Search PubMed⌕ Search

Biomedical subjects

A Sarin

Publications and source records attributed to A Sarin.

36 records · Page 2Linked to original sources
PubMed1995

Cytotoxic effect of TNF and lymphotoxin on T lymphoblasts.

Recombinant TNF and lymphotoxin trigger the apoptotic death of normal mouse and human T lymphocyte blasts in vitro. This cytotoxic effect does not involve the Fas death pathway and differs from the TNF-triggered death of tumor cells in several respects: 1) It is a slower process, requiring 2 to 3 days; 2) it is blocked, rather than enhanced, by cycloheximide; and 3) based on the agonistic effect of anti-TNF receptor Abs, it involves a synergistic effect of both the 55-kDa TNFR1 and the 75-kDa TNFR2, as opposed to the dominance of TNFR1 for tumor cytotoxicity. The TNF-induced death of blasts is potently inhibited by IL-2, as well as by IL-1, IL-4, IFN-gamma, and IL-12. Because activated T cells secrete both TNF and LT, these findings reveal a new pathway for Ag-induced down-modulation of T cell responses.

Animals↗
PubMed1995

A protease-dependent TCR-induced death pathway in mature lymphocytes.

Several cysteine and serine protease inhibitors previously shown to block TCR-induced death of 2B4 T hybridoma cells were tested for their ability to block various T lymphocyte apoptotic death systems. TCR-induced death of both peripheral CD4+ and CD8+ T cell blasts was inhibited similarly to the hybridoma, but cell death in these cells induced by anti-Fas, gamma-irradiation, etoposide, or extracellular ATP was not blocked. For T cell lines, cell death induced by CTL or by IL-2 withdrawal was also not inhibited. TCR-induced death of immature CD+8+ thymocytes triggered by culture on immobilized anti-CD3 was not blocked by these protease inhibitors, whereas similar death induced in the resting CD4+8- thymocyte subset under these conditions was inhibited similarly to the T cell blasts. TCR-induced proliferation of the latter subset was modest in the absence of exogeneous IL-2, but was enhanced two- to fourfold by the protease inhibitors. These results show that a protease-dependent death pathway can be triggered by the TCR in mature T cells; similar protease-dependent steps are not common to the TCR-triggered activation pathway or other apoptotic death pathways in these cells.

Animals↗
PubMed1995

Cytokines in immune regulation/pathogenesis in HIV infection.

Two hallmarks of immunopathogenesis in the progression of HIV-infected individuals to AIDS are the loss of T helper (Th) cell function in response to antigens and the critical reduction in CD4+ T cell numbers. It is probable that these two phenomena are related. We observed that: (1) the failure to detect antigen-stimulated Th cell responses in vitro correlates with increased pokeweed mitogen/staphylococcal enterotoxin B (P/S)-stimulated and antigen-stimulated T cell death; and (2) both of these events are similarly modulated by immunoregulatory cytokines. Interleukin 2 (IL-2) and IL-12 (Th1-type cytokines), as well as antibodies to IL-4 and IL-10 (which are Th2-type cytokines) restore in vitro Th cell responses to recall antigens such as influenza virus and HIV envelope synthetic peptides (env). P/S-induced T cell death affects both CD4+ and CD8+ T cell subsets, whereas death induced by stimulation with env affects only CD4+ T cells. In both examples, Th1-type cytokines and antibodies to Th2-type cytokines protect against T cell death. In contrast, IL-4 and IL-10 do not protect against death, and anti-IL-12 antibody can enhance T cell death. Our findings indicate that the loss of Th cell function and increased T cell death seen in vitro are correlated, and that in vivo HIV infection gives rise to inappropriate cytokines resulting in immune dysfunction and immunopathogenesis.

Cytokines↗
PubMed1994

Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis.

In vitro T-cell receptor-induced programmed cell death in both activated T cells from human immunodeficiency virus-seronegative (HIV-) donors and resting T cells from HIV+ donors was substantially influenced by cytokines. Addition of exogenous recombinant "type 1" lymphokines interferon gamma and interleukin 2 (IL-2), as well as the macrophage-produced IL-12, which favor cell-mediated T-cell responses, blocks both systems of T-lymphocyte programmed cell death. In contrast, the "type 2" lymphokines IL-4 and IL-10, which favor antibody responses, either had no effect or enhanced these systems of in vitro T-cell programmed cell death. A role for endogenously produced cytokines was suggested by the inhibition of T-cell receptor-mediated death by antibodies against IL-4 and IL-10 and its enhancement by anti-IL-12 in cultures containing monocytes. These results demonstrate that the functional properties of type 1 and type 2 cytokine classes may be further extended to include their effects on T-cell programmed cell death and their possible role in the pathogenesis of HIV infection.

Apoptosis↗
PubMed1994

Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV+ donors by cysteine protease inhibitors.

In vitro activation of PBLs from HIV+ individuals resulted in programmed cell death (PCD) within 2 days in 58 of 95 HIV+ blood donors, in contrast to only two of 30 control HIV- donors. CD4+ and CD8+ T cells from HIV+ donors died under these conditions, and these cells showed apoptotic nuclear morphology and DNA fragmentation. To test the hypothesis that this cell death shares a common biochemical pathway with that induced by TCR cross-linking in normal dividing T cells, inhibitors of the calcium-activated cysteine protease calpain were tested for their ability to block the activation-induced PCD of HIV+ donors. The E-64 (epoxysuccinyl) class of cysteine protease inhibitors gave 40% to 60% inhibition of HIV+ PCD responses, while the aldehyde inhibitors, leupeptin and calpain inhibitor II, gave 60% to 67% inhibition. The involvement of this calpain-dependent death pathway in HIV-induced functional T helper cell deficiency was tested by examining the effect of calpain inhibitors on the defective Ag- and mitogen-dependent proliferative responses of HIV+ donors. Twenty to fifty percent of such defective responses were significantly restored toward normal levels by calpain inhibitors, whereas control responses by normal donors were largely unaffected. These data suggest that a calpain-dependent PCD pathway contributes to HIV-associated immunodeficiency and suggest the use of calpain inhibitors as a possible route to therapy of HIV infection.

Apoptosis↗
PubMed1994

Effect of gamma interferon on the expression of class I MHC antigens on fresh leukemic cells and their susceptibility to lysis by lymphokine activated killer cells.

Relationship between MHC class I antigen expression on PBLs from leukemia patients and their susceptibility to lysis by LAK cells was investigated. LAK cells induced small yet significant lysis of leukemic cells. In nine out of 14 cases studied, treatment with Interferon gamma (200 U/ml for 48 hours) resulted in a decrease in the LAK susceptibility of leukemic cells. In six of these cases, there was a concomitant increase in the expression of class I MHC antigen expression. In three samples, the increase in MHC class I antigen expression was not accompanied by a decrease in LAK susceptibility. IFN treatment had no effect on the binding of leukemic cells to LAK effector cells.

Down-Regulation↗
PubMed1993

Protease inhibitors selectively block T cell receptor-triggered programmed cell death in a murine T cell hybridoma and activated peripheral T cells.

The hypothesis that cytoplasmic proteases play a functional role in programmed cell death was tested by examining the effect of protease inhibitors on the T cell receptor-mediated death of the 2B4 murine T cell hybridoma and activated T cells. The cysteine protease inhibitors trans-epoxysuccininyl-L-leucylamido-(4-guanidino) butane (E-64) and leupeptin, the calpain selective inhibitor acetyl-leucyl-leucyl-normethional, and the serine protease inhibitors diisopropyl fluorophosphate and phenylmethylsulfonyl fluoride, all showed dose-dependent blocking of the 2B4 death response triggered by the T cell receptor complex and by anti-Thy-1. These protease inhibitors enhanced rather than inhibited IL-2 secretion triggered by T cell receptor cross-linking, showing that they did not act by preventing signal transduction. Growth inhibition induced by cross-linking the 2B4 T cell receptor, measured by inhibition of thymidine incorporation, was not generally blocked by these protease inhibitors. All five of these protease inhibitors enhanced rather than blocked 2B4 cell death triggered by dexamethasone, an agent previously shown to have a death pathway antagonistic with that of the TCR. 2B4 cytolysis by the cytotoxic agents staphylococcal alpha-toxin and dodecyl imidazole, and that caused by hypotonic conditions, was not significantly affected by the five protease inhibitors tested. The selected protease inhibitors blocked both the apoptotic nuclear morphology changes and DNA fragmentation induced by T cell receptor cross-linking, and enhanced both these properties induced by dexamethasone in 2B4 cells. The T cell receptor-induced death of activated murine lymph node T cells and human peripheral blood CD4+ T cells was blocked by both cysteine and serine protease inhibitors, showing that the protease-dependent death pathway also operates in these systems.

Animals↗
PubMed1993

B-cell mitogenic effect of dinitrophenyl derivative of Mycobacterium tuberculosis antigens.

Soluble antigens derived from the H37Ra strain of Mycobacterium tuberculosis (Ra antigen) induced marginal proliferative response in spleen cells from unsensitized mice. The FDNB derivative of this antigen (Ra-DNP), however, had a marked proliferation-inducing effect. An increase in the population of B-cells but a reduction in the T-cell population was noted in Ra-DNP-treated spleen cell cultures. BSA-DNP derivatives used as control had no effect on mouse spleen cell proliferative activity. Moreover, addition of BSA-DNP along with Ra did not improve the proliferative response to the latter, indicating that in order to obtain proliferative activity, DNP residues must be present on Ra antigens themselves. Thymidine incorporation studies using sorted cell populations indicated that B-cells proliferated in response to Ra-DNP. The effect of Ra-DNP was neither blocked by Polymyxin-B treatment, nor retained by an endotoxin removal column, suggesting that lipopolysaccharide was not responsible for the B-cell mitogenic effect of Ra-DNP. As compared to Ra antigen, Ra-DNP derivative was found to bind more efficiently to B-cells as well as to mouse Ig. Additionally, lymph node cells derived from Ra-sensitized mice proliferated significantly better in response to Ra-DNP. These results indicate that FDNB derivatization of Ra antigen renders it more reactive with B-cells, which may in turn be responsible for a better T-cell reactivity of the derivative, since B-cells can act as antigen-presenting cells. It is possible that DNP residues may facilitate the interaction of Ra antigen with B-cells, perhaps through their Ig receptor.

Animals↗
PubMed1993

MHC class I up-regulation protects some but not all targets against LAK-mediated lysis: possible implications for the existence of LAK cell subpopulations using different recognition strategies.

The effect of gamma-interferon (gamma-IFN) was examined on the lymphokine-activated killer (LAK) cell susceptibility and the levels of major histocompatibility complex (MHC) class I antigen expression on YAC, P815 and EL4 cells. IFN induced a marked increase in the MHC class I antigen expression on all target cells, a concomitant decrease in LAK sensitivity was observed for YAC and P815 cells but not for EL4 cells. In competition experiments, lysis of YAC cells by LAK cells was inhibited by control or IFN-treated YAC and P815 cells, but not by control or IFN-treated EL4 cells. Moreover, lysis of EL4 cells was not inhibited by control or IFN-treated YAC cells. Our results suggest that the effectors killing EL4 are distinct from those killing YAC and/or P815 and that the former are not influenced by the levels of MHC class I antigens on target cells.

Animals↗
PubMed1990

Necessity for interaction between adherent and non-adherent rat spleen cells for the generation of a suppressor factor of NK activation.

Whole rat spleen cell populations in culture release constitutively a factor which suppresses the NK activation in response to interleukin-2. Culture supernatants derived from adherent (AD) and non-adherent (NAD) cell preparations obtained from rat spleen cells, did not have a suppressor activity comparable to that present in the culture supernatants of whole spleen cells. When reconstituted mixtures of the AD and NAD cells were cultured, high levels of suppressor activity could again be demonstrated in the culture supernatants, indicating that some kind of co-operation between AD and NAD cells was needed for efficient generation of the suppressor. Non-suppressive culture supernatants derived from NAD cells became suppressive when AD cells were cultured in them. On the other hand, relatively little suppressor activity was generated when NAD cells were cultured in non-suppressive culture supernatants from AD cells. Our results seem to indicate that NAD cells may release some agent which is not itself a suppressor but either (a) induces the generation of suppressor activity from AD cells, or (b) is "processed" into a suppressor agent by AD cells.

Animals↗
PubMed1990

Quantitative estimation of major histocompatibility complex antigens on live tumour cells.

Quantitation of major histocompatibility complex (MHC) antigens on cells can accurately be done by using a flowcytometer. Since flowcytometer is not freely accessable an alternate, simple method for relative quantitation of MHC antigens has been devised. In this procedure, YAC lymphoma cells were first treated with a monoclonal anticlass I MHC antibody and then with a rabbit anti mouse Ig-antibody coupled to peroxidase, followed by colour development using a substrate of peroxidase enzyme. Various assay parameters have been optimized. The validity of the procedure was examined by assessing the enhanced MHC expression on YAC cells treated with a soluble rat spleen derived factor, by the new procedure as well as by the flowcytometer. Comparable results were obtained by using both techniques.

Animals↗
PubMed1989

Lack of optimal activation of natural killer levels by interleukin-2 in rat spleen cells: evidence for suppression.

The effect of human recombinant IL-2 on the levels of natural killer (NK) activity in spleen cells derived from BALB/c mice and different strains of rats was studied. Enhancement of murine NK activity in response to IL-2 was readily demonstrable. Levels of NK activity in control as well as IL-2-treated spleen cells from Wistar, Sprague-Dawley, Fischer, and Long-Evans rats increased initially and peaked on Day 1 or 2 of culture. No significant differences between the control and the IL-2-treated cultures was found in this duration. The subsequent fall in NK activity was slower in IL-2-treated cultures of Fischer and Long-Evans rat spleen cells resulting in a significant difference between the NK levels in control and IL-2-treated cells on Day 5 and Day 7 of the culture. In the case of Wistar and Sprague-Dawley rats, the boosting effect of IL-2 on NK levels was either poor or nonexistent. Even though NK activation was poor, spleen cells of all strains of rats did proliferate in response to IL-2, indicating that the IL-2 preparation used was biologically active on rat spleen cells. Rat spleen cells cultured alone or with IL-2 released a factor(s) in the culture supernatant which could suppress the IL-2-induced NK activation in mouse spleen cells. Indomethacin could block the release of suppressor factor by cultured rat spleen cells. Moreover the NK levels in rat spleen cells could be augmented by IL-2 in the presence of indomethacin. These results indicate that the subdued IL-2-induced NK activation in bulk cultures of rat spleen cells could be due to spontaneous release of prostaglandins by the cultured cells.

Animals↗
PubMed1989

Interleukin-2-induced decrease in the buoyant density of cytotoxic cells and its relationship with proliferation.

Interleukin 2 (IL-2) is known to induce an augmentation of natural killer activity. In the present study we have used discontinuous Percoll density gradients to investigate the changes in the buoyant density of killer effector cells generated in response to IL-2. In all systems examined (mouse and rat spleen cells and human peripheral blood mononuclear cells), the cytolytic effectors generated in response to IL-2 have markedly lower buoyant densities compared to fresh natural killer cells. Our results also suggest that if a single layer of 44.2% (v/v) Percoll is used, almost all IL-2-induced cytolytic activity can be enriched in the cells which float on this layer whereas the heavier cells from the pellet are devoid of cytotoxic activity. The contribution of proliferative activity to (a) the generation of cytotoxicity and (b) the decrease in the buoyant density of the IL-2-induced killer cells was also studied in the mouse system. Natural killer levels in mouse spleen cells treated with mitomycin C could be significantly augmented by IL-2. Moreover, the effector cells generated in control as well as mitomycin-C-treated spleen cells in response to IL-2 had the same low buoyant densities. These results indicate that proliferation is not a prerequisite for the activation of killer activity and a reduction in buoyant density in response to IL-2.

Animals↗
PubMed1988

Interleukin-2 induced activation of natural killer cells in rats and mice: a comparative study.

Effects of interleukin-2 (IL-2) on the natural killer (NK) activities of BALB/c mouse and Wistar rat spleen cells were compared. While mouse spleen cells cultured alone rapidly lost NK activity, co-culture with IL-2 resulted in a marked enhancement of NK activity. In contrast, the levels of NK activity of rat spleen cells cultured alone increased and remained high for 3 days and declined thereafter. Addition of human recombinant IL-2 or purified rat IL-2 did not influence the NK levels in rat spleen cell bulk cultures. Both IL-2 preparations were however biologically active as shown by their capacities to induced proliferation in rat spleen cells. Rat spleen cells suppressed the IL-2 activation of mouse spleen cells in a dose dependent manner, indicating a suppressor influence generated by rat spleen cells. Culture supernatants of rat spleen cells cultured with or without IL-2 for 3 or 5 days could also suppress the mouse spleen NK activation in response to IL-2. The suppressor activity could be concentrated on a 5K MW cut-off Amicon filter indicating that the molecular weight of the factor is more than 5000. These results indicate that a suppressor of IL-2 induced NK activation of mouse spleen cells is released by cultured rat spleen cells.

Animals↗
PubMedDate not supplied

Depression.

Explore the source record for details and available documents.

Adolescent↗