bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adoptively transferred antigen-specific T cells can be grown and maintained in large numbers in vivo for extended periods of time by intermittent restimulation with specific antigen plus IL-2.
Authors: Chen W , Reese V A , Cheever M A 
Published: December 2022

Abstract
The aim of the current study was to determine whether cultured tumor Ag-specific T cells could be induced to grow and maintained functional in large numbers in vivo by intermittent restimulation in vivo with specific Ag plus IL-2. T cells derived from spleens of B6 mice (Thy-1.2) immune to FBL-3, a Friend virus-induced leukemia, were activated by in vitro stimulation with irradiated FBL-3 and expanded by culture for 14 days with low concentrations of IL-2. The resultant FBL-3-specific T cell lines were adoptively transferred into cyclophosphamide pretreated congenic hosts (B6/Thy-1.1), and restimulated every 14 days by an injection of irradiated FBL-3 plus a 7-day course of IL-2. Donor T cells residing in the host were identified and quantified by use of antibody to the Thy-1.2 allele. The results confirmed that stimulation with FBL-3 on the day of transfer (day 0) plus IL-2 on days 0 to 6 induced rapid growth of donor T cells to approximately an 11-fold increase in total donor T cell number recoverable from host ascites and spleen by day 7. However, prolonging the course of IL-2 administration to 35 days did not maintain the number or the specific cytolytic function of donor T cells. By contrast, intermittent restimulation with specific Ag plus IL-2 induced intermittent regrowth of donor T cells in vivo, maintained the number of donor T cells in vivo at greater than the number input for longer than 1 mo, and allowed detection of substantially augmented donor T cell-mediated specific antitumor function over that period of time.
Generation of cytolytic activity with anti-CD3 monoclonal antibodies involves both IL-2-independent and -dependent components.
Authors: Stohl W , Tovar Z , Talal N 
Published: December 2022

Abstract
We have generated potent Ag-nonspecific cytolytic activity in PBMC cultures without exogenous IL-2 by stimulating the cells with anti-CD3 mAb. Three anti-CD3 mAb (147, 446, 454) each induced cytolytic activity against both K562 and Daudi targets, albeit to different degrees. The differences among the anti-CD3 mAb could not be explained by differences in their isotypes or avidity constants, by the number of anti-CD3 mAb molecules initially bound per cell, or by preferential or differential binding to TCR alpha/beta+ vs TCR gamma/delta+ cells. Each anti-CD3 mAb appeared to induce cytolytic activity via, in part, an IL-2-independent component, as evidenced by: 1) the generation of potent cytolytic activity in mAb 446-stimulated cultures despite undetectable IL-2 levels; 2) the frequent inability of exogenous IL-2 (10 U/ml) to generate as much cytolytic activity as that induced by mAb 147 or 454, despite the low levels of IL-2 (less than U/ml) in the latter cultures; and 3) the different kinetics in generation of cytolytic activity between IL-2 and anti-CD3 mAb. Moreover, exogenous IL-2 enhanced anti-CD3-induced cytolytic activity for each anti-CD3 mAb. However, IL-2-dependent processes also contributed to the generation of cytolytic activity, because anti-p55 IL-2R mAb in combination with anti-p75 IL-2R mAb partially inhibited generation of anti-CD3-induced cytolytic activity, albeit to a lesser degree than the inhibition by these anti-IL-2R mAb of generation of IL-2-induced cytolytic activity. By demonstrating the generation of potent cytolytic activity in the absence of exogenous IL-2, these studies may assist in the development of more effective and less toxic clinical adoptive immunotherapy protocols.
Abnormalities of lymphokine gene expression in patients with common variable immunodeficiency.
Authors: Sneller M C , Strober W 
Published: December 2022

Abstract
Common variable immunodeficiency (CVI) is a syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and increased occurrence of both autoimmune disease and malignancy. In our study we examine the expression of lymphokine genes in mitogen-activated T cells from four patients with CVI. T cells from patients with CVI did not differ significantly from normals in total T cell number, CD4/CD8 ratio, CD45R expression, or proliferation in response to PHA. However, T cells from this group of patients did exhibit significant abnormalities of mitogen-induced lymphokine gene expression. T cells from patients exhibited significantly decreased expression of IL-2, IL-4, IL-5, and IFN-gamma when compared to normal controls. In contrast to these abnormal findings, mitogen-activated T cells from patients with CVI expressed normal amounts of IL-2R alpha and c-myc suggesting that these patients have a selective abnormality of T cell activation. Furthermore, it is likely that the deficient production of IFN-gamma by patient T cells is partially due to the abnormality of IL-2 production as the levels of IFN-gamma mRNA detected during the initial IL-2-independent phase of T cell activation were normal and the addition of exogenous rIL-2 was able to normalize IFN-gamma production by PHA-stimulated patient cells. Finally, supernatants from PHA-activated cultures of patients PBMC were deficient in their ability to support Ig secretion by Staphylococcus A Cowan's-activated normal B cells suggesting that these T cell abnormalities may contribute to the pathogenesis of this syndrome.
Granulocyte-macrophage colony-stimulating factor stimulates human monocyte accessory cell function.
Authors: Smith P D , Lamerson C L , Wong H L , Wahl L M , Wahl S M 
Published: December 2022

Abstract
We investigated the effect of recombinant human granulocyte-macrophage CSF (rhGM-CSF) on the accessory cell function of purified human monocytes. Compared with untreated monocytes, rhGM-CSF-treated monocytes promoted enhanced mitogen- and Ag-stimulated lymphocyte proliferation. This enhancement was significantly inhibited by mAb to rhGM-CSF. In experiments designed to define the mechanism of rhGM-CSF augmentation of accessory cell function, rhGM-CSF was shown to cause a dose-dependent increase in monocyte expression of surface HLA-DR molecules and stimulated secretion of IL-1, both important in monocyte T cell interactions. Further studies demonstrated that levels of HLA-DR and IL-1 mRNA were increased by rhGM-CSF, indicating transcriptional regulation of gene expression for HLA-DR and IL-1. Thus, rhGM-CSF augments accessory cell function by human monocytes, and this augmentation correlates with rhGM-CSF-induced increases in transcription of the HLA-DR and IL-1 genes leading to increased expression of surface HLA-DR and secretion of IL-1.
Temporal expression of different pathways of 1-arginine metabolism in healing wounds.
Authors: Albina J E , Mills C D , Henry W L , Caldwell M D 
Published: December 2022

Abstract
Arginine can be metabolized by inflammatory cells through at least two pathways. One is an oxidative l-arginine deiminase (OAD) that results in the formation of citrulline and reactive nitrogen intermediates. The other is arginase, which determines the production of ornithine and urea. The temporal expression of these pathways in an experimental wound model (s.c. implanted polyvinyl alcohol sponges in the rat) was investigated by examining the concentrations of amino acids and of nitrite in fluids obtained from the sponges 6 h to 15 day after implantation. These analyses revealed two distinct periods during which the arginine concentration in the fluids was markedly below plasma levels. During the early period (less than 3 days after sponge implantation) wound fluid contained more citrulline and nitrite than at any other time, suggesting OAD activity. In contrast, ornithine accumulated in the fluids during the late decrease in arginine concentration that extended beyond day 3, during which time the wound fluid also contained a high arginase activity. This time-dependent expression of different pathways of arginine metabolism in wounds was confirmed in sponge cultures containing [guanido-14C]-l-arginine. Cells contained in sponges harvested less than 48 h after implantation metabolized labeled arginine mainly to labeled citrulline, whereas labeled urea was produced during culture of sponges harvested after this time. The low arginine content of wound fluid did not appear to be rate limiting for the expression of OAD in late sponges because no OAD activity was evidenced when 4 mM arginine was added to the cultures. These results indicate that the OAD pathway is expressed in this model predominantly during the early, polymorphonuclear leukocyte-predominant, phase of repair. At this time, the reactive nitrogen intermediates resulting from the metabolism of arginine may mediate some of the events characteristic of early inflammation, including microbiostasis, vasodilation, and inhibition/reversal of platelet aggregation. In turn, the late suppression of this pathway and the catabolism of arginine through arginase may promote macrophage function within wounds.
The regulation of resistance to Schistosoma mansoni by auto-anti-idiotypic immunity. II. Global qualitative and quantitative regulation.
Authors: Phillips S M , Lin J J , Walker D J , Linette G P , Fathelbab N G , Perrin P J 
Published: December 2022

Abstract
These studies explore the suppression of resistance to schistosomiasis mansoni through interactions of autologous immune functions derived from an induced anti-idiotypic response. This anti-clonotypic response is induced by immunization with syngeneic L3T4+ receptor-bearing lymphoblasts and for the sake of description is termed "auto-anti-idiotypic". It is antigenically restricted and cannot be induced by allogeneic cells. Anti-idiotypic immunization profoundly suppressed the development of protective immunity after exposure to irradiated cercariae and altered a wide variety of functional humoral and cellular immune responses to the parasite. In addition to quantitative suppressive effects, the anti-idiotypic network also regulated qualitative aspects of the immune response by increasing the heterogeneity and reducing the functional binding avidity of antibody for Ag. These effects also were reflected in analogous alterations in cellular reactivity, using the criteria of the Ag mediated blast transformation and delayed type hypersensitivity. Thus idiotypic regulation can mold the specificity and sensitivity of the immune response to Schistosoma mansoni by affecting quantitative and qualitative responses. Manipulation of idiotypic recognition provides an approach to optimize the expression of protective resistance to schistosomiasis.
Regulation of B cell responses to the variant surface glycoprotein molecule in trypanosomiasis. II. Down-regulation of idiotype expression is associated with the appearance of lymphocytes expressing antiidiotypic receptors.
Authors: Theodos C M , Mansfield J M 
Published: December 2022

Abstract
The current study examines the idiotypic expression and regulation of variant surface glycoprotein (VSG)-specific B cell responses during African trypanosomiasis. Utilizing competitive inhibition RIA analysis, we detected antibodies in the serum of BALB/cByJ mice infected with Trypanosoma brucei rhodesiense clone LouTat 1.5 that recognized the same VSG epitopes as three VSG 1.5-specific mAb. These epitope-specific antibody responses were detectable by day 5 of infection, peaked by day 10, and then declined slowly through day 15 of infection. VSG-specific antibodies detectable in the serum of infected BALB/cByJ mice included those that were idiotypically cross-reactive with the VSG 1.5-specific mAb. These idiotypically defined, VSG-specific antibody responses appeared to peak around day 7 of infection, but then declined to near preimmune levels by day 15 of infection, demonstrating that the aggregate epitope-specific response was composed only in part by the idiotypically cross-reactive responses. Although corresponding antiidiotypic antibodies could not be detected in infected sera during periods of up- or down-regulation of idiotypically defined antibodies, flow cytometry analysis of lymphocytes isolated from the spleens of LouTat 1.5-infected BALB/cByJ mice revealed the presence of antiidiotypic receptor-bearing cells. These cells were detectable primarily during days 10 to 12 of infection and subsequently down-regulated their receptors, or declined in numbers, to near preimmune levels by day 15 of infection. The appearance of these antiidiotypic receptor-bearing cells coincides with the decline of idiotypic antibody present in the serum of the LouTat 1.5-infected mice and may represent nascent evidence for idiotypic regulation of trypanosome-specific immune responses in infected animals.
Rejection of mouse sarcoma cells after transfection of MHC class II genes.
Authors: Ostrand-Rosenberg S , Thakur A , Clements V 
Published: December 2022

Abstract
Th cells are stimulated by peptide Ag presented in the context of MHC class II molecules. We have reasoned that immune responses against tumors may be more efficient if tumor cells were class II Ag positive, and thereby able to directly function as APC to stimulate tumor-specific Th cell proliferation. We have tested this hypothesis by using DNA-mediated gene transfer to generate syngeneic MHC class II Ag-expressing mouse Sal sarcoma cells (Sal/Ak transfectants). Autologous A/J mice challenged i.p. or s.c. with Sal/Ak transfectants do not develop tumors, whereas A/J mice challenged with the class II negative parental Sal tumor have a high tumor incidence. Furthermore, immunization of the autologous host with Sal/Ak transfectants completely protects against subsequent challenge with wild-type Sal cells. MHC class II-expressing tumor cells, therefore, stimulate an improved tumor-specific immune response, and the immunity is cross-reactive with the class II negative tumor. Inasmuch as the transfected MHC class II gene product is not functioning as a target molecule for autologous tumor rejection, the improved immunogenicity of the Sal/Ak cells is probably due to stimulation of a tumor-specific Th cell population. The increased immunogenicity of Sal/Ak cells is, therefore, probably the result of direct presentation of Sal tumor-associated Ag in the context of tumor cell MHC class II molecules to Th lymphocytes. These studies demonstrate that induction of tumor cell MHC class II Ag expression is a potential strategy for tumor-specific immunotherapy, and suggest that tumor immunity may be enhanced by improved Th cell generation.
Role of ICAM-1 in antigen presentation demonstrated by ICAM-1 defective mutants.
Authors: Dang L H , Michalek M T , Takei F , Benaceraff B , Rock K L 
Published: December 2022

Abstract
We report a methodology for selecting APC with mutations that have impaired their ability to present Ag to T cells. A20 B lymphoblastoid cells were mutagenized and then repeatedly cocultured with murine T-T hybridomas in the presence of specific Ag. During these cocultures, the T-T hybridomas kill the competent APC, allowing the outgrowth of inactive variants. Two variants, A20.M1 and A20.M2, were isolated and studied in detail. These variants are impaired in their ability to present multiple Ag to T cells. This defect is also observed for the presentation of processing independent peptides by fixed APC indicating that a lesion exists in a post-Ag processing step. The level of expression of MHC molecules is unaffected and the functional defect in the APC is not localized to a particular MHC molecule. In contrast, these mutants were found to have a selective decrease in the expression of the murine homolog of ICAM-1, and the residual ability of these cells to present Ag was not blocked by anti-ICAM-1 mAb. Conversely, Ag presentation by the wild-type A20 is inhibited by anti-ICAM-1 mAb. Similarly, anti-LFA-1 mAb inhibited the response of T cells to Ag presented by the wild-type A20 to a much greater degree than by the mutant cells, indicating that LFA-1 is involved in interaction of T cells with the former, but not latter, APC. In the apparent absence of a contribution of LFA-1 to the T cell-APC interaction, either as a result of mAb blocking or the disruption of the APC membrane, the mutant and wild-type APC have a similar level of Ag-presenting activity. Reconstitution of ICAM-1 expression in these mutants by transfection with murine ICAM-1 cDNA fully restores their ability to present Ag. Together these results demonstrate that a murine ICAM-1 homolog is expressed on A20 B cells, where it functions as a major cell interaction molecule. The degree of functional impairment in these mutant APC gives insight into the contribution of cell interaction molecules to efficient Ag presentation and T cell-B cell interaction. Finally, these results also demonstrate the feasibility of selecting APC with mutations affecting Ag presentation.
Evidence implicating utilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones.
Authors: Gajewski T F , Schell S R , Fitch F W 
Published: December 2022

Abstract
We have reported recently that high concentrations of anti-CD3 mAb inhibited IL-2-dependent proliferation of TH1 but not TH2 clones. The selective inhibitory effect on TH1 clones suggested that the two helper T lymphocyte subsets might utilize different TCR-associated signal transduction mechanisms. In the present study, we demonstrate that this distinction was not due to a gross difference in the level of TCR expression by TH1 and TH2 clones. Inhibition of TH1 proliferation by anti-CD3 mAb appeared to depend on calcium for maximal effect, suggesting that a substantial elevation of intracellular free calcium concentration ([Ca2+]i) might not occur after ligation of the TCR complex of TH2 clones. Calcium ionophore inhibited IL-2-dependent proliferation of both subsets, suggesting that receptor/ligand systems which stimulate elevated [Ca2+]i would be expected to inhibit proliferation. Although elevated [Ca2+]i and generation of inositol phosphates were readily detected in TH1 clones, these second messengers were not detected following stimulation of TH2 clones via the TCR complex. In addition, lymphokine production by TH1 clones was more sensitive to inhibition by cholera toxin, 8-bromoadenosine 3':5'-cyclic monophosphate, and cyclosporin A than was lymphokine production by TH2 clones. Collectively, these results suggest that TH1 and TH2 clones utilize distinct TCR-associated signal transduction mechanisms for lymphokine gene expression. The difference in signaling mechanisms suggests a potential pharmacologic target for intervention in situations where inappropriate activation of TH1 or TH2 cells occurs in vivo.
Requirement of the thymus for the recovery of anti-alloantigen helper T cells from tolerance induced by intravenous presensitization with allogeneic cells.
Authors: Kitagawa S , Sato S , Azuma T , Hori S , Hamaoka T , Fujiwara H 
Published: December 2022

Abstract
Intravenous presensitization of C57BL/6 (B6) mice with class I H-2-disparate B6-C-H-2bm1 (bm1) whole spleen cells and class II H-2-disparate B6-C-H-2bm12 (bm12) spleen cells depleted of APC resulted in almost complete elimination of the respective anti-bm1 and anti-bm12 reactivities. However, the reduced alloreactivities as assessed by Th cell capacities (proliferative responses and IL-2 production) were recovered around 8 wk after the i.v. presensitization in euthymic B6 mice. In contrast, background levels of bm1- or bm12-specific reactivities were revealed to last more than 12 wk after the presensitization in B6 mice which had been thymectomized prior to the i.v. presensitization. Such a reduced alloreactivity was also observed in the capacity to reject bm1 or bm12 skin grafts, and prolongation of graft survival was strikingly enhanced in the thymectomized group compared to that induced in the nonthymectomized group. However, there was an important difference in such prolongation in the thymectomized hosts between bm1 and bm12 grafts; a considerable percentage (greater than 80%) of bm12 skin grafts continued to take more than 5 mo, whereas about 90% of bm1 grafts were rejected by around 5 mo along with the emergence of weak, but detectable anti-bm1 Th and cytotoxic T cell activities. These results indicate that 1) i.v. presensitization regimen is capable of eliminating in vitro and in vivo alloreactive capabilities but these alloreactivities can be recovered in euthymic hosts with T cell repopulating potential and 2) there are differential requirements of the thymus for repopulating anti-bm1 (Lyt-2+) and anti-bm12 (L3T4+) T cell activities.
Monoclonal antibodies block murine IL-4 receptor function.
Authors: Beckmann M P , Schooley K A , Gallis B , Vanden Bos T , Friend D , Alpert A R , Raunio R , Prickett K S , Baker P E , Park L S 
Published: December 2022

Abstract
IL-4 is a cytokine which can induce B-lymphocyte proliferation, increase cell-surface Ia expression, and induce some activated B cells to differentiate and begin to secrete IgE. IL-4 binds specifically to a cell-surface receptor (IL-4R) on cells from a variety of lineages including T and B cells. In general both primary cells and in vitro cell lines express less than 5000 receptors per cell. Utilizing a subclone of the cytotoxic T cell line CTLL-2 expressing a high level of IL-4R, mAb against the murine IL-4R were prepared. Two mAb have been identified which have different properties. These antibodies, designated M1 and M2, recognize sequences specific to the murine IL-4R. Immunoprecipitation studies with M1 and M2 on CTLL-2 cells have identified the receptor as a Mr = 145,000 cell-surface protein. Similar results have been obtained with the recently isolated full length murine IL-4R cDNA expressed in COS-7 cells. In addition the antibodies are capable of inhibiting IL-4 binding. One antibody, M1, is also a potent inhibitor of IL-4-induced proliferation. These antibodies will be useful in dissecting a wide array of activities attributed to IL-4.
Transcriptional modulation of human IL-6 gene expression by verapamil.
Authors: Walz G , Zanker B , Barth C , Wieder K J , Clark S C , Strom T B 
Published: December 2022

Abstract
Calcium channel-blocking agents interfere with the initial increase of cytosolic calcium that follows mitogenic stimulation of T lymphocytes. In cultures of mitogen-stimulated PBMC, verapamil also blocked T cell accumulation of cytoplasmic IL-2-encoding mRNA. In sharp contrast, the addition of verapamil to PHA and PMA-stimulated PBMC augmented the mitogen-stimulated increases in nuclear transcription of IL-6-encoding mRNA, steady state levels of IL-6 encoding mRNA, and release of IL-6 bioactivity. These experiments indicated that an increased IL-6 transcriptional rate rather than stabilization of transcripts accounted for the increased cytoplasmic IL-6 mRNA levels and subsequent expression of IL-6 bioactivity. These effects were not produced by nicardipine, another potent calcium channel blocker, or EGTA. We suggest that a non-calcium-dependent, IL-6 regulatory factor, absent or inactive in verapamil-treated cultures, inhibits IL-6 gene activation in mitogen-stimulated PBMC. Failure to express this inhibitory factor would result in IL-6 gene superinduction at a transcriptional level.