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Biomedical subjects

M M Simon

Publications and source records attributed to M M Simon.

162 records · Page 9Linked to original sources
PubMed1981

Quantitative studies on T cell diversity. II. Determination of the frequencies and Lyt phenotypes of two types of precursor cells for alloreactive cytotoxic T cells in polyclonally and specifically activated splenic T cells.

Two different limiting dilution systems have been applied to compare precursor frequencies of alloreactive cytotoxic T cells (CTL-P) in the polyclonally and specifically activated lymphocyte populations and in selected Lyt T cell subsets. Both systems make use of T cell growth factor for T cell expansion but differ with respect to the activation step in that lymphocytes are either activated directly with allogenetic stimulator cells or are sensitized polyclonally with concanavalin A (Con A) in bulk culture before their expansion under limiting dilution conditions. In polyclonally activated C57BL/6 lymphocyte populations, two types of CTL-P specific for H-2d alloantigens could be identified: a frequent set with a frequency of 1/100-1/300, and a rare set with a frequency of 1/2,000-1/8,000. In contrast, only a single CTL-P set was found in specifically activated populations with a frequency similar to that of the frequent CTL-P found on Con A blasts. In Con A blasts, the frequent at higher cell concentrations by suppressor T cells, whereas rare CTL-P were insensitive to this suppressive mechanism. Whereas in specifically activated T cells, the predominant CTL-P phenotype was Lyt-123, the predominant Lyt phenotypes for the frequent and the rare CTL-P found in Con A blasts were Lyt-123 and Lyt-123, respectively, which suggests that they represent primary and secondary CTL-P, respectively. The results are discussed with respect to previous reports on the involvement of Lyt T cell subsets in the generation of cytotoxic responses and their regulation by T suppressor cells.

Animals↗
PubMed1981

Effector T lymphocytes in lymphocytic choriomeningitis virus-infected mice. Cytolytic activity of Lyt-23 spleen cells in vitro does not correlate with elimination of infectious virus from spleens.

The T lymphocytes from mice recovering from infection with lymphocytic choriomeningitis virus were selected for subclasses by treatment with anti-Lyt antisera and complement. Lyt-23 cells and mixtures of lyt-1 and Lyt-23 cells caused up to one-half the destruction of cultivated target cells as compared with untreated T lymphocytes; Lyt-1 cells alone were not cytotoxic. Selected and unselected spleen T cells were also inoculated intravenously into previously infected mice. Whereas unselected cells reduced infectious virus in the spleens of the recipients approximately 100-fold, only marginal effects, which were not preferentially associated with one particular subclass, were seen with selected LYT-23 or Lyt-1 lymphocytes or a mixture of both. Apparently the Lyt-23 cells, shown to by cytolytic for infected cells in vitro, did not cause elimination of a measurable quantity of the virus from mice.

Animals↗
PubMed1981

Generation of effector cells from T cell subsets. III. Synergy between Lyt-1 and Lyt-123/23 lymphocytes in the generation of H-2-restricted and alloreactive cytotoxic T cell.

Lyt-123/23 and Lyt-1 T cell subsets, positively selected by separation on the fluorescence-activated cell sorter, were tested in vitro for their role in the generation of H-2-restricted and alloreactive cytotoxic T cells. It is shown that in the proliferation assay, both T cell subsets responded equally well to H-2 and non-H-2 antigens (H-Y), respectively. In contrast, none of the selected Lyt subsets, but only the mixed population containing Lyt-1 and Lyt-123/23 lymphocytes gave rise to both H-2-restricted (anti H-Y, anti-trinitrophenyl) and alloreactive (anti-H-2) cytotoxic lymphocytes. The data imply an essential role of Lyt-1 cells as inducers or helpers in the generation of all cytotoxic lymphocytes from their precursors in the Lyt-123/23 pool.

Animals↗
PubMed1981

Function, target-cell preference and cell-surface characteristics of herpes-simplex virus type-2-induced non-antigen-specific killer cells.

Wild-type and congenitally athymic nude mice injected with herpes-simplex virus type 2 (HSV 2) responded with a local outburst of non-antigen-specific killer cells masking any virus-specific response. Cytolytic activity could be assayed on mouse-tumor cell lines and on syngeneic or allogeneic non-transformed cells from various sources. Some of the tumor cell lines and proteose-peptone-induced peritoneal exudate cells were lysed more efficiently after infection with either HSV 2, vaccinia or influenza A virus. Preference for virus-infected target cells was already expressed 24 hours after HSV-2 injection. Killing activity was not H-2-restricted, not complement- or immunoglobulin-dependent and did not involve Fc receptors. The cytotoxic cells were non-adherent and could be shown to express Thy1, Quat4, and Quat4 cell-surface antigens. They lacked immunoglobulin and Lyt1: Lyt2,3 determinants. The functional and serological characteristics identify the HSV-2-induced cytolytic cells as natural killer (NK) cells. The potential importance of this cell population for natural resistance will be discussed.

Animals↗
PubMed1981

Genetic control of B cell function. II. Antibody responses of inbred mice to red blood cells are controlled at the B cell level.

Inbred strains of mice can be classified into high and low responders with respect to their antibody responses to RBC. In this paper, we investigate the cellular basis of the difference in responsiveness between high- and low-responder strains. In cell-mixing experiments with purified B cells, T cells, and macrophages from 2 different combinations of H-2-identical high- and low-responder strains, we find that the B cells determine high and low responsiveness, whereas T cells and macrophages from low responders function equally as well as those of high responders. We could also exclude that suppressor T cells play an important role in determining high and low responsiveness. It is therefore suggested that low responsiveness is a defect of B cells to become activated in a T helper cell-dependent antibody response. In the previous paper of this series we showed that a limited number of genes (possibly 2), 1 linked to the Igh gene complex and the other(s) of unknown linkage, control the level of responsiveness. Taken together, we think that this represents a novel example of a genetic polymorphism in B cell function that is sufficiently simple, genetically and functionally, to provide a genetic approach to the study of B cell activation.

Animals↗
PubMed1980

Quantitative studies on T cell diversity. I. Determination of the precursor frequencies for two types of streptococcus A-specific helper cells in nonimmune, polyclonally activated splenic T cells.

A limiting-dilution system is described that makes use of T cell growth factor T cell expansion and allows the determination of precursor frequencies for various regulatory and effector T cells in nonimmune, polyclonally, or specifically activated T cell populations. Two different sets, a frequent and a rare set, of T helper cell precursors with specificity for trinitrophenyl-group A streptococcal vaccine, could be identified: the frequent set is of the Lyt-123 phenotype, and is present at frequencies of from 1/1,000 to 1/6,000 splenic T cells. It is only active at low cell numbers, whereas it is completely inactivated at greater cell numbers, presumably by suppressor T cells of lower frequency but greater potency. The rare set is of the Lyt-1 phenotype, is present at frequencies of from 1/10,000 to 1/70,000, and is not sensitive to suppressor cells present within the tested cell numbers. We suggest that the frequent set contains primiary helper cell precursors, whereas the rare set contains helper T memory cells preselected by previous exposure to other antigens. The results are discussed with respect to other reports on the involvement of more than one set of helper cells in antibody production.

Animals↗
PubMed1980

Generation of effector cells from T cell subsets. II. Lyt 123 T cells contain the precursors for all primary cytotoxic effector cells and for cells involved in the regulation of cytotoxic responses.

Mixed responder populations, consisting of selected Lyt-2,3+ cells and unselected T cells from two congenic mouse strains differing in their Lyt-2,3 alleles, were used to study the role of Lyt-1,2,3+ cells in the generation of cytotoxic effector cells in vitro. The fact that, under these conditions, all primary alloreactive and H-2-restricted killer cells ar generated from the unselected T cell population and not from the selected Lyt-2,3+ subset is demonstrated. Isolated, unsensitized Lyt-2,3+ cells are able to produce primary alloreactive cytotoxic T lymphocytes (CTL) when incubated with alloantigen alone, but appear to be suppressed in the pesence of Lyt-1,2,3+ cells. In contrast, mixtures of Lyt-2,3+ cells selected from C57BL/6 T cells previously primed to alloantigen in vitro, and unselected T cells from the Lyt-2,3-congenic partner after exposure to the same antigen give rise to cytotoxic effector cells which derive mainly from the primed Lyt-2,3+ cell pool and not from the unselected T cell population. Both populations were able to generate CTL when sensitized separately with the alloantigen. The data suggest that Lyt-1,2,3+ cells contain all primary precursors for both H-2 restricted and alloreactive killer cells, as well as lymphocytes suppressing the formation of cytotoxic effector cells from unsensitized Lyt-2,3+ cells. The Lyt-2,3+ cell pool most likely contains the secondary CTL precursors. In addition, the same antigen-primed Lyt-2,3+ pool contains suppressor cells which inhibit the formation of primary CTL from Lyt-1,2,3+ cells. The data are discussed with respect to the regulation of cytotoxic responses.

Animals↗
PubMed1979

Specific Lyt 123 cells are involved in protection against Listeria monocytogenes and in delayed-type hypersensitivity to listerial antigens.

Specific anti-Lyt antisera and complement were used to determine the Lyt phenotype of peritoneal exudate T lymphocytes from Listeria monocytogenes-immune mice. It was found that Lyt 123+ T cells are crucially involved both in protection against listerial infection and in delayed-type hypersensitivity (DTH) to listerial antigens. Thus, both functions critically depend on a T-cell subclass phenotypically different from that which mediates DTH to noninfectious antigens and help in antibody formation on the one hand, as well as those T cells mediating cytotoxic reactions on the other.

Animals↗
PubMed1979

Generation of virus-specific cytotoxic T cells in vitro. I. Induction conditions of primary and secondary Sendai virus-specific cytotoxic T cells.

H-2-restricted cytotoxic T cells specific for Sendai virus were generated in vitro in a primary response from normal mouse lymphocytes cultured in the presence of infective as well as inactivated Sendai virus. Antigen-presenting cells of different origin, including T cells, were found to be effective stimulators. Antibodies to Sendai virus were shown to inhibit the activation of specific precursor killer cells when added to cultures before, but not after, the addition of viral antigen. Data obtained by Lyt phenotyping, revealed that precursor killer cells specific for Sendai virus reside in the Lyt-2,3+ T cell population and that Lyt-1,2,3+ T cells are not required for the generation of cytotoxic lymphocytes. Different activation kinetics were demonstrated for primary and secondary antiviral cytotoxic responses, and the analysis of the proliferation and stimulation requirements suggests qualitative differences.

Animals↗
PubMed1979

Generation of effector cells from T cell subsets. I. Similar requirements for Lyt T cell subpopulations in the generation of alloreactive and H-2 restricted killer cells.

Lyt T cell subsets involved in the generation of H-2 restricted and alloreactive cytotoxic effector cells were analysed using anti Lyt antisera. Our data show that Lyt 1, 2, 3+ T cells are required for the induction of primary and secondary H-2 restricted and TNP-specific killer cells. In contrast, primary and secondary H-2 restricted and virus-specific T effector cells were obtained from selected Lyt 2, 3+ T cell populations and were not dependent on the presence of Lyt 1, 2, 3+ T cells. Allogeneic responses to selected K, I, or D region differences were obtained only in the presence of Lyt 1, 2, 3+ T cells; yet alloreactive killer cells were effectively generated from selected Lyt 2, 3+ T cell popluations deprived of Lyt 1, 2, 3+ T cells, when responder and stimulator cells differed at either K + D, K + I, I and D regionre is no qualitative difference between alloreactive and H-2 restricted cytotoxic responses in their requirements for particular Lyt T cell subsets. The findings indicate that the number of different antigenic determinants rather than their association with MHC self determinants is critical for the requirement of Lyt 1, 2, 3+ T cells during the sensitization phase.

Animals↗
PubMedDate not supplied

The outer surface protein A (OspA) of Borrelia burgdorferi: a vaccine candidate and bioactive mediator.

In the search for a suitable vaccine candidate for Lyme borreliosis the principles of protective immunity were studied in a murine model of Borrelia burgdorferi infection. It was found that the spirochetal outer surface protein A (lipOspA) in its native and recombinant lipidated form induces monospecific immune sera, which in passive transfer experiments protect SCID mice against experimental and tick-borne infection and disease. These and similar findings of independent groups led to the development of a vaccine formulation containing lipOspA. When tested in clinical phase I/II safety trials the recombinant lipOspA vaccine was shown to be safe, immunogenic and able to elicit borreliacidal antibodies. At present, clinical phase III efficacy trials are being conducted. B. burgdorferi infection involves the dissemination of the spirochetes from the site of the tick bite, infection of distant organs, and induction of a chronic inflammatory process. Recent studies indicate that the spirochetes may utilize host-derived enzyme systems to increase their virulence/pathogenicity. It was found that lipOspA serves as a surface receptor for the host-derived proteolytic enzyme plasmin(ogen), the central component of the so-called plasminogen activator system. Moreover, it was found that spirochetes are able to activate endothelial cells and blood-derived leukocytes, such as monocytes/macrophages, B cells and T cells, to express functions and/or secrete molecules, which are known to promote inflammatory responses. Part of these activities were exerted by the isolated lipOspA. The studies indicate an important role of lipOspA, both for the induction of a protective immune response by the host, as well as for the pathogenic processes elicited during B. burgdorferi infection.

Adult↗
PubMedDate not supplied

Aged murine killer T-cell clones acquire specific cytotoxicity for P815 mastocytoma cells.

T-cell clones that grow continuously in tissue culture have become a major tool for studying the properties of T lymphocytes. It is therefore important to know to what extent such clones resemble their normal counterparts. Several reports have appeared recently which demonstrate that long-term T-cell lines may lose the specificity for which they were initially selected and acquire cytotoxic activity to a variety of targets, typical of the activity displayed by natural killer cells. We now report a number of instances in which murine cytotoxic T-cell clones have lost their original specific cytotoxic activity but have acquired strong specific cytotoxic activity for P815 mastocytoma target cells. Loss of the original specificity was usually observed after continuous in vitro cultivation for more than 6 months. We propose that this novel type of cytotoxicity should be called aged killer activity.

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