Search PubMed⌕ Search

Biomedical subjects

T B Strom

Publications and source records attributed to T B Strom.

At least 199 records · Page 11Linked to original sources
PubMed1988

Blocking of T cell activation at the G1A/G1B interface of the cell cycle and prevention of expression of interleukin 2 receptors by alloactivated suppressor T lymphocytes.

Suppressor T (Ts) leukocytes affect various immune reactions including the activation of T cells by alloantigens. It is, however, not known where Ts interfere with the sequence of events supporting T cell activation and proliferation. In the present studies, alloantigen selective Ts were activated by in vitro priming with heat-inactivated allogeneic leukocytes in the mixed leukocyte reaction (MLR). Such Ts, or a soluble factor thereof, were shown to interfere with the progression of MLR responder cells from the G1A to the G1B phase of the cell cycle. In the presence of Ts, most MLR responder cells did not express interleukin 2 receptors, although a small minority of cells constantly escaped Ts inhibition. Moreover, Ts modified MLR contained only minor interleukin 2 (IL-2) bioactivity suggesting also an effect of Ts cells on IL-2 synthesis. The addition of exogenous IL-2 to Ts modified MLR increased 3H-thymidine incorporation although Ts retained the capacity to regulate the proliferative response in a dose-dependent fashion. Phenotypic analysis of allostimulated T cells proliferating in the presence of preformed Ts and exogenous IL-2 revealed a conspicuous failure of T helper cells to proliferate in response to alloantigen despite the presence of very high IL-2 concentrations.

Interleukin-2↗
PubMed1988

Synergy between subtherapeutic doses of cyclosporine and immunobiological manipulations in rat heart graft recipients.

Cyclosporine in combination with other chemical or biological immunosuppressive modalities has been useful in clinical and experimental organ transplantation. In these studies, the efficacy of adjunctive subtherapeutic doses of CsA given to immunologically enhanced heart graft recipients or to animals treated with an anti-IL-2 receptor monoclonal antibody (ART18) are described. Individually, the treatment entities are only partially effective. In rats undergoing active and passive enhancement alone, heart allograft survival was increased to 25 +/- 12 days in two-thirds, indefinitely in one-third. After ART18 treatment, grafts survive 21 +/- 1 days. Grafts are accepted permanently in animals receiving full-dose CsA (15 mg/kg X 7), but are rejected acutely (c. 7 days) when subtherapeutic doses (1.5 mg/kg X 7) are used. However, when subtherapeutic doses of CsA are given in combination with immunological enhancement or with interleukin-2-receptor-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy spare selectively T cells with suppressor activity in vivo; in enhanced animals, the W3/25+ subset is responsible for prolonged graft survival, the OX8+ fraction is responsible in ART18-treated animals and in CsA-treated animals. Both subpopulations show suppressor activity in the later stages of combination treatment. IL-3 production is increased significantly in these states of unresponsiveness, an observation also noted during maintenance CsA treatment; this seems to correlate with suppressor activity. Immunoperoxidase studies of the graft infiltrates emphasize the synergistic effects of combination treatments. Thus, subtherapeutic doses of CsA plus biologic host manipulations produce greatly increased graft survival by affecting selectively different host immune mechanisms.

Animals↗
PubMed1988

Endotoxin-associated protein: interleukin-1-like activity on serum amyloid A synthesis and T-lymphocyte activation.

Bacterial endotoxins or lipopolysaccharides (LPS) elicit a variety of biologic activities in intact animals and various in vitro systems. LPS from most gram-negative bacteria have appeared to have similar biologic activities regardless of the species of origin or method of preparation of the LPS. More recent studies have suggested differences in the effects of protein-rich as opposed to protein-free LPS in inducing mitogenesis of lymphocytes from endotoxin-resistant C3H/HeJ mice. These studies examine other activities of endotoxin-associated protein (EAP), purified to less than 0.007% contamination with LPS, and demonstrate that this material has activity mimicking some of the effects of interleukin-1 (IL-1). EAP proved to be as potent as LPS in eliciting rises in concentrations of serum amyloid A (SAA) and was active in both endotoxin-sensitive (CF1) and endotoxin-resistant (C3H/HeJ) mice. In contrast to LPS, which mediates its SAA-inducing activity by release of an inducer (IL-1) from LPS-stimulated macrophages, EAP appeared to act directly to induce SAA production, in that incubation with macrophages failed to increase its activity. EAP also exhibited IL-1-like activity in the lymphocyte-activating factor assay when both CF1 and C3H/HeJ thymocytes and macrophages were tested. The lymphocyte-activating factor activity of EAP was not blocked by addition of polymyxin B. In addition, EAP exerted stimulatory activity on resting human T lymphocytes, costimulated with Sepharose-bound anti-CD3 monoclonal antibody 64.1, comparable to that observed with purified human monocyte IL-1. These studies indicate that proteins from procaryotic cells may act as cytokines for some eucaryotic cells.

Animals↗
PubMed1988

Cell receptor specific targeted toxins: genetic construction and characterization of an interleukin 2 diphtheria toxin-related fusion protein.

We have genetically replaced the diphtheria toxin receptor binding domain with a DNA insert encoding the T-cell growth factor interleukin-2 (IL-2). The toxin-related IL-2 fusion gene encodes a 70,586 dalton protein, pro-IL-2-toxin. The mature form of IL-2-toxin is exported to the periplasmic space of recombinant Escherichia coli and has a molecular weight of 68,086. IL-2-toxin has been partially purified from periplasmic extracts of recombinant E. coli, and it is shown to contain immunologic determinants intrinsic to both its diphtheria toxin and IL-2 components. The chimeric toxin is targeted toward IL-2 receptor bearing T-cells in vitro.

Cell Line↗
PubMed1987

Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells.

We investigated effects of corticosteroids on interleukin 1 (IL-1) production in monocyte-like tumor cell line, U937. Release of IL-1 activity by bacterial toxin-stimulated cells was completely blocked by 10 nM dexamethasone (Dex). We examined the question whether corticosteroids suppress IL-1 production by blocking transcription of IL-1 mRNA, or by blocking IL-1 synthesis at a post-transcriptional step. Northern blot hybridization analysis indicated that Dex, 10 nM, completely blocked accumulation of IL-1 beta-encoding mRNA in U937 cells. Dex-mediated inhibition of IL-1 release appeared to be glucocorticoid receptor-mediated and was abrogated by progesterone. In addition, Dex at high concentrations could inhibit post-transcriptional synthesis of IL-1 by prestimulated U937 cells. Although Dex, 500 nM, did not change IL-1 mRNA levels in prestimulated cells, it completely blocked IL-1 release and induced a transient increase in cellular cyclic adenosine 3',5'-monophosphate (cAMP) levels. Dex-mediated inhibition of IL-1 release in prestimulated cells is likely to occur via increased levels of cAMP, which have been shown to block post-transcriptional IL-1 synthesis. Our results indicate that glucocorticoids suppress IL-1 synthesis by two distinct mechanisms, blocking transcription of IL-1 mRNA during monocyte activation, and blocking post-transcriptional IL-1 synthesis via cAMP.

Aldosterone↗
PubMed1987

Two phenotypically distinct populations of T cells have suppressor capabilities simultaneously in the maintenance phase of immunologic enhancement.

The events leading to immunologic enhancement in LEW rats immunized actively with Brown Norway (BN) rat spleen cells and passively with LEW anti-BN hyperimmune serum 11 and 10 days before receiving (LEW X BN)F1 cardiac allografts, respectively, have been studied. Cellular suppressor mechanisms developing during the induction phase of this phenomenon have recently been shown to be mediated by W3/25+ T cells in an antigen-specific manner. The present study suggests that the late maintenance phase of immunologic enhancement is mediated in vivo by simultaneously present separate donor-specific T cell subpopulations of W3/25+ and OX8+ phenotypes. Splenocyte subsets from grafted recipients greater than 100 days after transplantation were adoptively transferred into unmodified syngeneic LEW rats that received a specific test allograft 24 hr later, or into B recipients bearing indefinitely surviving heart grafts. Test graft survival was prolonged significantly in the first group and not altered in the second. Indeed, nonoverlapping W3/25+ and OX8+ cell fractions were separately responsible for suppression. However, when suppressor activity was tested in vitro in a three-component coculture mixed lymphocyte reaction, no suppression by T cells was obtained; this lack of correlation between in vivo and in vitro results has also been noted by other investigators in different systems. Thus, in the maintenance phase of actively and passively induced immunologic enhancement, interplay between two phenotypically distinct T cells with suppressor characteristics, but not putative cell-surface blocking factors, seems to prevent development of an alloreactive response and mediate host unresponsiveness.

Animals↗
PubMed1987

Inhibitory effects of anti-interleukin 2 receptor and anti-L3T4 antibodies on delayed type hypersensitivity: the role of complement and epitope.

Although it is often assumed that anti-T cell antibodies mediate immunosuppression by targeting T cells for destruction, other activities should be considered. To dissect the mechanisms by which anti-L3T4 and anti-interleukin 2 receptor (IL 2R) monoclonal antibodies (Mab) mediate immunosuppression, the effects of anti-L3T4 and two complement-fixing anti-IL 2R Mab of the same isotype, but defining functionally distinct epitopes, were probed in a delayed type hypersensitive (DTH) model using BALB/c as well as two C5-deficient mouse strains. Low doses of anti-L3T4 and the M7/20 anti-IL 2R Mab, which competitively blocks IL 2 binding, inhibit DTH in BALB/c mice whereas an anti-receptor antibody which does not block the IL 2 binding site did not effectively abrogate DTH. Interestingly, anti-L3T4, but not M7/20 anti-IL 2 Mab treatment blocked DTH in the C5-deficient strains. On the other hand, M7/20 does not cause immunosuppression solely by blocking the IL 2R from occupancy by IL 2 because binding to T blasts by M7/20 is equivalent in BALB/c and C5-deficient strains. Consequently, immunosuppression mediated by anti-IL 2R Mab is dependent on both IL 2 receptor site blockade and C5. Clearly, anti-L3T4 and M7/20 have disparate requirements for C5 in mediating immunosuppression. There can be no doubt that factors other than the cellular targeting patterns influence the immunosuppressive activities of Mab. Ideally, anti-T cell Mab should fix complement and inhibit T cell function.

Animals↗
PubMed1987

Selective immunosuppression with anti-interleukin 2 receptor-targeted therapy: helper and suppressor cell activity in rat recipients of cardiac allografts.

(LEW X BN)F1 cardiac allografts are rejected within 8 days in unmodified LEW rats. ART18, a mouse anti-rat IgG1 monoclonal antibody which binds specifically in vitro to the interleukin 2 receptor (IL 2R) molecule expressed primarily on activated T cells, prolongs allograft survival in a dose-dependent fashion to ca. 3 weeks (p less than 0.001) after being administered for 10 days after transplantation. This effect was related to the specificity of the antibody for IL 2R, as therapy with ART62 (a monoclonal antibody recognizing MHC class I antigen but not binding the rat IL 2R) was ineffectual. Suppressor activity was detected in spleen cells of ART18-treated grafted hosts: in vivo, splenic T suppressor/cytotoxic fraction adoptively transferred into normal LEW improved donor-specific but not third-party test graft survival (17 days, vs. 8 days, respectively, p less than 0.001); in vitro, mixed lymphocyte reaction was profoundly but nonspecifically inhibited (less than 5% of test mixed lymphocyte reaction, p less than 0.001 as compared to acutely rejecting controls). In contrast, splenic T helper (Th) cells from ART18-treated hosts were functionally depressed, as noted by their passive transfer into immunologically anergic B recipients of cardiac allografts (rejection in ca. 40 days, vs. ca. 13 days after transfer of Th from specifically sensitized rats). ART18 treatment also resulted in diminished elaboration of IL 2 as compared to normal (p less than 0.005) or acutely rejecting hosts (p less than 0.001); however, a remarkable increase in the production of IL 3 occurred (p less than 0.001). These results demonstrate that IL 2R-targeted therapy of immunocompetent graft recipients produces a selective immune defect in which donor-specific T suppressor cells are spared, but Th cells attenuated or destroyed. Decreased elaboration of IL2 concomitantly augments the release of IL 3, a lymphokine which might play a role in suppressor effect in vivo. In addition, IL 2R-targeted therapy of the immunodeficient graft recipients abrogates the capacity of alloactivated T cells to re-establish acute immune responsiveness.

Animals↗
PubMed1987

Humoral and cellular mechanisms in acute allograft injury.

An intact thymus-competent immune system seems both necessary and sufficient for acute allograft rejection. T-lymphocytes fulfill a form of Kochs postulate in this regard: (1) They are present in rejecting allografts; and (2) rejection is abrogated by depriving the host of T cells but can be recreated by providing such T cell-deficient hosts with purified T cells. However, the dilemma of whether Th or Tc cells actually mediate allograft rejection remains. Although belonging to opposite immunologic "teams," they act on each other in many ways, interactions that are probably just the beginning of the complex cascade of both specific and nonspecific host immunologic events, both cell mediated and humoral, that are stimulated by the presence of allogeneic tissues.

Acute Disease↗
PubMed1987

Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein.

We have genetically replaced the diphtheria toxin receptor binding domain with a synthetic gene encoding interleukin-2 (IL-2) and a translational stop signal. The diphtheria toxin-related T-cell growth factor fusion gene encodes a 70 586-d polypeptide, pro-IL-2-toxin. The mature form of IL-2-toxin has a deduced mol. wt of 68,086 and is shown to be exported to the periplasmic compartment of Escherichia coli (pABI508), and contain immunologic determinants intrinsic to both its diphtheria toxin and IL-2 components. IL-2-toxin has been purified from periplasmic extracts of recombinant strains of E. coli (pABI508) by immunoaffinity chromatography using immobilized anti-IL-2. The purified chimeric toxin is shown to selectively inhibit protein synthesis in IL-2 receptor bearing targeted cells, whereas cell lines which do not express the IL-2 receptor are resistant to IL-2-toxin action.

Bacterial Proteins↗
PubMed1987

Differential effect of gamma-irradiated and heat-treated lymphocytes on T cell activation, and interleukin-2 and interleukin-3 release in the human mixed lymphocyte reaction.

Heat-inactivated (45 degrees C/1 hr) lymphocytes selectively activate suppressor T cells in the mixed lymphocyte reaction (MLR), while no significant proliferation and cytotoxic T lymphocyte activation can be detected. It is not well understood why hyperthermic treatment abolishes the stimulatory capacity of lymphocytes since HLA-DR molecules remain detectable immediately following heat exposure. In order to further characterize the requirements for Ts activation we studied the effects of hyperthermic treatment on cellular protein and DNA synthesis and cell surface protein expression in proliferating T and B cells; interleukin (IL)-1, IL-2, and IL-3 release following allogeneic stimulation with heat treated cells (HMLR); and IL-2 receptor expression as an indicator of T cell activation in the HMLR. Hyperthermic treatment reduced cellular protein synthesis as estimated by 14C-leucine uptake to about 15%, and DNA synthesis (3H-thymidine incorporation) to about 5% of untreated control cells. In contrast to y-irradiated cells, viability of heated cells rapidly declined within the first 24 hr. Hyperthermic treatment doubled binding of mouse immunoglobulin paralleled by an increased expression of IL-2 and transferrin receptors, while expression of HLA-DR and 4F2 proteins appeared unchanged. Stimulation with heated cells triggered the release of IL-1- and an IL-3-like bioactivity but did not induce IL-2 synthesis and/or release, thus explaining the lack of proliferation in the HMLR. Addition of exogenous IL-2 but not IL-1 restored HMLR proliferation. A comparison of allostimulation with y-irradiated and heat-treated cells revealed that significantly fewer T cells were induced to express IL-2 receptors at day 3 (14% vs. 8%, P less than 0.001) and at day 6 (42% vs. 21%, P less than 0.05) with heat-inactivated stimulators. We conclude that metabolically compromised lymphocytes activate Ts and are sufficient to stimulate IL-1 and IL-3 synthesis but do not transmit an unknown signal required for the activation of IL-2 synthesis and IL-2 receptor expression on a yet-to-be-defined T cell subset.

DNA↗