Mitogenic Substances Research Articles

Activation of T lymphocytes by lectins and carbohydrate-oxidizing reagents viewed as an immunological recognition of cell-surface modifications seen in the context of "self" major histocompatibility complex antigens.

AbstractThe experiments reported here were directed at the question of whether polyclonal activation of T cells by mitogenic substances results as a consequence of (a) a truly antigen‐independent stimulation of T cells through mitogen receptors, bypassing requirements for T cell‐specific recognition or (b) an immunological reaction, similar in principle and requirements to T cell activation induced by antigen. Several lines of evidence have provided strong support for the latter interpretation. First, the ability of several mitogenic substances to induce polyclonal T cell activation was found to be crucially dependent upon cell surface expression of major histocompatibility complex (MHC) products. Thus, the presence of alloantisera or monoclonal antibodies directed against either class I (SD) determinants or class II (Ia) products on the responding cell population resulted in a sizeable dose‐dependent inhibition of the mitogenic response. Additional studies using spleen cells from normal F1 mice or F1→parent bone marrow chimeras provided the most direct and convincing evidence for a specific immunological role of MHC products in mitogenic T cell activation. Here, the concanavalin A response of normal F1 T cells was found to be inhibited by alloantisera against either parental haplotype, while the H‐2‐heterozygous F1→parent chimeras were only inhibited by antisera against the H‐2 of the parent in which they matured and possessed functional, MHC‐restricted helper T cells.The inherent characteristics and reactivities which endow only certain lectins to exert a mitogenic effect were specifically examined in light of the observed dependence for MHC expression in these mitogenic reactions. Using a panel of 20 different lectins as affinity absorbents for cell surface glycoproteins, it was found that only mitogenic lectins were capable of binding to cell surface‐expressed H‐2 products (both K/D and la). The results obtained here are discussed in support of the concept that mitogeninduced T cell responses involve an immunological recognition of cell surface modifications seen in the context of self H‐2 antigens.

Mitogenic substances in staphage lysate (SPL)

Mitogenic substances in staphage lysate (SPL)

Population dynamics of arterial cells during atherogenesis: VII. Comparison of loss of endothelial cells over abdominal aortic intimal cellular masses (ICM) with that over non-ICM areas in swine fed a hyperlipidemic diet for 60 days

One of the earlies events in the development of an intimal atherosclerotic lesion may be an alteration in the endothelial cell barrier, allowing the entry of injurious or mitogenic substances, resulting in proliferation of arterial smooth muscle cells. Intimal smooth muscle cell proliferation in atherosclerosis appears to begin in intimal cellular masses (ICM), which are normally occurring intimal structures made up of 2 to 10 layers of smooth muscle cells found predominantly in relation to branching points of arteries. If endothelial cell loss is a precursor of overt atherosclerotic lesions, the loss should be greater over ICM than over areas showing no ICM. This study presents evidence suggesting that in swine the endothelial cell barrier is compromised over intimal cell masses more than in non-ICM regions prior to development of overt atherosclerotic lesions. The method used was to label swine aortic endothelium and ICM using tritiated thymidine. All swine were then placed on a low-fat, low-cholesterol diet for 15 days, at which time five baseline animals were sacrificed; the remaining five were placed on a hyperlipidemic (HL) diet and sacrificed 60 days later. The rate of endothelial cell growth, division patterns, and loss of labeled endothelial cells in the HL swine was determined by comparing the findings in this group with the baseline group. Smooth muscle cells of ICM and non-ICM medial regions were similar in regard to labeling indices in the baseline swine and in regard to division patterns in 60-day HL diet swine, except one which was an active lesion. None of the remaining ICM were active lesions and thus were suitable for study of the covering endothelial cells in what can be assumed to be the prodromal stage of lesion development. The approximate area of the abdominal aorta occupied by intimal cell mass was considerably more than we had anticipated, averaging more than 20%. The labeling indices and endothelial cell division patterns over ICM and non-ICM in the baseline swine were similar. In contrast, the labeling index was lower, and grain count changes indicated more endothelial cell divisions over ICM areas than over non-ICM areas in the hypercholesterolemic swine. Calculation showed that the percentage of endothelial cell loss over ICM in the HL swine was more than twice as great as endothelial cell loss over non-ICM areas. The results of this study suggest the possibility that in the assumed prodromal phase of experimental aortic atherosclerosis in young swine, the endothelial cell barrier may be compromised selectively over areas of predilection for the future development of atherosclerotic lesions. This occurs before there is any evidence of focal increase in intimal smooth muscle cell proliferation, which we regard as the earliest detectable stage of lesion development.

A CLUSTER OF HODGKIN'S DISEASE IN A SMALL COMMUNITY<subtitle>EVIDENCE FOR ENVIRONMENTAL FACTORS</subtitle>

A cluster of Hodgkin's disease (HD) cases occurred in a small rural town of 1250 people. Ten cases of HD and three cases of non-Hodgkin's lymphoma were identified within or linked to this town since 1954. This town therefore had an average annual incidence and mortality for HD of 29.3 and 16.7 cases per 100,000 population, respectively. Most cases of HD demonstrated case-contact associations, and a distinct geographic distribution. The data suggested that there was an environmental agent responsible for the elevated rates of HD. One unique aspect of this cluster is that this town has only one industry, a large grain elevator. The cases closely surrounded this elevator. We postulate that residents of the town are subject to chronic immune stimulation from mitogenic substances in this environment. These agents may alter immunity in the residents of this community and predispose them to acquiring HD.

Enhancement of [3H-Methyl]Thymidine Incorporation and Replication of Rat Chondrocytes Grown in Tissue Culture by Plasma, Tissue Extracts and Vasopressin1

A pituitary mitogenic peptide, which stimulates cellular replication of a variety of cells maintained in tissue culture, has been identified by other investigators. To study this mitogenic substance, we developed an assay to measure mitogenic substances utilizing fetal rat chondrocytes grown in monolayer culture. Mitogenic activity of added test substances was determined by [3H-methyl]thymidine incorporation into trichloroacetic acid insoluble cell products and increase in total cell number after 24 h exposure. Extracts of whole pituitary glands were more potent in stimulating these cellular indices than either those of liver or muscle, confirming that the chondrocytes are sensitive to the described mitogen. Identically prepared extracts of either anterior or posterior pituitary lobes were mitogenic indicating the presence of two or more mitogenic substances in crude pituitary extracts. Synthetic lysine vasopressin and a beef pitressin concentrate stimulated thymidine incorporation into chondrocytes in the absence of calf serum and this effect was additive to that of calf serum, suggesting that the mitogenic substance of posterior pituitary extracts was vasopressin. The maximum effective dose of vasopressin leading to an increase in either thymidine incorporation or total cell number was between 100 to 500 pg/ml, and as little as 50 pg/ml of hormone elicited an increase in total cell number. The mitogenic effect of both vasopressin and calf serum on chondrocytes was partially inhibited by 1 X 10(-4)M N, O'dibutryl cyclic adenosine 3',5' monophosphate suggesting that cell division of chrondrocytes may be under tonic control by the andenylyl cyclase system. We conclude that vasopressin is a potent mitogen for chondrocytes maintained in tissue culture and its presence must be rigorously excluded in evaluating mitogenic activity of pituitary or serum concentrates.

Lymphocyte response to T-cell mitogen during experimental gingivitis in humans.

This study was conducted to evaluate the dose response relationships of peripheral blood lymphocytes (PBL) by stimulation of phytohemagglutinin (PHA) during the onset of oral inflammation. Eleven dental students underwent a 3-week experimental gingivitis program (Löe et al., 1965). At time zero, weeks 1, 2, and 3, and after 1 week of reinstituted oral hygiene (week 4), the plaque accumulations were evaluated, the degree of gingival inflammation was assessed, and a blood sample was taken. Quadruplicate microcultures each containing 2 x 10(5) PBL in 0.2 ml of tissue culture medium 199 and 10% fetal calf serum were stimulated with five concentrations of PHA (10 to 0.5 mug/ml) and incubated for 78 h at 37 C in 5% CO2. [3H]thymidine was added to each culture for the final 8 h. The cultures were then harvested and counted by liquid scintillation, and stimulation indexes (SI) were determined. At time zero the maximum PBL response occurred at a PHA concentration of 5 mug/ml (SI = 100). During weeks 1, 2, and 3 the location of the maximum PBL response shifted to a lower PHA concentration (1.0 mug/ml) and increased to over SI =400. The phenomenon of shifting peak PHA responses to lower PHA concentrations could be observed after only 1 week of developing gingival inflammation. The PBL response returned to pre-experimental values after 1 week of reinstituted oral hygiene, which resolved the oral inflammation. The findings show that a dose response relationship exists between PHA concentrations and the PBL response. If these dose response changes seen during developing gingival inflammation are ignored, either a decrease, increase, or no change in PBL response can be shown depending upon the PHA concentration evaluated. Owing to the dose-dependent nature of this PBL response, it is advisable to routinely use dose response curves in order to properly evaluate the full responsiveness of PBL to mitogenic substances.

Depression of hepatic gluconeogenesis and the hypoglycemia of endotoxin shock

Depression of hepatic gluconeogenesis and the hypoglycemia of endotoxin shock

Lymphocyte Activation

Abstracts of papers presented at the Nordic Symposium, 1st and 2nd of December, 1972, in Helsinki, Finland.The meeting was sponsored by:Minerva Institute for Medical Research, Folkhälsen Institute for Genetics, Swedish Cancer Society, Study Group for Mitogenic Substances, and arranged by: Theodor H. Weber & Valdemar T. Skoog.The topics covered were: general and clinical aspects of lymphocyte activation and separation and surface characteristics of T and B lymphocytes.