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Cancer Biotherapy & Radiopharmaceuticals Dec 2003This paper is presented as a sequel to the Mitogen Information Summaries article, representing a condensation of salient features involved with facilitating the curative... (Review)
Review
This paper is presented as a sequel to the Mitogen Information Summaries article, representing a condensation of salient features involved with facilitating the curative potential of the more important mitogen applications. Following is a resumé of the critical attributes of mitogen therapy relative to the management of malignant tumors: (1) An inherent capability to recognize and destroy mutated or damaged tissues without altering those that are normal; (2) The capacity to induce global immunostimulation by the nonspecific activation of CD4+/- and CD8+/- cells with balanced production of a variety of cytokines able to stimulate B cell, NK cell, and macrophage pathways, at the same time augmenting myeloproliferation; (3) The ability to afford protection and accelerated recovery from the immunosuppressive and myelosuppressive effects of tumors, infections, GvH reactions, and autoimmune states along with the surgery, irradiation, chemotherapeutic agents, antibiotics, and suppressive factors used in their management; (4) Berke's in vitro data from the lectin-dependent cellular cytotoxicity (LDCC) system showing that systemic administration of mitogens such as PHA-L4 should indeed prove destructive to virtually any type of malignancy, leaving normal tissues undamaged; and (5) The potential of these activities to reconstitute the immune competence so vital to lasting cures. The potential role of L4 immunotherapy for infections may be defined by the following criteria: those, including drug-resistant infections, not satisfactorily treatable otherwise; those in which a rapid response is essential; those that are subclinical, latent, recurrent, chronic, persistent, highly lethal, or opportunistic; those in patients with impaired immune responses; and most importantly, those that are not likely to be adversely affected by immunostimulation. Certain paths of administration such as the intralesional (for granulomas), intrapleural (for pleurisy, empyema), and intraperitoneal (for peritonitis) routes might be tested as supplements to intravenous administration in treating infections using dosages comparable to tumor therapy. Intradermal or dermal applications might be used alone for localized viral or fungal skin lesions. The comparative advantages of each mitogen are listed as follows: PHA-L4, longest experience and most complete, including use in humans; Fraction IV PHA, nonagglutinating, otherwise comparable to L4; PWM, nonagglutinating in the broad mitogenic range, high potency that reduces dosage requirements, noncommercial product preferable for experimental studies and for potential advancement to human use.
Topics: Animals; Forecasting; Humans; Immunotherapy; Mitogens
PubMed: 14969603
DOI: 10.1089/108497803322702879 -
Immunologic Research Feb 2023The proliferation of antigen-specific lymphocyte clones, the initial step in acquired immunity, is vital for effector functions. Proliferation tests both in immunology... (Comparative Study)
Comparative Study
The proliferation of antigen-specific lymphocyte clones, the initial step in acquired immunity, is vital for effector functions. Proliferation tests both in immunology research and diagnosis are gaining attendance gradually, while the use of adult healthy individuals as controls of pediatric patients is a question. This study aimed to investigate and compare mitogen-stimulated proliferation responses of total lymphocytes and T- and B-lymphocyte subsets in adult and children healthy donors. Nineteen children and 20 adult healthy donors were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) purified from peripheral blood samples of the donors, by Ficoll gradient centrifugation, were stained with CFSE and were cultured in a 37 ℃ CO incubator for 120 h with the absence or existence of polyclonal activators: PHA and CD-Mix. After cell culture, PBMCs were stained with monoclonal antibodies against CD4 and CD19, and proliferation percentages of CD4 T and CD19 B cells, together with total lymphocytes were determined by flow cytometry. This study revealed similarities between children and adult age groups, concerning mitogenic stimulation of the lymphocytes. The only difference was a significantly high proliferation of pediatric CD4 T cells in response to PHA. CD4 T cell responses against PHA were inversely correlated with altering age. When pediatric individuals were distributed into age groups of 0-2 years, 3-5 years, and 6-18 years, PHA responses of CD4 cells were found to be diminished with advancing age. These findings propose the possibility of enrollment of adult healthy individuals as controls for pediatric patients.
Topics: Adult; Child; Child, Preschool; Humans; Infant; Infant, Newborn; CD4-Positive T-Lymphocytes; Cell Proliferation; Flow Cytometry; Leukocytes, Mononuclear; Lymphocyte Activation; Mitogens; Adolescent
PubMed: 36261686
DOI: 10.1007/s12026-022-09328-2 -
Cancer Biotherapy & Radiopharmaceuticals Jun 1997Ideal treatment of HIV-1 infections should include an agent that can reverse the capacity of the virus to evade destruction by hiding in sanctuaries and by frequently... (Review)
Review
Ideal treatment of HIV-1 infections should include an agent that can reverse the capacity of the virus to evade destruction by hiding in sanctuaries and by frequently mutating the epitopes it displays. The rapid proliferation of virions during the years of symptomatic quiescence obligates rapid replacement of CD4+ lymphocytes that leads to a gradual attrition of the T lymphocytes needed to control infections. In vitro evidences suggest that, given systematically, certain mitogenic lectins would interfere with HIV-1 invasion of CD4+ cells by blocking gp120 molecules on the viral membrane before activating T lymphocytes subsequent to binding with their Ti/CD3 molecules. The nonspecific nature of antiviral effector cells generated by this activation should circumvent HIV-1 mutations at the same time it reconstitutes depleted T lymphocytes, stimulates myelopoiesis, and reinforces resistance to malignancies and infections prevalent with the immunodeficiency state. Properly coordinating these effects with appropriate combinations of reverse transcriptase and protease inhibitors could theoretically expedite complete elimination of HIV in a timely fashion that shorten the required treatment duration and excludes the detrimental effects of virus mutations. The proper sequence of this treatment should be maximum reduction of the HIV-1 load with drug combinations, control of complicating infection by other means to reduce mitogen-induced tissue necrosis, and addition of systemic PHA-L4 administration regulated to maintain a 5-10 micrograms/mL serum concentration. The antiviral regimen should be continued an undetermined time beyond when HIV-1 is no longer detectable, and systemic L4 administration until satisfactory immunologic and hematologic competences are re-established. Partially-matched mitogen-activated adoptive leukocyte therapy might be additionally helpful.
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; HIV-1; Humans; Immunotherapy, Adoptive; Interleukin-12; Lectins; Mitogens; T-Lymphocytes
PubMed: 10851467
DOI: 10.1089/cbr.1997.12.213 -
Science (New York, N.Y.) Jun 2020Multicellular organisms use mitogens to regulate cell proliferation, but how fluctuating mitogenic signals are converted into proliferation-quiescence decisions is...
Multicellular organisms use mitogens to regulate cell proliferation, but how fluctuating mitogenic signals are converted into proliferation-quiescence decisions is poorly understood. In this work, we combined live-cell imaging with temporally controlled perturbations to determine the time scale and mechanisms underlying this system in human cells. Contrary to the textbook model that cells sense mitogen availability only in the G cell cycle phase, we find that mitogenic signaling is temporally integrated throughout the entire mother cell cycle and that even a 1-hour lapse in mitogen signaling can influence cell proliferation more than 12 hours later. Protein translation rates serve as the integrator that proportionally converts mitogen history into corresponding levels of cyclin D in the G phase of the mother cell, which controls the proliferation-quiescence decision in daughter cells and thereby couples protein production with cell proliferation.
Topics: Cell Proliferation; Cyclin D; G1 Phase; G2 Phase; Humans; Mitogen-Activated Protein Kinase Kinases; Mitogens; Protein Biosynthesis; Signal Transduction; Stem Cells
PubMed: 32241885
DOI: 10.1126/science.aay8241 -
The American Journal of Physiology May 1997Serotonin (5-hydroxytryptamine) has been known for the last half century to influence vasoactivity and to participate in neurotransmission. More recently, this compound... (Review)
Review
Serotonin (5-hydroxytryptamine) has been known for the last half century to influence vasoactivity and to participate in neurotransmission. More recently, this compound has been recognized to cause proliferation of a variety of cells in culture, including those of vascular smooth muscle. Furthermore, the proliferative effect is synergistic with that of more conventional growth-producing polypeptides. A hypertrophic, as well as a proliferative response, has been shown to occur in some smooth muscle cells. Whether the mitogenic effect is initiated through a cell surface receptor or a serotonin transporter, or both depending on the cell type, is currently unresolved. Most evidence indicates that cellular cyclic nucleotides play an important role in the intracellular signaling process for growth regulation by serotonin, and newer studies point to protein phosphorylation pathways as being important in the mitogenic response. It has been proposed that, through these signaling pathways, serotonin plays an important role in remodeling of both the pulmonary and systemic circulations.
Topics: Animals; Biological Transport, Active; Cell Physiological Phenomena; Humans; Hypoxia; Mitogens; Receptors, Serotonin; Serotonin; Signal Transduction; Vascular Diseases
PubMed: 9176241
DOI: 10.1152/ajplung.1997.272.5.L795 -
Journal of Visualized Experiments : JoVE Dec 2016Lymphocyte proliferation in response to antigenic or mitogenic stimulation is a readily quantifiable phenomenon useful for testing immunomodulatory (i.e.,...
Lymphocyte proliferation in response to antigenic or mitogenic stimulation is a readily quantifiable phenomenon useful for testing immunomodulatory (i.e., immunosuppressive or immunostimulatory) chemical compounds and biologics. One of the earliest steps during mitogenesis is cell enlargement or blastogenic transformation, whereupon the cell volume increases before division. It is usually detectable in the first several hours of T-lymphocyte stimulation. Here, we describe a rapid method to quantify blastogenesis in T lymphocytes isolated from mouse spleens and human peripheral blood mononuclear cells (PBMCs) using an automated cell counter. Various commonly used proliferation assays for the most part are laborious and only reflect the overall population effect rather than individual cellular effects within a population. In contrast, the presented automated cell counter assay provides rapid, direct, and precise measurements of cell diameters that can be used for assessing the effectiveness of various mitogens and immunomodulatory drugs in vitro.
Topics: Animals; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Mitogens; T-Lymphocytes
PubMed: 28060354
DOI: 10.3791/55212 -
Developmental Biology May 1986Single fiber-satellite cell units from skeletal muscle of adult rats were used to study the regulation of satellite cell proliferation. The satellite cells remained...
Single fiber-satellite cell units from skeletal muscle of adult rats were used to study the regulation of satellite cell proliferation. The satellite cells remained quiescent during culture in serum-containing medium but could be induced to enter the cell cycle by exposure to a saline extract of crushed adult muscle. The activity in the extract has a molecular weight greater than 30K and is heat and trypsin sensitive. The mitogenic activity does not result from transferrin. Little or no activity was obtained from crushed extracts of heterologous tissues. Proliferation of myogenic cells from rat embryos was also stimulated by the muscle mitogen but growth of muscle fibroblasts was not enhanced. The time response of satellite cell proliferation after exposure to the muscle mitogen showed that the cells enter DNA synthesis after a lag period of 18 hr and proliferate with a generation time of 12 hr. This confirms that satellite cells in adult muscle are in G0, or an extended G1. The mitogen is also effective in stimulating muscle growth and myoblast fusion in vivo when injected into 1-week-old rat pups. These experiments suggest that muscle regeneration is initiated by the release of an endogenous mitogen from traumatized muscle.
Topics: Animals; Cell Division; Cells, Cultured; Chick Embryo; DNA; Mitogens; Muscles; Rats; Rats, Inbred Strains; Stem Cells; Tissue Extracts; Transferrin
PubMed: 3699242
DOI: 10.1016/0012-1606(86)90235-6 -
Journal of Toxicology and Environmental... Sep 2022Environmental contaminants perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are present in human serum at the highest concentration among all per- and...
Environmental contaminants perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are present in human serum at the highest concentration among all per- and polyfluoroalkyl substances (PFAS). Serum concentrations as high as 500 ng and 3000 ng PFOA/ml have been detected in individuals living near contamination sites and those occupationally exposed, respectively. Animal and human studies indicated that PFOA and PFOS at these serum concentrations perturb the immune system. The aim of this study was to examine the effects of exposure of human peripheral blood mononuclear cells (PBMC) to 1, 10, or 100 µM PFOA or PFOS in a medium with serum (RPMI-1640 + 5% human AB serum) on the measurement of proliferation, T cell activation, generation of memory T cells, and cytokine production/secretion. In addition, these immune system parameters were assessed for PBMC in a serum-free medium (OpSFM), which was stimulated with phytohemagglutinin (PHA) (2.5 µg/ml) or influenza vaccine antigen (0.625 µg/ml Flu Ag). PFOS decreased proliferation stimulated by PHA or Flu Ag. With Flu Ag stimulation, PFOA and PFOS inhibited the generation of memory T cells in a concentration-dependent manner. In OpSFM, PFOA and PFOS produced no marked change in proliferation and no inhibition of T cell activation. Cytokines measured in the media with Luminex methodology indicated decreased PBMC secretion of IFN-γ by PFOA and PFOS in medium with serum, but no alteration in OpSFM. The results indicated that changes in immune parameters due to PFOA or PFOS following Flu Ag stimulation are medium (±serum) dependent.
Topics: Alkanesulfonic Acids; Animals; Caprylates; Fluorocarbons; Humans; Leukocytes, Mononuclear; Mitogens
PubMed: 35611390
DOI: 10.1080/15287394.2022.2075816 -
European Journal of Clinical... Mar 2024Impaired T-cell responses to mitogens and high T-cell activation marker (TAM) expression on Mycobacterium tuberculosis-specific T-cells characterize immunopathology in...
Impaired T-cell responses to mitogens and high T-cell activation marker (TAM) expression on Mycobacterium tuberculosis-specific T-cells characterize immunopathology in patients with tuberculosis (TB). In a study of patients with TB (n = 60) and asymptomatic contacts (controls, n = 37), we found that TB patients had higher CD38 T-cell proportions specific for M. tuberculosis protein (PPD), yet total proportions of PPD-specific T-cells were comparable. Notably, both activated (CD38) and total IFN-γ T-cells from TB patients had lower mitogen (phytohemagglutinin, PHA)-induced responses. This impaired mitogen response improved the classification efficacy of the TAM-TB assay, especially employing the PPD/PHA-induced T-cell ratio.
Topics: Humans; Mitogens; Tuberculin; Tuberculosis; Mycobacterium tuberculosis; T-Lymphocytes; Antigens, Bacterial
PubMed: 38167987
DOI: 10.1007/s10096-023-04741-3 -
Experimental Cell Research Nov 1988We have followed the induction of protein synthesis in mitogen-activated human peripheral blood mononuclear cells during the transition from quiescence, or G0, through...
We have followed the induction of protein synthesis in mitogen-activated human peripheral blood mononuclear cells during the transition from quiescence, or G0, through the prereplicative phase and into first S phase. Doses of mitogens optimal for proliferative response preferentially enhance the synthesis of a subset of intracellular proteins during the approximately 24-h lag interval. The mitogenic lectin phytohemagglutinin (PHA) and OKT3, a mitogenic monoclonal antibody to the CD3 component of the T cell antigen receptor, preferentially enhance bands of the same molecular weight in one-dimensional SDS-PAGE. The proteins are low detergent soluble (0.1% Triton X-100) "cytoplasmic" cellular components and some have been identified as single spots on two-dimensional gels. Bands of 51 and 66 kDa are induced early in lag phase (4 h after stimulation) but are transiently synthesized, decreasing later in lag phase. The majority of the mitogen-induced proteins, 39, 51, 55, 60, 73, and 95 kDa are enhanced by mid lag phase (12 h after stimulation). With the exception of the 55-kDa band, five of these proteins are clearly enhanced in T cells purified after mitogen stimulation. The same five bands show sustained synthesis in actively cycling cells 42-48 h after stimulation and are major synthesized proteins, and corresponding bands are synthesized in a transformed T cell line, MOLT-4. Two of the proteins in this group that are most prominently synthesized during the lag interval have been previously identified as the heat shock proteins, HSP 90 (95-kDa band) and HSC 70 (73-kDa band). We speculate that this group of five proteins, including HSP 90 and HSC 70, may be coordinately expressed in actively replicating T cells and may have some common structural or functional role in sustaining the replicative state.
Topics: Antibodies, Monoclonal; Cell Line; Heat-Shock Proteins; Humans; Interphase; Mitogens; Molecular Weight; Phytohemagglutinins; Protein Biosynthesis; T-Lymphocytes
PubMed: 3262525
DOI: 10.1016/0014-4827(88)90349-7