta T cells activated during CVB3 infection, and finally that different subpopulations of gamma delta+ T cells may either promote or inhibit Th1 cell responses.

Animals↗

PubMed2000

Role of endothelial cell denudation and smooth muscle cell dedifferentiation in neointimal formation of human vein grafts after coronary artery bypass grafting: therapeutic implications.

OBJECTIVE: To provide better insights into the genesis of neointimal thickening in human vein grafts early after surgery. DESIGN: Retrospective study. SETTING: Tertiary referral centre. SUBJECTS: 18 distal anastomotic sites of patent grafts, obtained at necropsy from eight patients who died over differing periods (ranging from two days to nine months) after the procedure. MAIN OUTCOME MEASURES: Immunohistochemical evaluation of smooth muscle cell phenotype modulation in relation to proliferative activity. RESULTS: The earliest changes are characterised by loss of surface lining endothelial cells and insudation of blood corpuscular elements admixed with fibrin-platelet thrombus. At sites of injury vimentin positive and actin negative spindle shaped cells appear in the intima, while the related pre-existent media shows focal absence of actin positive smooth muscle cells. Proliferative activity colocalises at these sites. With time distinct neointimal thickening occurs, associated with disappearance of proliferative activity and a phenotypic shift of the smooth muscle cells. CONCLUSIONS: The observation that luminal endothelial cell denudation, with insudation of the intima with blood elements, occurs in the very early stages suggests that these phenomena are responsible for the observed dedifferentiation of pre-existent smooth muscle cells, known to be a prerequisite for cell proliferation and the evolution of intimal thickening. It is likely, therefore, that platelet released growth factors play a pivotal role, which thus may provide a target for preventive pharmacological intervention.

Aged↗

PubMed2005

Changes in the human muscle force-velocity relationship in response to resistance training and subsequent detraining.

Previous studies show that cessation of resistance training, commonly known as "detraining," is associated with strength loss, decreased neural drive, and muscular atrophy. Detraining may also increase the expression of fast muscle myosin heavy chain (MHC) isoforms. The present study examined the effect of detraining subsequent to resistance training on contractile performance during slow-to-medium velocity isokinetic muscle contraction vs. performance of maximal velocity "unloaded" limb movement (i.e., no external loading of the limb). Maximal knee extensor strength was measured in an isokinetic dynamometer at 30 and 240 degrees/s, and performance of maximal velocity limb movement was measured with a goniometer during maximal unloaded knee extension. Muscle cross-sectional area was determined with MRI. Electromyographic signals were measured in the quadriceps and hamstring muscles. Twitch contractions were evoked in the passive vastus lateralis muscle. MHC isoform composition was determined with SDS-PAGE. Isokinetic muscle strength increased 18% (P < 0.01) and 10% (P < 0.05) at slow and medium velocities, respectively, along with gains in muscle cross-sectional area and increased electromyogram in response to 3 mo of resistance training. After 3 mo of detraining these gains were lost, whereas in contrast maximal unloaded knee extension velocity and power increased 14% (P < 0.05) and 44% (P < 0.05), respectively. Additionally, faster muscle twitch contractile properties along with an increased and decreased amount of MHC type II and MHC type I isoforms, respectively, were observed. In conclusion, detraining subsequent to resistance training increases maximal unloaded movement speed and power in previously untrained subjects. A phenotypic shift toward faster muscle MHC isoforms (I --> IIA --> IIX) and faster electrically evoked muscle contractile properties in response to detraining may explain the present results.

Adaptation, Physiological↗

PubMed2003

Prion proteins and infertility: insight from mouse models.

A wealth of evidence points to an abnormal form of the prion protein called PrP(Sc) as the transmissible agent responsible for prion diseases. However, the physiological function of its normal conformer, the cellular prion protein (PrP(C)), is still unknown. Recently, a homologue of PrP(C) was discovered and denoted Doppel (Dpl). In contrast to PrP, mice deficient for Dpl suffer from an important pathological phenotype: male sterility. This phenotype shifts the attention from the brain, where most of the investigations on Dpl have been performed, to testis, raising hope to resolve the long lasting search of PrP(C) function.

Animals↗

PubMed2003

Increased mitogenic and decreased contractile P2 receptors in smooth muscle cells by shear stress in human vessels with intact endothelium.

OBJECTIVE: We investigated the role of shear stress in regulating P2 receptors in human umbilical vein. METHODS AND RESULTS: Using a novel, computerized, biomechanical perfusion model, parallel vessel segments were randomized to simultaneous perfusion under high (25 dyn/cm2) or low (<4 dyn/cm2) shear stress at identical mean perfusion pressure (20 mm Hg) for 6 hours. In the endothelium, no significant P2 receptor mRNA differences were found. In smooth muscle cells (SMCs), high shear stress decreased P2X1 receptors, whereas P2Y2 and P2Y6 receptors were upregulated. These findings were consistent at the mRNA level (real-time reverse transcription-polymerase chain reaction), protein level (Western blot), and morphologically (immunohistochemistry). The changes were more pronounced in the subintimal layer of the media. CONCLUSIONS: Our findings suggest that shear stress might regulate gene expression in SMCs more than in the endothelium in intact vessels. Decreased expression of the contractile P2X1 receptor could lead to reduced vascular tonus and increased blood flow. Because P2Y2 and P2Y6 receptors stimulate growth and migration of SMCs, increased expression of these receptors could promote vascular remodeling induced by shear stress. The pattern of upregulation of mitogenic P2Y receptors and downregulation of contractile P2X1 receptor is similar to changes seen in the phenotypic shift from contractile to synthetic SMCs.

Blotting, Western↗

PubMed2006

Implications of early structural-functional changes in the endothelium for vascular disease.

By location, between the blood and tissues and the multiple functions, the endothelial cells (ECs) play a major role in securing body homeostasis. The ECs sense all variations occurring in the plasma and interstitial fluid, and respond (function of intensity), initially by modulation of their constitutive functions, then by dysfunction, expressed by temporarily altered functions and a phenotypic shift, and ultimately by injury/death. In dyslipidemia/hyperglycemia, the initial response of EC is the modulation of 2 constitutive functions: permeability and biosynthesis. Increased transcytosis of plasma beta-lipoproteins leads to their accumulation within the hyperplasic basal lamina, interaction with matrix proteins, and conversion to modified and reassembled lipoproteins (MRL). This generates a multipart inflammatory process and EC dysfunction characterized by expression of new cell adhesion molecules and MCP-1 that trigger T-lymphocytes and monocyte recruitment, diapedesis, and homing within the subendothelium where activated macrophages become foam cells. The latter, together with the subendothelial accrual of MRL, growth factors, cytokines, and chemokines, and accretion of smooth muscle cells of various sources lead to atheroma formation; in advanced disease, the EC overlaying atheroma take up lipids, become EC-derived foam cells, and the cytotoxic ambient ultimately conducts to EC apoptosis. Understanding the mechanisms of EC dysfunction is a prerequisite for EC-targeted therapy to reduce the incidence of cardiovascular diseases.

Animals↗

PubMed1998

Blockade of CC chemokine receptor 5 (CCR5)-tropic human immunodeficiency virus-1 replication in human lymphoid tissue by CC chemokines.

The CC chemokines MIP-1alpha, MIP-1beta, and RANTES suppress replication of certain HIV-1 strains in cultured PBMC and T cell lines by blocking interaction of gp120 with CC chemokine receptor 5 (CCR5). However, the same chemokines can enhance HIV-1 replication in cultured macrophages. The net effect of chemokines on HIV-1 infection in intact lymphoid tissue, the major reservoir of HIV-1 in vivo, is unknown and unpredictable since the tissue contains both T lymphocytes and macrophages. Here we show that exogenous MIP-1alpha, MIP-1beta, and RANTES markedly suppressed replication of CCR5-tropic HIV-1 strains in blocks of human lymphoid tissue infected ex vivo. Moreover, endogenous MIP-1alpha, MIP-1beta, and RANTES were upregulated in tissues infected ex vivo with CXC chemokine receptor 4-tropic but not CCR5-tropic HIV-1. Such an upregulation may contribute to the virus phenotype shift in the course of HIV disease in vivo.

Chemokine CCL3↗

PubMed2000

Molecular mechanisms involved in the differentiation of spermatogenic stem cells.

In male mammals, spermatogenesis proceeds for the reproductive lifetime of the animal. The continuation of this process depends upon a pool of spermatogenic stem cells within the testes that undergo asymmetric division to both maintain the stem cell population and give rise to progenitors that will proceed through spermatogenesis to generate mature spermatozoa. Thus, the development of functional spermatozoa may be divided into two distinct stages. The second, the process of spermatogenesis, is dependent upon the first, the successful formation of spermatogenic stem cells. Although spermatogenesis is characterized by marked cellular differentiation, the initial stages of germ line differentiation involve an avoidance of the differentiation signals acting during embryo development. The germ line is set aside early in embryo development and, while the primordial germ cells remain refractory to the differentiation signals affecting the soma, they undergo a number of phenotypic shifts before and after colonizing the genital ridge. Upon colonization of the genital ridge, the somatic tissue of the male genital ridge directs the final differentiation events that result in the formation of spermatogenic stem cells. It is this cell population that provides the basis for the maintenance of spermatogenesis in the adult.

Animals↗

PubMed1999

Responses of vascular smooth muscle cell to extracellular matrix degradation.

Vessels remodel to compensate for increases in blood flow/pressure. The chronic exposure of blood vessels to increased flow and circulatory redox-homocysteine may injure vascular endothelium and disrupt elastic laminae. In order to understand the role of extracellular matrix (ECM) degradation in vascular structure and function, we isolated human vascular smooth muscle cells (VSMC) from normal and injured coronary arteries. The apparently normal vessels were isolated from explanted human hearts. The vessels were injured by inserting a blade into the lumen of the vessel, which damages the inner elastic laminae in the vessel wall and polarizes the VSMC by producing a pseudopodial phenotypic shift in VSMC. This shift is characteristic of migratory, invasive, and contractile nature of VSMC. We measured extracellular matrix metalloproteinases (MMPs), tissue plasminogen activator (tPA), tissue inhibitor of metalloproteinase (TIMP), and collagen I expression in VSMC by specific substrate zymography and Northern blot analyses. The injured and elastin peptide, val-gly-val-ala-pro-gly, treated VSMC synthesized active MMPs and reduced expression of TIMP. The level of tPA and collagen type I was induced in the injured, invasive VSMC and in the val-gly-val-ala-pro-gly treated cells. To demonstrate the angiogenic role of elastin peptide to VSMC we performed in vitro organ culture with rings from normal coronary artery. After 3 days in culture the vascular rings in the collagen gel containing elastin peptide elaborated MMP activity and sprouted and grew. The results suggest that val-gly-val-ala-pro-gly peptide generated at the site of proteolysis during vascular injury may have angiogenic activity.

Amino Acid Sequence↗

PubMed2000

[Circulation of the poliovirus in endemic zones with children vaccinated by the oral polio vaccine].

Strategies aiming to eradicate the poliovirus and poliomyelitis seek primarily to eliminate wild strains associated with the disease, by means of world wide vaccination campaigns using the oral attenuated vaccine (OPV). OPV contains attenuated viral strains which retain their replicating capacity in the digestive tract and thus induce the development of an antiviral local intestinal immunity and limit the circulation of the virus. In such a context, poliomyelitis surveillance laboratories should study above all cases of acute flaccid paralysis (AFP), highlighting the circulation of wild strains, identifying regional reservoirs and guiding vaccination strategies. Alongside circulation, there appear to be important genetic and phenotypic shifts in vaccinating strains, since the OPV is capable of preserving a reservoir of pathogenic stains and thereby impairing vaccination efficacy and the eradication of the virus. Furthermore, non-polio enteroviruses should be considered as a source of emerging pathogenic strains. These questions are being studied by the Pasteur Institute with the objective of determining the effects of OPV campaigns on the circulation of the poliovirus. We have studied the poliovirus vaccine and the circulation of wild strains in urban and peripheral urban areas in African countries known to be endemic for poliomyelitis (Central African Republic, Madagascar, Côte d'Ivoire). The study population consisted of children who had already been vaccinated and new-borns in the course of vaccination. We also evaluated the diffusion of the vaccine strains in their immediate environment. Genetic interchanges were taken into account. For children who received the 3-4 OPV doses, asymptomatic virus excretion was insignificant (0.4-2.4%). The rate of virus excretion in the surrounding environment of children in the course of being vaccinated was relatively low (1.76-5.3%). Our study also detected variant and recombinant strains.

Central African Republic↗

PubMed2004

[Reprogramming of adult human pancreatic duct cells as functional beta cells].

The most plausible therapy for type I diabetes is restoration of the functional beta cell mass, as is proven by the clinical success of transplantation of donor beta cells. This approach, however, is very limited by the low number of donor organs available. One solution for this shortage would be well controlled generation of beta cells for transplantation. The bona fide beta progenitor cell is not known yet. As duct cells of the adult human pancreas show a high degree of plasticity, they were genetically manipulated to transdifferentiate into beta cells. The transcription factor neurogenin 3, a master switch of embryogenesis of the endocrine pancreas, was ectopically expressed in adult human pancreatic duct cells. Neurogenin 3 induced a phenotypic shift by activation of a series of endocrine marker genes, among which insulin. However, the number of insulin-producing cells and the amount of insulin per cell were low and the transdifferentiated duct cells remained glucose insensitive. A strategy for optimizing the reprogramming of adult human duct cells to beta cells is proposed.

Cell Differentiation↗

PubMed1985

Repopulation of the mouse thymus after sublethal fission neutron irradiation. I. Sequential appearance of thymocyte subpopulations.

The T cell composition of the thymus of sublethal fission neutron-irradiated CBA/H mice was analyzed with cytofluorometry and immunohistology, using monoclonal antibodies directed to the cell surface antigens Thy-1, T-200, MT-4, Lyt-1, Lyt-2, and MEL-14. The results of this investigation show that whole body irradiation with 2.5 Gy fission neutrons results in a severe reduction and degeneration of the cortex, whereas the medulla is affected to a lesser extent. Irradiation selects, within 24 hr, for a population of dull Thy-1+, bright T-200+, bright Lyt-1+ cells localized in the medulla. Phenotype analysis of the regeneration of the thymus, which starts at about 5 days after irradiation, reveals the sequential appearance of: 1) "null" cells, i.e., lymphoblasts negative for all tested antigens, mainly in the subcapsular area but also in the medulla; 2) Thy-1+ "only" and T-200+ "only" cells in the subcapsular area; 3) Thy-1+, T-200+ cells; and 4) Thy-1+, T-200+, MT-4+, Lyt+ cells in the cortex. In addition, an increased MEL-14 expression is observed in correlation with the expression of Thy-1 and T-200 determinants during the regeneration of the thymus. From day 10 on up to at least 150 days after irradiation, no differences can be observed in the thymus of irradiated and age-matched sham-irradiated control mice, as measured by the expression and distribution of Thy-1, T-200, MT-4, Lyt-1, Lyt-2, and MEL-14 antigens. The observed sequence in phenotype shift in the regeneration of the thymus after irradiation is discussed in view of recently published data on the differentiation of the T cell system.

Animals↗

PubMed1988

Effects of different thyroid treatments on the biochemical characteristics of rabbit myocardium.

It is well established that extreme dysthyroidism drastically alters the biochemical character of cardiac muscle. The purpose of this study was to determine if minor thyroid treatments would result in significant changes in the character of three major biochemical systems of muscle: metabolic; calcium regulating; and contractile systems. Different groups of New Zealand white rabbits had continuous time release propylthiouracil (PTU) pellets (500, 300, 200 and 100 mg) or triiodothyronine (T3) pellets (15 and 25 mg) subcutaneously implanted for 21 days. The ventricular myosin phenotypes shifted from 92% V3 myosin in the control rabbit hearts to 55% V3 and 10% V3 in the 15 mg and 25 mg T3 groups, respectively. PTU treatment resulted in a complete shift to the V3 myosin isoform. The sarcoplasmic reticulum Ca2+-ATPase activity increased with T3 and decreased with PTU treatments, except in the 500 mg PTU group. Ca2+-ATPase activity in the groups either side of the euthyroid group (100 mg PTU and 15 mg T3) did not change significantly. The glycolytic or aerobic potentials of the myocardium did not change with any of these minor thyroid treatments. It was concluded that the metabolic, enzymes, sarcoplasmic reticulum Ca2+-ATPase and myosin isozymes have different sensitivities to thyroid treatment and that minor thyroid treatments do result in significant changes in the biochemical character of the myocardium. These findings indicate that subclinical deviations in euthyroid status may affect myocardial biochemical character.

Animals↗

PubMed1993

Detection of residual disease in AML patients by use of double immunological marker analysis for terminal deoxynucleotidyl transferase and myeloid markers.

In the majority of patients with acute myeloid leukemia (AML) immature leukemic subpopulations expressing myeloid markers and terminal deoxynucleotidyl transferase (TdT) are present. The normal counterparts of these double-positive cells are rare in bone marrow (BM) (< 0.03%; if they occur at all) and are not detectable in peripheral blood (PB). In 14 patients with TdT+ AML at diagnosis, we have performed a prospective follow-up study to monitor the myeloid-marker+, TdT+ cells during and after chemotherapy. One patient did not obtain complete remission (CR), a second patient relapsed under therapy, whereas the other 12 patients were in cytomorphological CR at the end of chemotherapy. During subsequent follow-up, seven of these 12 patients developed one or two relapses (total of ten relapses). Nine of these ten relapses were preceded by a gradual increase of myeloid-marker+, TdT+ cells in BM and PB samples over a period of 14-38 weeks. Based on comparable results in BM and PB samples and doubling times of 15-20 days, we propose that monitoring of AML patients should include PB sampling each 4-6 weeks. In one patient the relapse was not preceded by a gradual increase of double-positive cells. This false negative result was caused by a phenotypic shift, since at relapse the AML cells did not express TdT. In the five AML patients who still are in continuous cytomorphological CR for 32-46 months we repeatedly detected relatively high percentages of myeloid-marker+, TdT+ cells in BM (up to 0.1%) and PB (up to 0.02%). Although we could not prove the leukemic origin of these double-positive cells, they might represent residual dysplastic AML cells which survived chemotherapy but which are not capable of causing leukemia regrowth as yet. This would be in line with recent polymerase chain reaction studies, which could demonstrate the persistence of leukemic clones in the majority of AML patients in continuous CR. It is concluded that double immunofluorescence labeling for myeloid markers and TdT is useful for detection of residual disease in TdT+ AML patients. A gradual increase of double-positive cells is suggestive for leukemic cell growth and can be used to predict relapse.

Acute Disease↗

PubMed1994

Heart failure: an update on pathophysiology.

Myocardial hypertrophy is an established risk factor for cardiovascular morbidity and mortality. Beyond quantitative and mechanical aspects hypertrophy is associated with alterations in cardiac gene expression, resulting in a more fetal-like myocyte phenotype with a fragile Ca++ homeostasis. Depressed expression of sarcoplasmatic reticulum ATPase is the hallmark of this overload phenotype. Conversely, the gene expression and the activity of sodium calcium exchanger is up-regulated in endstage heart failure. Both alterations contribute to prolonged cytosolic Ca++ transients, disturbed relaxation and, probably, to electrophysiologic instability. Angiotensin II is a growth promoting agent and several lines of circumferential evidence suggest that the local formation of angiotensin II might contribute to the trophic response and phenotype shift in cardiac overload. The cardiac gene expression of angiotensin converting enzyme and angiotensinogen is increased early after cardiac overload and in patients with severe heart failure. Chronic ACE inhibition suppresses plasma and tissue ACE activity, reduces LV hypertrophy and improves long-term survival. The hallmark of the peripheral adaptation in chronic heart failure is systemic vasoconstriction, associated with neurohumoral activation. Several mechanisms are involved in the impaired peripheral perfusion, including increased sympathetic tone and increased vascular stiffness. Recently, data suggest an important role of the endothelium for perfusion of skeletal muscle in heart failure. Endothelium-dependent dilation of resistance vessels is blunted in patients with severe chronic heart failure. Conceivably, this abnormality may be involved in the impaired reactive hyperemia in patients with chronic heart failure. Moreover, alterations of skeletal muscle emerge in chronic heart failure contributing to reduced exercise performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗

PubMed1995

[Hepatic neoductules].

Proliferation of preexisting bile ducts, ductular metaplasia of hepatocytes and proliferation and differentiation of liver stem cells are discussed in the pathogenesis of neoductular structures in the liver. Under the condition of experimental bile duct obstruction and in extrahepatic bile duct stenosis neoductular structures are first the result of proliferation and sprouting of preexisting ducts and cholangioles. Especially in later stages of cholestasis but also in other chronic progredient liver diseases such as chronic alcoholic liver disease and chronic active hepatitis periportal hepatocytes may show a phenotypic shift towards ductular epithelia. In postnatal liver diseases hepatocytes first express keratin 7 and later keratin 19 during ductular transdifferentiation. This is in contrast to embryonal cholangiogenesis. In alpha-1-antitrypsin-deficiency, hemochromatosis, Wilson's disease, and chronic active hepatitis B cellular deposites typically located in hepatocytes such as alpha-1-AT, siderin, copper, HBs-Ag, and HBc-Ag can also be found in neoductular cells close to hepatocytes. These deposites seem to be retained during the ductular transdifferentiation of hepatocytes. Expression of bile duct-type integrin subtypes and TGF beta 1 in neoductular cells are involved in the changing parenchymal/mesenchymal interplay during neoductogenesis, resulting in periductular basal membrane and periductular fibrosis. In FNH the ductular transdifferentiation of hepatocytes is integrated in the histogenesis of micronodules and portal tract equivalents of these tumor-like lesions. Ductular structures in hepatoblastomas and especially in combined hepatocellular and cholangiocarcinomas (CHCC) may reflect the common embryologic derivation of hepatocytes and biliary epithelia. Non-neoplastic liver tissue in resection specimens of our CHCC showed a lower rate of cirrhosis, and a significantly higher Ki 67-LI of neoductular cells compared to liver tissue in resection specimens of HCC and liver metastases. 3 of 10 CHCC had developed in alpha-1-AT-deficiency, in which this protease-inhibitor was predominantly retained in periportal hepatocytes. These findings in non-neoplastic tumor-bearing liver tissue suggest that CHCC include a special histogenic type of primary liver carcinoma which in analogy to some experimental liver tumors might develop from periportal parenchymal cells.

Animals↗

PubMed1984

Analysis of variability in albumin content of sister hepatoma cells and a model for geometric phenotypic variability (quantitative shift model).

A model (quantitative shift model) is presented that can account for the phenomenon termed geometric phenotypic variability in which quantitative variation occurs along a square root 2-fold geometric series. The model is based on data for variability in albumin content in hepatoma cells and has three basic assumptions: (i) The albumin genes on each chromosome are active and under independent quantitative regulation. (ii) The rate of albumin gene transcription per cell is the sum of the rates of transcription of the genes of each chromosome. (iii) The mechanism that controls the rate of transcription is highly variable so that at each cell cycle there is a high probability (P = 0.1-0.3) that on the newly synthesized chromatid the rate of transcription of the albumin gene will be different from that of the old chromatid. However, if the rate is different, it will usually be either half or twice the levels of the old chromatid. A computer program was developed based on the model that can generate quantitative diversity in single cells that mimics the pattern of variability in albumin content between sister hepatoma cells, among cells in clonal colonies, and in cell populations where the periodicities in single-cell distributions are compared by Fourier transform analysis. It was determined that the rate of phenotypic variability is indirectly proportional to the magnitude of the quantitative shift in albumin content and that it can be as high as 0.3 per cell per generation. Also, the square root 2 factor in geometric phenotypic variability appears to be an average of a family of values and not the actual value of the smallest quantal shift.

Animals↗

PubMed2000

A shift in the phenotype of melan-A-specific CTL identifies melanoma patients with an active tumor-specific immune response.

In a significant proportion of melanoma patients, CTL specific for the melan-A(26/7-35) epitope can be detected in peripheral blood using HLA-A2/peptide tetramers. However, the functional capacity of these CTL has been controversial, since although they prove to be effective killers after in vitro expansion, in some patients they have blunted activation responses ex vivo. We used phenotypic markers to characterize melan-A tetramer(+) cells in both normal individuals and melanoma patients, and correlated these markers with ex vivo assays of CTL function. Melanoma patients with detectable melan-A tetramer(+) cells in peripheral blood fell into two groups. Seven of thirteen patients had a CCR7(+) CD45R0(-) CD45RA(+) phenotype, the same as that found in some healthy controls, and this phenotype was associated with a lack of response to melan-A peptide ex vivo. In the remaining six patients, melan-A tetramer(+) cells were shifted toward a CCR7(-) CD45R0(+) CD45RA(-) phenotype, and responses to melan-A peptide could be readily demonstrated ex vivo. When lymph nodes infiltrated by melan-A-expressing melanoma cells were examined, a similar dichotomy emerged. These findings demonstrate that activation of melan-A-specific CTL occurs in only some patients with malignant melanoma, and that only patients with such active immune responses are capable of responding to Ag in ex vivo assays.

Adult↗