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PubMed2004

[Inhibitory effects of human bone marrow mesenchymal stem cells and cord blood mononuclear cells on mixed lymphocyte response and PHA induction transformation].

To study and compare the immunomodulatory functions of human bone marrow mesenchymal stem cell (MSC) and cord blood mononuclear cell (CBMNC) in vitro, human bone marrow MSC were separated with Percoll (1.073 g/L) and cultured in low-glucose DMEM, and cord blood mononuclear cells were isolated with Ficoll (1.077 g/L). These two kinds of cells were added to mixed lymphocyte cultures and PHA induction transformation cultures with various concentrations. The proliferation of lymphocytes was measured by MTT method, effects of MSC and CBMNC on mixed lymphocyte response and PHA-induced lymphocyte transformation were investigated. The results showed that both 5 x 10(4), 1 x 10(4) MSC and 2 x 10(5) CBMNC could inhibit the mixed lymphocyte response (MLR) and PHA induced transformation. But with lower concentrations (MSC < or = 1 x 10(3), CBMNC < or = 1 x 10(5)), the inhibition effects of MSC and CBMNC were less consistent. 1 x 10(2) MSC and 1 x 10(4) CBMNC mainly increased the lymphocyte activation. In addition, the inhibition ratio of 5 x 10(4) MSC (MLC 65.3%, PHA 79.1%) was higher than that of 2 x 10(5) CBMNC (MLC 8.6%, PHA 37.3%). It is concluded that larger numbers of both MSC and CBMNC showed negative immunomodulatory functions and inhibited the mixed lymphocyte response and induction of transformation in vitro. Moreover, the inhibitory effect of MSC was much stronger than that of CBMNC.

Bone Marrow Cells↗
PubMed1987

HTLV-III large envelope protein (gp120) suppresses PHA-induced lymphocyte blastogenesis.

The addition of inactivated preparations of purified human T cell lymphotropic virus (HTLV-III) was found to inhibit normal human lymphocyte phytohemagglutinin (PHA)-induced blastogenesis but had no effect on concanavalin A (Con A), pokeweek mitogen, or allogeneic stimulation. The inhibition was concentration-dependent and also dependent on adding the virus preparation before or at the same time as PHA. The CD4 molecule is the receptor for HTLV-III binding. Immunopurified large envelope protein (gp120) from HTLV-III was found to bind to the CD4 molecule and also inhibited PHA-induced lymphocyte blastogenesis. These results suggest that the gp120 viral protein may alter immune function by binding to the CD4 molecule, which in turn serves as an "off" signal to lymphocyte response to PHA stimulation. Alternatively, by binding to the CD4 molecule, gp120 may interfere with the interaction of this molecule with class II histocompatibility antigens on accessory cells, thus selectively suppressing PHA response.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

Comparisons of 12-tetradecanoylphorbol-13-acetate (TPA) and PHA as mitogens in the T-lymphocyte colony assay.

12-O-tetradecanoylphorbol-13-acetate (TPA) has multiple effects on the capacity of human T-lymphocytes to form colonies in soft agar. This compound is directly mitogenic for T-lymphocytes; the optimal concentration (100 ng/ml) stimulates an average of 2862 +/- 583 colonies/7.5 X 10(5) cells plated. Furthermore, TPA can act synergistically with PHA to induce a greater number of colonies than can either mitogen alone. Sephadex G10 nonadherent (NA) cells can be directly stimulated by TPA; by contrast, these isolated T cells do not respond to PHA alone. These data indicate that the phorbol ester is able to provide an inductive signal for T cells, allowing them to respond to the plant lectin. Using T-cell subsets isolated by monoclonal antibodies and complement cytotoxicity, PHA is able to induce colony growth of T4 cells; T8 cells fail to respond unless cocultured with exogenous IL-2. TPA can directly stimulate colony formation by both subsets. In cultures stimulated with either TPA or PHA, approximately equal numbers of colonies are generated in the presence of IL-2, suggesting that T4 and T8 cells have similar proliferative capabilities. Phenotypic studies of cells contained in colonies showed differences between the two mitogens. With PHA, more than 98% are both T11 and T3 positive; by contrast, approximately one-third of the cells stimulated by TPA are T11 +, T3-.

Cell Separation↗
PubMedDate not supplied

[Phytohemagglutinin (PHA) skin tests: its relevance in carcinology (author's transl)].

The skin response to 1 microgram Phytohemagglutinin (PHA) was studied in 359 subject including 235 cancer patients and 124 without cancer. Responses to PHA, tuberculin, candidin were compared. A positive skin response to PHA was observed in 88% of patients without malignancy. This percentage remained almost equal in older patients (more than 70 years). Among patients with advanced malignancies, there was a fall down to 64.5% of the percentage of positive responses. A negative response to both PHA and tuberculin was observed in 6% of patients without malignancy and 28% of cancer patients. 38 +/- 5 days was the average survival of this last group. The arguments favouring the fact that PHA induces cutaneous basophilic hypersensitivity are reviewed. An advantage of this test is that no presensitization is required.

Evaluation Studies as Topic↗
PubMed1983

Ontogeny of con A and PHA responses of chicken blood cells in MHC-compatible lines 6(3) and 7(2).

The development of T cell responsiveness to Con A and PHA was examined in two MHC-compatible inbred chicken lines, RPRL 6(3) and 7(2), at ages 2 to 118 days posthatching. These lines are respectively resistant or susceptible to Marek's disease, a naturally occurring, virally induced T cell lymphoma. Between-line comparisons were made of optimal in vitro responses of diluted serum-free blood cells to each mitogen in two groups of chicks tested over ages 2 to 63 and 41 to 118 days. Over 2 to 63 days, Con A responses increased with age at the same rate in each line, but 7(2) responses averaged 2.3 times higher than 6(3). The increase with age was dependent on blood lymphocyte counts, which also increased with age in parallel in both lines. In contrast, the between-line difference in responsiveness was dependent on intrinsic reactivity of cells as well as lymphocyte counts. Covariance analysis was used to estimate that line 7(2) was 1.4 times higher than 6(3) in intrinsic cell reactivity, after accounting for the effect of the twofold higher blood lymphocyte counts in 7(2), and that this intrinsic difference contributed almost one-half the total difference. Over 41 to 118 days Con A responses no longer increased with age, although lymphocyte counts were still increasing, and the line difference (2.6 times) was now almost entirely contributed by a 2.3-fold superiority of 7(2) blood cells in intrinsic reactivity. The line difference in PHA responses was the reverse of the above in young chicks, with 6(3) responses greater than 7(2) in spite of lower lymphocyte counts. In additional chicks tested over 5 to 26 days, intrinsic reactivity of 6(3) cells to PHA averaged 4.5 times higher than 7(2). There was an abrupt decline in intrinsic reactivity of line 6(3) blood cells between 26 and 41 days to a level equal with 7(2). After this age, line 7(2) responses were 1.8 times greater than those of 6(3), and this difference was dependent solely on lymphocyte count differences. The results suggest that different gene systems mediate blood cell responses to PHA as compared with Con A. The pattern of developmental differences between inbred lines indicates the existence of distinct or partly overlapping T cell subsets with different reactivities to PHA or Con A, and of higher suppressor activity of adherent cells in line 6(3) blood. Both these differences may be related to line 6(3) inherited resistance to Marek's disease.

Aging↗
PubMed1981

Density profiles and purification of chronic myeloid leukemia cells forming colonies in the PHA-leukocyte feeder assay.

Recently, PHA supplemented culture techniques have been introduced for growing colonies of myeloid leukemia cells. To prepare purified leukemic colony forming cell (CFC) suspensions for further studies, a discontinuous albumin density gradient separation method was applied to bone marrow and blood from patients with chronic myelocytic leukemia. It was found that the PHA-responding CFC were recovered, just as the leukocyte feeder layer stimulated CFC (Robinson CFC), from the light density fractions (1.056, 1.059 and 1.062 g/ml). Density profiles of the precursor cells forming colonies of Ph1 positive cells in the PHA-leukocyte feeder and Robinson assays appeared similar. T-lymphocyte progenitor cells, which also proliferate into colonies in the PHA-leukocyte feeder assay, were in majority harvested from the more dense fractions of the gradient. E-rosette tests and chromosome analysis were used to distinguish between leukemic and lymphocytic colonies. The density distributions of the PHA responsive leukemic CFC (Ph1 chromosome positive) and T-lymphocyte CFC (Ph1 negative) partially overlapped and a complete separation of leukemic and lymphocytic CFC was not achieved.

Bone Marrow Cells↗
PubMed1980

In vitro immune response of human peripheral lymphocytes. V. PHA- and protein A-induced human B colony formation and analysis of the subpopulations of B cells.

Human B colony formation was observed with PHA or protein A as a mitogen. Preculture of B cells with mitogens in the presence of irradiated T cells for 3 days was a prerequisite for the induction of B cell colonies. About 300 to 700 colonies per 10(6) seeded cells were detected and a linear relationship between the number of cells seeded and the number of colonies developed was observed. Cells in PHA-induced colonies had surface IgM and/or IgD but no cytoplasmic Ig, whereas cells recovered from protein A-induced colonies had cytoplasmic Igs that were not only IgM but IgG and IgA. In each of the protein A-induced colonies, a sequential appearance of IgM-, IgG-, and IgA-producing cells was observed from day 3 to day 5, showing that IgM-, IgG-, and IgA-producing cells were derived from a single precursor cell. PHA and protein A had an additive effect on the number of colonies induced. About 50% of colonies induced in the presence of both PHA and protein A had Ig-producing cells. These results suggest that PHA and protein A may stimulate distinct subsets of B cells into colony formation.

Animals↗
PubMed1980

Effect of lipopolysaccharide (LPS) on the thymocyte response to PHA: strain difference.

Thymocytes responded well to PHA in terms of [3H]-TdR incorporation if they were precultured in the presence of LPS, whereas fresh thymocytes or thymocytes pre-cultured in the absence of LPS responded poorly to PHA. The PHA response of thymocytes pre-cultured with LPS for several hours was similar to that of fresh spleen cells in the kinetics and dose-response profiles. The effect of LPS was found on thymocytes from BALB/c.Cr, AKR/Jms, and DDD/1 mice, but was not observed on those from C3H/HeJms and C57Bl/6J mice, indicating that there is a strain difference in the PHA responsiveness of LPS-pre-cultured thymocytes. In contrast to thymocytes, the response of spleen cells to PHA was enhanced in both C57Bl/6J and BALB/c.Cr mice by pre-culture with LPS.

Animals↗
PubMed1981

The effect of ampicillin on the response of human lymphocytes to PHA.

The effect of ampicillin on the sensitivity of human lymphocytes to PHA was examined by measuring the following parameters: temperature-stable E rosette formation: leukocyte migration inhibition: DNA synthesis. It was found, that ampicillin present in the culture medium at a concentration of 50 microgram/ml does not change E rosette formation, intensifies the inhibition of leukocyte migration and modulates the proliferative response to PHA. The magnitude and direction of this last effect depended upon the preparation of PHA used and on its dose. Ampicillin enhanced DNA synthesis in cultures stimulated by submitogenic, as well as supraoptimal doses of PHA-Wellcome and suppressed the DNA synthesis in cultures containing optimal mitogenic doses of PHA-Difco.

Ampicillin↗
PubMed1977

Ontogeny of mitogenic responsiveness to PHA and sheep erythrocytes and lymphokine production in foetal guinea-pigs.

Pre-culture of spleen cells for 24 h before addition of activator greatly improved the mitogenic response to phytohaemagglutinin (PHA) and sheep erythrocytes (SRBC). Spleen cells were separated into plastic-adherent and non-adherent populations and in some experiments purified further to 'macrophages' and 'lymphocytes' respectively. A critical mixture of lymphocytes and macrophages (10:1) gave twice the mitogenic response of lymphocytes alone to PHA and SRBC in cultures of foetal, juvenile and adult guinea-pig spleen cells. Vigorous mitogenic responses to PHA and SRBC were found at 36 days of gestation. The mitogenic response increased from 46-56 days of gestation to above adult level. Lipopolysaccharide (LPS) obtained by the Westphal method was a superior mitogen to LPS extracted by the Boivin technique. Plaque-forming cells (PFC) could not be induced in vitro at any age even with the addition of LPS. Evidence was obtained for mitogenic and blastogenic lymphokines produced by lymphocytes activated with PHA or produced by lymphocytes activated with PHA or SRBC (but not LPS). These lymphokines were produced by activated splenic lymphocytes of a 40-day-old foetus; older animals showed no evidence for a quantitative increase in lymphokine production. The onset and maturation of mitogenic responsiveness in the guinea-pig and human foetus is compared by age-equivalence.

Animals↗
PubMed1987

Efferent projections of the subthalamic nucleus in the rat: light and electron microscopic analysis with the PHA-L method.

Efferent projections of rat subthalamic nucleus were studied by use of the axonal transport of phaseolus vulgaris-leucoagglutinin (PHA-L), and the results were analyzed with light and electron microscopes. PHA-L injections in the subthalamic nucleus (STH) resulted in heavy labeling of fiber plexus with en passant boutons and terminals in the pallidal complex, i.e., the entopeduncular nucleus (EP), the globus pallidus (GP) and the ventral pallidum (VP), and the substantia nigra pars reticulata (SNR). Labeling in GP was characterized by two distinct bands of labeled terminals oriented dorsoventrally, whereas labeling in SNR was patchy. STH efferents to the pallidum and SNR displayed a mediolateral topographic organization. With regard to dorsoventral organization, projections to GP were inverted, but those to SNR were not. There were moderate projections to the neostriatum and sparse projections to the frontal cortex, substantia innominata, substantia nigra pars compacta (SNC), pedunculopontine tegmental nucleus, ventral part of the central gray matter including the dorsal raphe nucleus, and the mesencephalic and pontine reticular formation. PHA-L injections in the zona incerta and the lateral hypothalamic area resulted in fiber and terminal labelings in many structures, including the basal forebrain, EP, SNC, and other brainstem areas that overlap with some of the terminal sites of STH projections. Ultrastructural observations of PHA-L labeled processes in GP and SNR revealed that STH terminals in both structures contained small pleomorphic vesicles and formed asymmetrical contacts. These contacts were mainly on dendritic shafts, but some were on somata. It also was observed that the myelinated axons of STH neurons lost their myelin after reaching their target areas and the synaptic boutons arose from relatively thin unmyelinated axons.

Animals↗
PubMed1989

Anterograde tracing of the rat olivocerebellar system with Phaseolus vulgaris leucoagglutinin (PHA-L). Demonstration of climbing fiber collateral innervation of the cerebellar nuclei.

The olivocerebellar climbing fiber system was investigated in the rat with anterograde Phaseolus vulgaris leucoagglutinin (PHA-L) tracing. The specific objective of the study was to find morphological evidence of climbing fiber collaterals innervating the cerebellar nuclei. Small iontophoretic injections of PHA-L were placed in different parts of the inferior olivary complex, and labelled olivocerebellar fibers could be traced to their termination as climbing fibers in sagittal zones of the contralateral cerebellar cortex. Reaching the cerebellum via the restiform body, the labelled olivocerebellar axons entered the deep cerebellar white matter anterior to the cerebellar nuclei. Most of these thicker, nonterminal axons continued dorsally around the nuclei, but some ran through them. Bundles of fibers could be followed into the folial white matter toward their cortical zones of termination. Depending on which part of the olivary complex that was injected with PHA-L, labelled axons were seen to converge on different regions of the cerebellar nuclei, where dense plexuses of thin varicose terminal fibers appeared. Quantitative estimates of the innervation ranged from 1.7 to 4.3 million boutons per mm3 in the fastigial (FN), interposed, and main parts of the lateral cerebellar (LCN) nuclei, whereas the parvicellular portion of LCN demonstrated 15-20 million varicosities per mm3. Frequently, thicker olivocerebellar axons, which seemed directed toward the cerebellar cortex, were seen to send a fine collateral branch toward these areas of nuclear innervation. As controls, PHA-L was injected into the degenerated olivary complex of 3-acetylpyridine-treated rats. Neither cortical climbing fiber terminals nor nerve terminal plexuses in the nuclei appeared in these experiments. In cases with injection sites extending into the reticular formation, substantial mossy fiber labelling was present bilaterally in the cortex, but the cerebellar nuclei were devoid of labelled innervation or demonstrated only a few larger diameter fibers. The projection of the inferior olivary complex to the cerebellar nuclei was strictly topographically organized and agreed in principle with the organization described in the cat by Groenewegen et al. ('79). The caudal medial accessory olive (MAO) projected to FN, the rostral MAO to the posterior interposed nucleus (NIP), the rostral part of the dorsal accessory olive (DAO) to the anterior interposed nucleus (NIA), and the principal olive (PO) to LCN.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Projections from the lateral nucleus to the basal nucleus of the amygdala: a light and electron microscopic PHA-L study in the rat.

A recent study, carried out in the monkey brain demonstrated a hitherto undescribed projection from the lateral to the basal nucleus of the amygdaloid complex. In the present study, we used light and electron microscopic techniques to determine whether a similar connection exists in the rat brain and to define what type(s) of synaptic contacts are produced by fibers of this projection. Injections of the lectin tracer Phaseolus vulgaris leucoagglutinin (PHA-L) were placed into several levels of the lateral nucleus and the distribution of fibers in the basal (basolateral) nucleus was evaluated. All lateral nucleus injections resulted in labeled fibers in the basal nucleus, though the density and distribution of labeled fibers depended on the position of the injection site within the lateral nucleus. In general, the heaviest labeling of the basal nucleus was observed after injections at midrostrocaudal levels of the lateral nucleus, especially when the injection was located ventrally. Fibers originating from cells labeled by these injections were observed throughout much of the rostrocaudal extent of the basal nucleus. Rostrally situated injections resulted in substantially lower levels of labeled fibers in the basal nucleus. Injections placed caudally in the lateral nucleus resulted in light to medium levels of labeled fibers in the basal nucleus; the terminal field in these cases did not extend as far rostrally as after the rostral and midlevel injections. Electron microscopic analysis of PHA-L labeled fibers revealed that they contributed synapses to the basal nucleus. The majority of PHA-L labeled terminals formed asymmetric contacts on dendritic spines or shafts; a smaller number of PHA-L labeled terminals formed symmetrical synapses.

Amygdala↗
PubMed1994

Intra-amygdaloid projections of the lateral nucleus in the cat: PHA-L anterograde labeling combined with postembedding GABA and glutamate immunocytochemistry.

Research on the implication of the amygdala in classical fear conditioning suggests that the central amygdaloid nucleus is the output station of the amygdala for conditioned fear responses, while the lateral nucleus acts as the input nucleus, at least for auditory conditioned stimuli. However, the nature and locus of the plastic changes taking place between these two nuclei are unknown partly because the neurotransmitter(s) used by intra-amygdaloid projections of the lateral nucleus has not been identified. To address this issue in cats, anterograde tracing with Phaseolus vulgaris-leucoagglutinin (PHA-L) was combined with postembedding immunocytochemistry for gamma-aminobutyric acid (GABA) and glutamate. Two sectors can be recognized in the lateral nucleus of the cat: a shell located laterally along the external capsule, and a core. Iontophoretic injections of PHA-L in these two sectors revealed that they have nonoverlapping intra-amygdaloid targets with the exception of a common projection to the central lateral nucleus. The core projects mainly to itself and to the basomedial nucleus, whereas the shell contributes a massive projection to the basolateral nucleus. No projection of the lateral nucleus to the central medial nucleus was found. Electron microscopically, PHA-L-labeled axon terminals in the lateral, basomedial, basolateral, and central lateral nuclei as well as in the perirhinal and insular cortices formed asymmetric synapses (100%; n = 289) with dendritic spines (77-100%). Moreover, postembedding immunocytochemistry revealed that PHA-L-labeled axon terminals are immunoreactive for glutamate but not GABA. Since most amygdaloid projections to the brainstem originate in the central medial nucleus, these results suggest that intra-amygdaloid targets of the lateral nucleus are involved in the transmission of auditory conditioned stimuli to the central medial nucleus. Moreover, these findings imply that intra-amygdaloid projections of the lateral nucleus use glutamate but not GABA as a neurotransmitter.

Amygdala↗
PubMed1998

Suppressed PHA activation of T lymphocytes in simulated microgravity is restored by direct activation of protein kinase C.

Utilizing clinostatic rotating wall vessel (RWV) bioreactors that simulate aspects of microgravity, we found phytohemagglutinin (PHA) responsiveness to be almost completely diminished. Activation marker expression was significantly reduced in RWV cultures. Furthermore, cytokine secretion profiles suggested that monocytes are not as adversely affected by simulated microgravity as T cells. Reduced cell-cell and cell-substratum interactions may play a role in the loss of PHA responsiveness because placing peripheral blood mononuclear cells (PBMC) within small collagen beads did partially restore PHA responsiveness. However, activation of purified T cells with cross-linked CD2/CD28 and CD3/CD28 antibody pairs was completely suppressed in the RWV, suggesting a defect in signal transduction. Activation of purified T cells with PMA and ionomycin was unaffected by RWV culture. Furthermore, sub-mitogenic doses of PMA alone but not ionomycin alone restored PHA responsiveness of PBMC in RWV culture. Thus our data indicate that during polyclonal activation the signaling pathways upstream of PKC activation are sensitive to simulated microgravity.

Antigen-Antibody Reactions↗
PubMed1993

Reduced activation of transcriptional factor AP-1 among peripheral blood T cells from elderly humans after PHA stimulation: restorative effect of phorbol diesters.

In the present study, we evaluated if aging influences the activation and characteristics of transcriptional factor AP-1 in human T cells. Using gel mobility shift assays, the activation of AP-1 was quantified in peripheral blood T cells from 11 elderly (mean 74 year) and young (mean 33 year) subjects following stimulation with PHA, PMA, or PHA plus PMA. The results showed that the activation of AP-1 was significantly reduced in PHA-stimulated T cells from the group of elderly subjects when compared to T cells from young subjects (P < 0.05). Even though PHA-stimulated T cells from 8 of the elderly subjects had pronounced impairments in the activation of AP-1, additional signals provided by costimulation with PMA frequently restored AP-1 activation to more normal levels. Other experiments demonstrated that the AP-1 complexes expressed by stimulated T cells of elderly and young subjects exhibited similar properties in gel shift assays with competing unlabeled AP-1 oligonucleotides and with blocking antibodies specific for Fos and Jun. Thus, these data suggest that the activation of AP-1 can be reduced in human T cells during aging and that these reductions may often be related to impairments in signal transduction rather than represent an absolute loss in the ability to express AP-1.

Adult↗
PubMed1987

PHA- and Con A-induced chemiluminescence of human blood mononuclear cells and granulocytes in luminol or lucigenin.

Phytohemagglutinin (PHA) and concanavalin A (Con A) can evoke a chemiluminescence (CL) response both in granulocytes and blood mononuclear cells. We have used two parallel systems to compare the quantity and quality of oxygen radicals produced during activation. While the luminol-enhanced CL response is linked to the myeloperoxidase-H2O2-chloride system, the lucigenin-dependent light production measures only the superoxide radical. PHA produced higher CL response in the presence of luminol than with lucigenin. Con A showed high CL response only in the lucigenin-enhanced system. The results suggest that while Con A induces mostly superoxide production, the membrane stimulus evoked by PHA produces light through the myeloperoxidase-H2O2-halide system. Granulocytes are less sensitive to PHA than the blood mononuclear cells. The sensitivity of the responses to several scavengers and enzymes support the differential production of oxygen radicals following activation via these two lectins.

Acridines↗
PubMed1977

PHA and endotoxin stimulation of human lymphocytes separated by albumin density gradient centrifugation.

Venous blood from eight healthy subjects was divided into four fractions on a discontinuous albumin density gradient. The percentage recovery of lymphocytes was 82.3%; the purity of the lymphocyte fractions was 83.6%. The lymphocytes were cultured with PHA and Endotoxin, and the samples were analysed after 24, 48, and 72 hours. After PHA stimulation immunoblasts appeared up to 59.3% in the cultures from the 19-21% albumin fraction. After Endotoxin stimulation the maximum (75.8%) was reached in the heavy (25-27% albumin) fraction. Thus, it is concluded that the lymphocytes which can be stimulated with both the mitogens have different densities, the PHA-stimulable T lymphocytes being ligther than the Endotoxin-stimulable B lymphocytes. It is also concluded that as a mitogen Endotoxin is equal to PHA.

Adult↗