scholarly journals STUDIES ON SOME PHYSICOCHEMICAL PROPERTIES OF A THYMUS HUMORAL FACTOR CONFERRING IMMUNOCOMPETENCE ON LYMPHOID CELLS

1970 ◽  
Vol 132 (5) ◽  
pp. 885-897 ◽  
Author(s):  
Nathan Trainin ◽  
Myra Small
Keyword(s):  
Lymphoid Cells ◽  
Humoral Factor ◽  
Active Principle ◽  
Target Cells ◽  
Graft Versus Host ◽  
Order Of Magnitude ◽  
Pass Through ◽  
Species Specific ◽  
Thymectomized Mice

By means of an assay of graft-versus-host activity some properties of the thymic humoral factor which confers immunocompetence upon lymphoid cells in vitro have been studied. Allogeneic and xenogeneic thymic preparations were found to activate lymphoid cells from neonatally thymectomized mice, enabling initiation of a graft-versus-host response. Thus, this thymus factor is apparently neither strain nor species specific. The active principle of calf thymus extracts was found to be in the supernatant after prolonged ultracentrifugation. When exhaustive dialysis and ultrafiltration through Diaflo membranes were performed, the active thymus agent was found to pass through both the dialysis sac and Diaflo UM-2 membranes. The molecule which confers immunocompetence upon lymphoid cells thus seems to be of molecular weight of an order of magnitude of 1000 or less. Dialyzed thymus preparations injected into neonatally thymectomized mice also restored the capacity of spleen cells of these mice to induce graft-versus-host activity. When injected into intact mice, thymus extract also increased the proportion of competent cells in the spleens of these animals, probably by activation of target cells originating outside the spleen.

scholarly journals IMMUNOCOMPETENCE OF SPLEEN CELLS FROM NEONATALLY THYMECTOMIZED MICE CONFERRED IN VITRO BY A SYNGENEIC THYMUS EXTRACT

1969 ◽  
Vol 130 (4) ◽  
pp. 765-775 ◽  
Author(s):  
Nathan Trainin ◽  
Myra Small ◽  
Amiela Globerson
Keyword(s):  
Host Response ◽  
Protein Concentration ◽  
Lymphoid Cells ◽  
Immune Reactivity ◽  
Spleen Cells ◽  
Graft Versus Host ◽  
Thymus Extract ◽  
Adult Mice ◽  
Thymectomized Mice

Impaired immunological competence of spleen cells from neonatally thymectomized C57B1/6 young adult mice was apparent when these cells were tested in an in vitro graft-versus-host assay. Spleen cell inocula prepared from thymectomized mice did not induce enlargement of (C3H/eb x C57BI/6)F1 newborn spleen explants, whereas the same number of cells from intact donors consistently initiated splenomegaly. Spleen enlargement was observed, however, when the explants were challenged by cells from thymectomized donors in the presence of syngeneic thymus extract, indicating that the spleen cells in suspension attained immunological competence under the influence of a non-cellular component of the thymus. Immunocompetence was also evident when the cells from thymectomized donors were first incubated with thymus extract for 1 hr and subsequently tested for reactivity. Cells from the same thymectomized donor mice exposed in parallel to extracts from syngeneic spleen or mesenteric lymph node at an equivalent protein concentration did not initiate a graft-versus-host response. These experiments demonstrate that immune reactivity in the graft-versus-host response involves activation of lymphoid cells by a humoral factor of the thymus acting directly upon these cells.

scholarly journals CELL-MEDIATED CYTOTOXICITY DURING REJECTION AND ENHANCEMENT OF ALLOGENEIC SKIN GRAFTS IN RATS

1972 ◽  
Vol 135 (6) ◽  
pp. 1301-1315 ◽  
Author(s):  
Hans-Hartmut Peter ◽  
Joseph D. Feldman
Keyword(s):  
Lymph Nodes ◽  
Thoracic Duct ◽  
Lymphoid Cells ◽  
Target Cells ◽  
Skin Grafts ◽  
Peak Activity ◽  
Adult Rats ◽  
Background Levels

Cell-mediated cytotoxicity (CMC) in spleens and lymph nodes of allografted rats was determined by release of 51Cr from labeled target cells incubated with aggressor lymphoid cells. CMC was first detected in grafted adult rats on day 5, peaked on days 7 and 8, and declined rapidly to background levels by days 9 to 11. In allografted neonates and in cyclophosphamide-treated or neonatally thymectomized adults CMC was a fraction of that observed in normal adult rats. Enhancing antibodies deferred in vivo peak activity of CMC in allografted neonates for 3–4 days, and blocked in vitro the action of aggressor lymphocytes by binding to target cells. Enhancing antibodies had no effect on the cytotoxicity of aggressor cells, but horse antibodies to rat thoracic duct cells inhibited in vitro CMC of aggressor cells.

scholarly journals CD18 Antibody Application Blocks Unwanted Off-Target T Cell Activation Caused by Bispecific Antibodies

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4596
Author(s):  
Joseph Kauer ◽  
Fabian Vogt ◽  
Ilona Hagelstein ◽  
Sebastian Hörner ◽  
Melanie Märklin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoid Cells ◽  
Bispecific Antibodies ◽  
Target Cells ◽  
Cytokine Release ◽  
Life Threatening ◽  
Blocking Antibodies

T cell-recruiting bispecific antibodies (bsAbs) are successfully used for the treatment of cancer. However, effective treatment with bsAbs is so far hampered by severe side effects, i.e., potentially life-threatening cytokine release syndrome. Off-target T cell activation due to binding of bispecific CD3 antibodies to T cells in the absence of target cells may contribute to excessive cytokine release. We report here, in an in vitro setting, that off-target T cell activation is induced by bsAbs with high CD3 binding affinity and increased by endothelial- or lymphoid cells that act as stimulating bystander cells. Blocking antibodies directed against the adhesion molecules CD18/CD54 or CD2/CD58 markedly reduced this type of off-target T cell activation. CD18 blockade—in contrast to CD2—did not affect the therapeutic activity of various bsAbs. Since CD18 antibodies have been shown to be safely applicable in patients, blockade of this integrin holds promise as a potential target for the prevention of unwanted off-target T cell activation and allows the application of truly effective bsAb doses.

scholarly journals HORMONE-LIKE ACTIVITY OF A THYMUS HUMORAL FACTOR ON THE INDUCTION OF IMMUNE COMPETENCE IN LYMPHOID CELLS

1974 ◽  
Vol 139 (1) ◽  
pp. 193-207 ◽  
Author(s):  
Abraham I. Kook ◽  
Nathan Trainin
Keyword(s):  
Adenyl Cyclase ◽  
Lymphoid Cells ◽  
Humoral Factor ◽  
Flufenamic Acid ◽  
Intracellular Camp ◽  
Immune Competence ◽  
Dibutyryl Camp ◽  
Spleen Cells ◽  
Antigenic Challenge

Experiments reported here were performed to understand the mechanism by which THF increases the immunocompetence of spleen cells from NTx mice. Dibutyryl cAMP or substances which increase intracellular levels of cAMP in lymphocytes such as Poly(A:U), theophylline, or PGE2 were shown to mimic the effect of THF and confer reactivity in an in vitro GvH response to spleen cells from NTx mice. Flufenamic acid, an antagonist to PGE2, was shown to inhibit the induction of competence by this substance. It was found that THF induces competence by activating membranal adenyl cyclase which leads to a rise in intracellular cAMP in thymus-derived cells only. These biochemical changes occur before antigenic stimulation and are unrelated to antigenic challenge. These findings indicate that THF exerts its effect via cAMP and are in agreement with the concepts which permit to classify THF as a thymus hormone.

Caspase Activation Is Required for Nitric Oxide–Mediated, CD95(APO-1/Fas)–Dependent and Independent Apoptosis in Human Neoplastic Lymphoid Cells

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4311-4320 ◽  
Author(s):  
Katerina Chlichlia ◽  
Marcus E. Peter ◽  
Marian Rocha ◽  
Carsten Scaffidi ◽  
Mariana Bucur ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Present Report ◽  
Lymphoid Cells ◽  
Jurkat Cells ◽  
Target Cells ◽  
No Production ◽  
No Donor ◽  
Synthase Inhibitor ◽  
Inhibitor Of Protein Synthesis

Abstract Nitric oxide (NO), an important effector molecule involved in immune regulation and host defense, was shown to induce apoptosis in lymphoma cells. In the present report the NO donor glycerol trinitrate was found to induce apoptosis in Jurkat cells that are sensitive to CD95-mediated kill. In contrast, a CD95-resistant Jurkat subclone showed substantial protection from apoptosis after exposure to NO. NO induced mRNA expression of CD95 (APO-1/Fas) and TRAIL/APO-2 ligands. Moreover, NO triggered apoptosis in freshly isolated human leukemic lymphocytes which were also sensitive to anti-CD95 treatment. The ability of NO to induce apoptosis was completely blocked by a broad-spectrum ICE (interleukin-1β converting enzyme)-protease/caspase inhibitor and correlated with FLICE/caspase-8 activation. This activation was abrogated in some neoplastic lymphoid cells but not in others by the inhibitor of protein synthesis cycloheximide. Our results were confirmed using an in vitro experimental model of coculture of human lymphoid target cells with activated bovine endothelial cells generating NO as effectors. Furthermore, the inhibition of endogenous NO production with the inducible NO synthase inhibitor NG-monomethyl-L-arginine caused a complete abrogation of the apoptotic effect. Our data provide evidence that NO-induced apoptosis in human neoplastic lymphoid cells strictly requires activation of caspases, in particular FLICE, the most CD95 receptor-proximal caspase. Depending on the cell line tested this activation required or was independent of the CD95 receptor/ligand system.

scholarly journals REJECTION OF TUMOR ALLOGRAFTS BY MOUSE SPLEEN CELLS SENSITIZED IN VITRO

1971 ◽  
Vol 133 (4) ◽  
pp. 821-833 ◽  
Author(s):  
Irun R. Cohen ◽  
Amiela Globerson ◽  
Michael Feldman
Keyword(s):  
Inhibitory Effect ◽  
Lymphoid Cells ◽  
Mouse Spleen ◽  
Target Cells ◽  
Functional Assay ◽  
Spleen Cells ◽  
Growth Of Tumor ◽  
Selection Of

This paper reports a model system of cellular immunity in which allosensitization of mouse spleen cells is induced in vitro. Allosensitization was achieved by culturing spleen cells upon monolayers of allogeneic fibroblasts. The ability of the spleen cells to inhibit the growth of tumor allografts in vivo served as a functional assay of sensitization. We found that unsensitized spleen cells or spleen cells sensitized against unrelated fibroblast antigens had no inhibitory effect on the growth of allogeneic fibrosarcoma cells when they were injected together into irradiated recipients. In contrast, spleen cells which were specifically allosensitized in vitro were found to be highly effective in inhibiting the growth of an equal number of allogeneic tumor cells. Several times more spleen cells from mice sensitized in vivo were required to produce a similar immune effect. This confirms the findings of previous studies which indicate that sensitization in cell culture can promote the selection of specifically sensitized lymphocytes. Preincubating sensitizing fibroblasts with allo-antisera blocked the allosensitization of spleen cells. This suggests that antibodies binding to fibroblasts may inhibit the induction of sensitization by competing with lymphocytes for antigenic sites. Mouse spleen cells which were able to recognize and reject tumor allografts in vivo were unable to cause lysis of target fibroblasts in vitro. Such fibroblasts, however, were susceptible to lysis by rat lymphoid cells sensitized by a similar in vitro method. These findings indicate that the conditions required for lymphocyte-mediated lysis of target cells may not be directly related to the processes of antigen recognition and allograft rejection in vivo.

scholarly journals Intrinsically disordered domain of kinesin-3 Kif14 enables unique functional diversity

2020 ◽  
Author(s):  
Ilia Zhernov ◽  
Stefan Diez ◽  
Marcus Braun ◽  
Zdenek Lansky
Keyword(s):  
Functional Diversity ◽  
Single Molecule ◽  
Mitotic Spindle ◽  
Cellular Functions ◽  
Protein Tau ◽  
Intrinsically Disordered ◽  
Order Of Magnitude ◽  
Pass Through ◽  
Domain I

ABSTRACTIn addition to their force-generating motor domains, kinesin motor proteins feature various accessory domains enabling them to fulfil a variety of functions in the cell. Human kinesin-3, Kif14, localizes to the midbody of the mitotic spindle and is involved in the progression of cytokinesis. The specific motor properties enabling Kif14’s cellular functions, however, remain unknown. Here, we show in vitro that it is the intrinsically disordered N-terminal domain of Kif14 that enables unique functional diversity of the motor. Using single molecule TIRF microscopy we observed that the presence of the disordered domain i) increased the Kif14 run-length by an order of magnitude, rendering the motor super-processive and enabling the motor to pass through highly crowded microtubule areas shielded by cohesive layers of microtubule-associated protein tau, which blocks less processive motors ii) enabled robust, autonomous Kif14 tracking of growing microtubule tips, independent of microtubule end-binding (EB) proteins and iii) enabled Kif14 to crosslink parallel microtubules and to drive the relative sliding of antiparallel ones. We explain these features of Kif14 by the observed increased affinity of the disordered domain for GTP-like tubulin and the observed diffusible interaction of the disordered domain with the microtubule lattice. We hypothesize that the disordered domain tethers the motor domain to the microtubule forming a diffusible foothold. We suggest that the intrinsically disordered N-terminal anchoring domain of Kif14 is a regulatory hub supporting the various cellular functions of Kif14 by tuning the motor’s interaction with microtubules.

scholarly journals Regulation of cytotoxic T-cell reactivity to syngeneic tumors by the thymus.

1978 ◽  
Vol 148 (2) ◽  
pp. 619-623 ◽  
Author(s):  
C L Reinisch ◽  
S L Andrew
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Cell Reactivity ◽  
Syngeneic Tumor ◽  
T Cell Reactivity ◽  
Syngeneic Tumors ◽  
Thymectomized Mice

Adult thymectomy has been shown to result in the enhanced capacity of splenic T cells to respond to and lyse syngeneic tumor cells in vitro. In addition, T cells from thymectomized mice which kill syngeneic tumor cells do not lyse either normal lymphoid or mitogen-stimulated syngeneic lymphoblast target cells. These findings indicate that the thymus exports a subpopulation of T cells sensitive to adult thymectomy which regulates the generation of cytolytic T cells directed against syngeneic tumor cells.

Caspase Activation Is Required for Nitric Oxide–Mediated, CD95(APO-1/Fas)–Dependent and Independent Apoptosis in Human Neoplastic Lymphoid Cells

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4311-4320 ◽  
Author(s):  
Katerina Chlichlia ◽  
Marcus E. Peter ◽  
Marian Rocha ◽  
Carsten Scaffidi ◽  
Mariana Bucur ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Present Report ◽  
Lymphoid Cells ◽  
Jurkat Cells ◽  
Target Cells ◽  
No Production ◽  
No Donor ◽  
Synthase Inhibitor ◽  
Inhibitor Of Protein Synthesis

Nitric oxide (NO), an important effector molecule involved in immune regulation and host defense, was shown to induce apoptosis in lymphoma cells. In the present report the NO donor glycerol trinitrate was found to induce apoptosis in Jurkat cells that are sensitive to CD95-mediated kill. In contrast, a CD95-resistant Jurkat subclone showed substantial protection from apoptosis after exposure to NO. NO induced mRNA expression of CD95 (APO-1/Fas) and TRAIL/APO-2 ligands. Moreover, NO triggered apoptosis in freshly isolated human leukemic lymphocytes which were also sensitive to anti-CD95 treatment. The ability of NO to induce apoptosis was completely blocked by a broad-spectrum ICE (interleukin-1β converting enzyme)-protease/caspase inhibitor and correlated with FLICE/caspase-8 activation. This activation was abrogated in some neoplastic lymphoid cells but not in others by the inhibitor of protein synthesis cycloheximide. Our results were confirmed using an in vitro experimental model of coculture of human lymphoid target cells with activated bovine endothelial cells generating NO as effectors. Furthermore, the inhibition of endogenous NO production with the inducible NO synthase inhibitor NG-monomethyl-L-arginine caused a complete abrogation of the apoptotic effect. Our data provide evidence that NO-induced apoptosis in human neoplastic lymphoid cells strictly requires activation of caspases, in particular FLICE, the most CD95 receptor-proximal caspase. Depending on the cell line tested this activation required or was independent of the CD95 receptor/ligand system.

scholarly journals STUDIES ON CELL-MEDIATED IMMUNITY TO LYMPHOCYTIC CHORIOMENINGITIS VIRUS IN MICE

1973 ◽  
Vol 137 (6) ◽  
pp. 1511-1525 ◽  
Author(s):  
Ole Marker ◽  
Mogens Volkert
Keyword(s):  
Time Course ◽  
Underlying Mechanism ◽  
Cell Interaction ◽  
Lymphocytic Choriomeningitis ◽  
Lymphoid Cells ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Sharp Maximum ◽  
Direct Cell

A large amount of experimental evidence has already been presented indicating the great importance of the cell-mediated immunity in the pathogenesis of the LCM virus infection in mice. In this laboratory a method which makes it possible to measure this cellular immunity quantitatively in vitro has been developed. The method is based on the determination of the radioisotope released after the interaction between specifically sensitized lymphocytes and syngeneic 1Cr-labeled LCM virus-infected target cells. By using this technique the time-course of the cell-mediated immunity has been established in acutely infected mice and in virus carriers adoptively immunized with syngeneic sensitized lymphocytes. Lymphocytes from acutely infected mice showed a strong lysing effect on the target cells, with a sharp maximum at about the 9th day after infection. The cell-mediated immunity in adoptively immunized virus carrier mice showed the same time-course, but in these animals the lytic effect of the lymphoid cells was considerably less pronounced. Lymphocytes from untreated virus carriers did not, however, have any effect on the target cells, and in these animals it was not possible to demonstrate any evidence of enhancing antibodies, In experiments employing serial dilutions of sensitized lymphocytes in normal cells a direct linear relationship between the number of sensitized lymphocytes and target cell destruction was found. These experiments seem to indicate that the underlying mechanism in the cytotoxic reaction is a direct cell-to-cell interaction.

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