bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversal of 1,3-bis(2-chloroethyl)-1-nitrosourea-induced severe immunodeficiency by transduction of murine long-lived hemopoietic progenitor cells using O6-methylguanine DNA methyltransferase complementary DNA.
Authors: Maze R , Kapur R , Kelley M R , Hansen W K , Oh S Y , Williams D A 
Published: December 2022

Abstract
Bone marrow toxicity is a dose-limiting side effect of chloroethylnitrosourea (CNU) chemotherapeutic alkylating agents. A major determinant of CNU cytotoxicity is the methylation of guanine at the O6-position and the subsequent formation of interstrand DNA cross-links. O6-Methylguanine DNA methyltransferase (MGMT) removes alkyl groups from the O6 position of guanine and has been shown to repair CNU-induced DNA damage. We have previously demonstrated that transplantation of murine bone marrow cells transduced with a recombinant retroviral vector expressing MGMT via the human phosphoglycerate kinase promoter (PGK-MGMT) protects animals in vivo from acute myelotoxicity associated with CNU treatment. In the present study, we examined the effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a commonly used CNU, on long term recovery of the lymphoid compartment, including thymus reconstitution, peripheral T and B cell populations, and lymphocyte mitogen responses in mice reconstituted with PGK-MGMT-transduced hemopoietic cells. Mice transplanted with either mock-infected control or PGK-MGMT-transduced stem cells were treated with five weekly doses of BCNU. Analysis of the lymphoid compartment demonstrated significant damage 3 mo after the last BCNU dose in control animals. In contrast, the profound deficiency in CD4+CD8+ double-positive thymocytes and mature lymphocytes observed in control mice surviving BCNU treatment was completely reversed in mice transplanted with PGK-MGMT-transduced bone marrow and was associated with molecular evidence of in vivo selection of transduced cells in the lymphoid compartment. Thus, long term immunodeficiency following CNU therapy may be prevented by genetic modification of murine hemopoietic stem cells with MGMT, leading to significant improvement in post-transplant immune function.
Dual role of HIV Tat in regulation of apoptosis in T cells.
Authors: McCloskey T W , Ott M , Tribble E , Khan S A , Teichberg S , Paul M O , Pahwa S , Verdin E , Chirmule N 
Published: December 2022

Abstract
Apoptosis has been suggested to be one of the major mechanisms of depletion of CD4+ T cells in HIV-1-infected individuals. Remarkably, HIV-1-infected cells appear protected from apoptosis, whereas bystander cells show increased apoptosis in lymph nodes of infected individuals. In this work, we present evidence that the trans-activating protein of HIV-1, Tat, has a dual role in regulation of apoptosis in T cells. While addition of exogenous Tat protein induced apoptosis in uninfected T cells, T cell clones stably expressing the Tat protein were protected from activation-induced apoptosis. The addition of exogenous Tat potentiated anti-CD3 mAb, anti-Fas IgM mAb, and TNF-alpha-induced apoptosis of T cells. Pretreatment of Tat with anti-Tat Ab abrogated Tat-induced apoptosis, but did not affect anti-Fas IgM Ab-induced apoptosis. Endogenously expressed Tat was analyzed in Jurkat T cell clones transfected with either full-length tat gene (101 amino acids), or in control cells containing an empty vector. The Tat101-transfected clones were resistant to anti-CD3-induced apoptosis, when compared with cells transfected with vector alone. Furthermore, cross-linking of CD4 molecules on T cells with gp160 and anti-gp160 Ab showed markedly decreased apoptosis in Tat101 cells compared with that induced in cells transfected with vector alone. Taken together, our results indicate that HIV-1 Tat can regulate apoptosis that may contribute to the immunopathogenesis of AIDS.
Homing potentials of circulating lymphocytes in humans depend on the site of activation: oral, but not parenteral, typhoid vaccination induces circulating antibody-secreting cells that all bear homing receptors directing them to the gut.
Authors: Kantele A , Kantele J M , Savilahti E , Westerholm M , Arvilommi H , Lazarovits A , Butcher E C , Mäkelä P H 
Published: December 2022

Abstract
Specific Ab-secreting cells (ASC) appear in the human blood as a response to oral and parenteral vaccination. The actual contribution of these cells to the defense of the body depends on their final effector site. The homing potentials of mucosally and parenterally induced ASC were compared by examining the homing receptor (HR) expression of circulating specific ASC in the blood of volunteers vaccinated orally or parenterally with the same Ag, Salmonella typhi Ty21a. Circulating lymphocytes were separated into receptor-positive and -negative populations, and the numbers of specific ASC were assayed. The alpha4 beta7 integrin, which acts as a gut HR, was expressed on all (99%) of the mucosally activated ASC, but on only 58% of the parenterally induced ASC or 58% of all Ig-secreting cells of the unvaccinated controls. L-selectin, the peripheral lymph node HR, showed an inverse distribution; it was found on 42% of mucosally activated ASC and on 86% of parenterally induced ASC. These results reveal that all of the circulating ASC after oral vaccination are committed to migrate to the mucosal compartment of the immune system, strongly arguing for a recirculation of activated mucosal cells in humans. By contrast, ASC induced by parenteral vaccination with the same Ag are mostly directed to the systemic compartment, yet a part of them has mucosal homing attitudes as well. These differences indicate that the site of Ag encounter determines the homing potential of the cell.
Staphylococcal enterotoxin B induces an early and transient state of immunosuppression characterized by V beta-unrestricted T cell unresponsiveness and defective antigen-presenting cell functions.
Authors: Muraille E , De Smedt T , Andris F , Pajak B , Armant M , Urbain J , Moser M , Leo O 
Published: December 2022

Abstract
Staphylococcal enterotoxin B (SEB) is a bacterial enterotoxin able to simultaneously bind to class II molecules on APCs and to selected V beta regions (including V beta 8) of the TCR complex. Administration of SEB to adult BALB/c mice results in clonal activation of T cells bearing V beta 8 receptors, leading to an excessive release of proinflammatory cytokines. This initial immune response is followed by a long-lasting state of V beta 8-specific unresponsiveness, thought to benefit both the host (as it contributes to the down-regulation of the inflammatory response) and the bacterium (through ligand-specific T cell anergy). However, it is not clear how this type of restricted unresponsiveness can effectively impair the generation of an antibacterial response. To gain insight into the mechanism by which Gram-positive bacteria subvert the host immune response, we have investigated the immune competence of SEB-treated mice 48 h following SEB administration. We demonstrate in this report that in vivo, SEB induces a transient but profound state of unresponsiveness affecting both T and Ag-presenting cell functions. Although in vivo activation by SEB appears to be V beta-restricted under our experimental conditions, SEB-treated mice displayed an early (lasting 48 to 72 h postinjection) and V beta-unrestricted unresponsive state characterized by the inability to produce IL-2 in response to polyclonal TCR mitogens including third party bacterial superantigens (staphylococcal enterotoxin A and toxic shock syndrome toxin 1, SEA and TSST-1, respectively), Abs to non-SEB reactive V beta regions (V beta 6), anti-CD3 epsilon Abs, and a lectin (Con A). Spleen cell populations from SEB-treated mice also displayed defective APC functions, possibly related to a selective decrease in splenic dendritic cells numbers. Taken together, these observations indicate that SEB induces an early and transient state of immunodeficiency in vivo, representing a potential mechanism for escaping host immune surveillance.
HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases.
Authors: Suzuki Y , Demoliere C , Kitamura D , Takeshita H , Deuschle U , Watanabe T 
Published: December 2022

Abstract
Cross-linking of the Ag receptors on lymphocytes initiates activation of the receptor-coupled tyrosine kinases. HS1 is one of the substrates of these kinases and has been shown to transduce the signals for both clonal expansion and deletion in lymphoid cells. To gain further insight into the mechanism of action of HS1, we have tried to identify a protein that interacts with HS1 by yeast two-hybrid screening. The isolated cDNA, designated HAX-1, encodes a novel 35-kDa protein. The HAX-1 gene is expressed ubiquitously among tissues, and its protein is localized mainly in mitochondria, but also in endoplasmic reticulum and nuclear envelope in the cell. HS1/HAX-1 association is confirmed by coimmunoprecipitation of these proteins in the lysates of B lymphoma cells and COS-7 cells transfected with the corresponding cDNA expression vectors. Colocalization of these proteins in the cell is evident under confocal laser scanning microscope. Deletion mutant analysis of these proteins reveals that the association is mediated by the amino terminal region of HS1 and the carboxyl-terminal half of HAX-1. The potential role of the HAX-1/HS1 complex is discussed.
Human autoreactive CD4+ T cell clones use perforin- or Fas/Fas ligand-mediated pathways for target cell lysis.
Authors: Vergelli M , Hemmer B , Muraro P A , Tranquill L , Biddison W E , Sarin A , McFarland H F , Martin R 
Published: December 2022

Abstract
It is well established that target cell lysis by MHC class I-restricted CD8+ T cells is an important defense mechanism during infections with intracellular pathogens or against tumor targets. On the other hand, little is known about the physiologic role and the mechanisms of cytotoxicity of CD4+ MHC class II-restricted T cells. We have recently demonstrated that human autoreactive CD4+ T cells specific for one candidate autoantigen of multiple sclerosis, myelin basic protein, can mediate cytotoxicity. In the present report, we analyze the cytolytic mechanisms employed by these cells. We show that individual T cell clones, regardless of their cytokine phenotype, can be noncytotoxic or lyse target cells via either perforin- or Fas/Fas ligand-mediated cytotoxicity.
Roles of calnexin and Ig-alpha beta interactions with membrane Igs in the surface expression of the B cell antigen receptor of the IgM and IgD classes.
Authors: Wu Y , Pun C , Hozumi N 
Published: December 2022

Abstract
Membrane Igs (mIgs) of all five classes are associated with Ig-alpha beta dimers on the B cell surface. While mIgM requires the presence of these two associated molecules for its surface expression, mIgD does not. To study the structural basis for this differential Ig-alpha beta dependence, we created mutant mIgM and mIgD molecules (chimeras and those with reciprocal point mutations in their transmembrane sequences) and identified two amino acid residues in the transmembrane region of the mIg heavy chains responsible for this transport difference. Without Ig-alpha beta, mIgM and mutant mIgD molecules remained endoglycosidase H sensitive, consistent with endoplasmic reticulum (ER) localization. The molecular chaperone calnexin has previously been implicated in retaining unassembled mIgs in the ER. However, we found that inhibition of the association between calnexin and newly synthesized mIgs by castanospermine treatment did not lead to surface expression of normally retained mIgs. Therefore, calnexin cannot be the only retention molecule. Furthermore, for both wildtype and mutant mIgDs, association with calnexin was rather transient, thereby ruling out calnexin being a major ER retention molecule for mIgDs. Our study with castanospermine also showed that calnexin is required for wildtype mIgD surface expression only if Ig-alpha beta is absent, while the latter alone can function to promote mIg folding, assembly, and transport. Further study using our system will help to identify novel molecules and characterize their involvement in the control of mIg transport.
CD28 ligation prevents bacterial toxin-induced septic shock in mice by inducing IL-10 expression.
Authors: Wang R , Fang Q , Zhang L , Radvany L , Sharma A , Noben-Trauth N , Mills G B , Shi Y 
Published: December 2022

Abstract
The pathogenesis of septic shock is due mainly to bacterial toxin stimulation of the immune system, resulting in an excessive production of proinflammatory cytokines. TNF-alpha has been implicated as a major mediator in septic shock. Coinjection of D-galactosamine and LPS or staphylococcal enterotoxin B induced a rapid-onset, low-dose form of septic shock syndrome and ultimately led to death. We found that both the septic shock syndrome and death could be prevented by administration of anti-CD28 Ab. The protection induced by anti-CD28 Ab was associated with a decrease in TNF-alpha levels in the circulation. In addition, serum from anti-CD28 Ab-treated mice was capable of inhibiting the production of TNF-alpha by bone marrow-derived macrophages following treatment with LPS, indicating that anti-CD28 Ab induced production of soluble factors that subsequently inhibited the production of TNF-alpha. We confirmed that one of the factors present in serum was IL-10, because anti-CD28 Ab treatment stimulated the expression of IL-10, both in splenocytes and in T cell lines. Furthermore, injection of anti-IL-10 Abs could abolish the protective effect of anti-CD28 Ab on septic shock. Anti-IL-10 Ab could also suppress the anti-CD28 Ab-induced inhibition of TNF-alpha production, either in vivo or in vitro. Thus, we conclude that ligation of CD28 induces expression of IL-10, which in turn suppresses TNF-alpha production and prevents septic shock.
Granulocyte-macrophage colony-stimulating factor and IFN-gamma restore the systemic TNF-alpha response to endotoxin in lipopolysaccharide-desensitized mice.
Authors: Bundschuh D S , Barsig J , Hartung T , Randow F , Döcke W D , Volk H D , Wendel A 
Published: December 2022

Abstract
The influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-gamma on the restoration of impaired TNF-alpha release in LPS-desensitized mice or their refractory macrophages was investigated. Mice pretreated with GM-CSF or IFN-gamma (50 microg/kg i.v.) and injected with 3 mg/kg LPS i.p. displayed increased plasma TNF-alpha levels compared with LPS controls. IL-10 was marginally up-regulated by GM-CSF but abrogated by IFN-gamma pretreatment. LPS-tolerant mice (30 microg/kg LPS i.p., -24 h) showed an attenuated plasma TNF-alpha and IL-10 response to LPS and survived LPS shock. Pretreatment of such mice with GM-CSF or IFN-gamma restored the previously impaired TNF-alpha response. In cultures of murine monocyte/macrophage-containing cell populations, i.e., alveolar, peritoneal, spleen, bone marrow cells, or blood, the presence of GM-CSF or IFN-gamma (10 ng/ml) resulted in an enhanced release of TNF-alpha initiated by 1 microg/ml LPS. Cells from LPS-tolerant mice showed a diminished responsiveness to LPS. However, when exposed to GM-CSF or IFN-gamma ex vivo, their TNF-alpha response to LPS was partially restored. These findings characterize GM-CSF and IFN-gamma as potent enhancers of LPS-induced TNF-alpha production in normal as well as in experimentally immunocompromised mice and provide the rationale for further experiments to explore the pharmacologic use of these cytokines for restoration of immunocompetence in sepsis-associated immunosuppression.
Expression of chemokine receptors by subsets of neurons in the central nervous system.
Authors: Horuk R , Martin A W , Wang Z , Schweitzer L , Gerassimides A , Guo H , Lu Z , Hesselgesser J , Perez H D , Kim J , Parker J , Hadley T J , Peiper S C 
Published: December 2022

Abstract
IL-8 is expressed by activated and neoplastic astrocytes and enhances the survival of hippocampal neurons in vitro. Since mRNA encoding chemokine receptors have been demonstrated in brain, the expression of chemokine receptors by specific cell types in anatomic regions of the central nervous system (CNS) was investigated. Archival tissues from various regions of the CNS were stained with specific mAbs to the Duffy Ag/receptor for chemokines, a promiscuous receptor that binds selected chemokines; the specific receptor for IL-8 (CXCR1); and the receptor (CXCR2) shared by IL-8 and melanoma growth stimulatory activity. The Duffy Ag/receptor for chemokines was expressed exclusively by Purkinje cells in the cerebellum. Chemokine binding and radioligand cross-linking confirmed the presence of a high affinity, promiscuous chemokine receptor in the cerebellum. Although CXCR1 was not expressed in the CNS, CXCR2 was expressed at high levels by subsets of projection neurons in diverse regions of the brain and spinal cord, including the hippocampus, dentate nucleus, pontine nuclei, locus coeruleus, and paraventricular nucleus, and in the anterior horn, interomediolateral cell column, and Clarke's column of the spinal cord. Fibers that express CXCR2 included those in the superior cerebellar peduncle and the substantia gelatinosa. Immunohistochemical analysis of the involved brain tissues from patients with Alzheimer's disease revealed expression of CXCR2 in the neuritic portion of plaques surrounding deposits of amyloid. These data suggest that chemokines may play a role in reactive processes in normal neuronal function and neurodegenerative disorders.
Distribution of Antibodies in the Serum and Organs of Rabbits
Authors: Freund Jules , Whitney Caroline E. 
Published: December 2022

Abstract
In a previous study of the distribution of agglutinins in the serum and organs of rabbits (1), it has been shown that the liver, spleen, kidney, lung, uterus and skin of actively or passively immunized rabbits accumulate approximately the same amount of antibodies per gram of organ. A decided difference was observed, however, in the rate of accumulation in these organs. In passively immunized animals the accumulation of agglutinins is rapid in the liver, spleen, kidney and lung. In these organs the accumulation was completed within from ten to fifteen minutes after the immune serum had been injected into the ear vein. On the other hand, in the uterus and particularly in the skin, the accumulation of antibodies continued for several hours.
In the first paper of this series it was suggested that the relatively early appearance of antibodies in the liver, spleen, kidney and lung may be connected with the relatively greater rate of lymph flow from these organs.
On the Racial Distribution of Some Agglutinable Structures of Human Blood
Authors: Landsteiner K. , Levine Philip 
Published: December 2022

Abstract
There are recorded in the literature some attempts to make a serological distinction of races with the methods that had proved successful in the differentiation of species. One may state that these efforts have not led to quite definite results. The claim of Bruck (1) that the sera of Caucasians, Chinese and Malays can be distinguished by means of complement fixation tests could not be confirmed by later workers.1 Marshall and Teague (6) observed some differences in similar tests but in their opinion the data are not so clear cut as to permit of a practical application. Negative results were obtained by Fitzgerald (7) who feels justified in concluding that with the method employed “the existence of specific racial differences … has not been proven.” Taking into account the difficulty of distinguishing the sera of closely related species, e.g., man and chimpanzee (Nuttal (8)), one would scarcely expect a more favorable outcome without resorting to very sensitive methods.
The Reticulo-Endothelial System and Antibody Production
Authors: Roberts Edward F. 
Published: December 2022

Abstract
An ever-increasing number of investigators are accepting the viewpoint that antibodies are accompaniments rather than causes of increased resistance. The validity of this opinion, however, will, undoubtedly, not be established until the site and mechanism of antibody elaboration have been determined. The few facts available indicate that the process of manufacture must be a function of cells or systems of cells widely distributed throughout the animal organism and of fixed-tissue origin. Such a system of cells is provided by the reticulo-endothelial system of Aschoff (1).
Many efforts have been made to link up the reticulo-endothelial cells with resistance to infection as well as to antibody production by methods of splenectomy or blockade, or a combination of the two. While these avenues of attack are admittedly weak, results fairly consistent, but not uniform, indicating a participation of the reticulo-endothelial system in resistance to infection have been obtained, although it must not be overlooked that the vast majority of experiments directed toward this problem have not included a sufficient number of cases to warrant the formulation of general conclusions.
Mathematico-Statistical Considerations on the Inheritance of the Human Blood Groups
Authors: Ichida Kenkichi 
Published: December 2022

Abstract
There are two principal hypotheses concerning the inheritance of human blood groups; one assumes the existence of two independent pairs of factors (the old hypothesis; v. Dungern-Hirszfeld (5), Ottenberg (34) (35) (36), Kirihara (28) (29), etc.) and the other is based on the assumption of triple allelomorphs (the new hypothesis; Bernstein (2) (3), Furuhata-Ichida-Kishi (8) (9) (10) (11) (12) (13), Furuhata (14) (15) (16) (17) (18) (19), Snyder (38). There is some essential difference between Bernstein's hypothesis and Furuhata's second hypothesis. Furuhata (12) (13) (16) (17) (19) maintains that the biochemical characters of the blood cells and sera in human blood are inherited always in a certain relationship, but he does not recognize the group-specific antigenicity of blood cells of the group O, as Bernstein supposes. They agree, however, in a point that they assume the three standard blood groups (ab/ab, Ab/Ab, aB/aB (Furuhata) RR, AA, BB (Bernstein)), and only a genotype in group AB.
Cutting Edge: The Chicken TCR ζ-Chain Restores the Function of a Mouse T Cell Hybridoma
Authors: Göbel Thomas W. F. , Bolliger Luca 
Published: December 2022

Abstract
The TCR/CD3 complex has been intensively studied in mammals, but it has been difficult to isolate homologues in other vertebrates. Here, we characterize the chicken ζ-chain, the first nonmammalian homologue identified. The comparison of mammalian and chicken ζ proteins revealed high identity of the transmembrane and the C-terminal cytoplasmic domains. Transfection of a mouse ζ-deficient cell line, with the chicken ζ gene, restored surface expression of the murine TCR/CD3 complex. The chicken ζ-chain was stably associated with the mouse TCR/CD3 components and fully restored its signaling capacity upon stimulation with Ab, superantigen, and peptide Ag. This is the first report of a nonmammalian TCR component that is capable of fully restoring a mammalian TCR in every aspect analyzed, thus demonstrating the enormous selective pressure to maintain the ζ-chain as a structural and signaling component over a period of 300 million years.