bluuebunny/crossref_metadata_2025_split huggingface dataset:
A soluble chimeric complement inhibitory protein that possesses both decay-accelerating and factor I cofactor activities.
Authors: Higgins P J , Ko J L , Lobell R , Sardonini C , Alessi M K , Yeh C G 
Published: December 2022

Abstract
A chimeric gene was constructed from the genes coding for the human complement regulatory proteins, membrane cofactor protein (CD46) and decay-accelerating factor (CD55). The recombinant chimeric gene was transfected into Chinese hamster ovary cells. The gene product is a soluble, glycosylated, 110-kDa protein named complement activation blocker-2 (CAB-2). This protein possesses both factor I cofactor activity and decay-accelerating activity, and inactivates classical and alternative C3/C5 convertases in vitro. The specific activity of CAB-2 against cell-associated convertases is greater than that of soluble forms of either membrane cofactor protein or decay-accelerating factor or of both factors combined. CAB-2 also blocks the activation of complement in vivo, inhibiting both the Arthus reaction and Forssman shock in guinea pigs. Studies in rats demonstrate CAB-2 to exhibit favorable biphasic pharmacokinetics with a t1/2 alpha of 10 min and a t1/2 beta of 8 h; the beta phase accounts for 93% of the administered dose. CAB-2 may be an effective therapeutic treatment of acute human diseases in which excessive complement activation causes damage to normal tissues.
Human platelets can initiate T cell-dependent contact sensitivity through local serotonin release mediated by IgE antibodies.
Authors: Matsuda H , Ushio H , Geba G P , Askenase P W 
Published: December 2022

Abstract
To investigate the role of human platelets in initiating Ag-specific contact sensitivity (CS), a mouse model employing human platelets was used. Intravenous injection of immune lymphoid cells containing Ag-specific CS-effector Thy1+ B220- T cells that were depleted of CS-initiating Thy1+, B220+ cells together with human platelets presensitized in vitro with Ag-specific IgE mAb led to elicitation of CS responses in recipient mice. The fact that this response was blocked by preincubation of platelets with an irrelevant IgE or with a mixture of anti-Fc epsilonRI alpha mAb and anti-Fc epsilonRII mAb suggested that IgE Fc epsilonR on platelets were involved. When platelets that were presensitized with Ag-specific IgE mAb were incubated in vitro with specific Ag in the presence of fresh mouse serum, a significant net release of [3H]serotonin (5-hydroxytryptamine, 5-HT) was observed. Furthermore, in vitro depletion of 5-HT from platelets or in vivo pretreatment of recipients with a 5-HT2A receptor antagonist (ketanserin) abolished the IgE-dependent CS initiation mediated by platelets. These results show that human platelets can initiate T cell-dependent CS responses through IgE mAb, and this CS initiation is mediated by 5-HT released from the platelets in an Ag-specific manner.
IL-13 protects mice from lipopolysaccharide-induced lethal endotoxemia: correlation with down-modulation of TNF-alpha, IFN-gamma, and IL-12 production.
Authors: Muchamuel T , Menon S , Pisacane P , Howard M C , Cockayne D A 
Published: December 2022

Abstract
IL-13 is a potent down-modulator of macrophage proinflammatory activity in vitro, similar in this context to the anti-inflammatory cytokines IL-4 and IL-10. Since IL-10 effectively confers protection to mice from LPS-induced lethal endotoxemia through inhibition of proinflammatory cytokine production, we investigated whether IL-13 may also be capable of providing protection in this experimental model of endotoxic shock. A single injection of recombinant murine IL-13 (rmIL-13; 0.5-10 microg) significantly increased survival in a dose-dependent manner when a lethal i.p. injection of endotoxin was administered to BALB/c mice. This effect appeared to be IL-13 specific, since survival was not affected in mice that received heat-inactivated rmIL-13. rmIL-13 provided significant protection to mice even when given 30 min after LPS injection; however, this protection decreased in a time-dependent manner as the administration of rmIL-13 was delayed by 1, 2, and 5 h following LPS injection. The protective effect of IL-13 was correlated with significant decreases in the production of the inflammatory mediators TNF-alpha, IFN-gamma, and IL-12 as well as a decrease in the anti-inflammatory mediator IL-10. Our data suggest that IL-13 provides protection from LPS-induced lethal endotoxemia in a manner that is similar to but independent from that of IL-10, and therefore can be added to the list of cytokine immunomodulators that might be beneficial in the treatment of septic shock.
Constitutive tyrosine phosphorylation of the vav proto-oncogene product in MRL/Mp-lpr/lpr mice.
Authors: Mimura T , Minota S , Nojima Y , Morino N , Hamasaki K , Furuya H , Yazaki Y 
Published: December 2022

Abstract
MRL/Mp-lpr/lpr (lpr) mice develop autoantibodies, vasculitis, and glomerulonephritis, which are similar to human systemic lupus erythematosus, and acquire a generalized, nonmalignant, lymphoproliferative disorder. CD4- CD8- CD3+ TCR alphabeta+ (double-negative, DN) T cells accumulate in spleen and lymph nodes, and become a major T cell population in vivo. These DN T cells, however, are refractory to various stimuli, including CD3, IL-2, CD28, PMA, and PHA. Recently, the lpr gene mutation has been identified as a mutant gene for Fas, resulting in expression defects of Fas Ag. It is still unclear, however, what kinds of mechanisms cause the dysfunction of lpr DN T cells. To elucidate the pathogenic mechanisms in abnormal DN T cells, biochemical analyses were conducted for the expression and tyrosine phosphorylation of the vav proto-oncogene product (Vav) in DN T cells from lpr mice. We demonstrated that Vav, a 95-kDa cytoplasmic protein, from lpr mice was constitutively tyrosine phosphorylated several times higher than in control +/+ mice, while expression of Vav protein in lpr and +/+ mice was equal. Additionally, in contrast with +/+ T cells, tyrosine phosphorylation of Vav, which normally increases within a minute of stimulation via TCR, did not increase in lpr DN T cells following PHA or Ab activation. Taken together with the suggested roles of Vav in multiple receptor-mediated signal transductions, our findings suggest that the functional abnormalities of lpr DN T cells may be related to Vav abnormal tyrosine phosphorylation, which could lead to impaired signaling between surface receptors and G proteins in this cell population.
Origin and function of circulating CD44 in non-Hodgkin's lymphoma.
Authors: Ristämaki R , Joensuu H , Grön-Virta K , Salmi M , Jalkanen S 
Published: December 2022

Abstract
Soluble isoforms of various adhesion molecules have recently been found in the circulation, but the physiologic effects of such molecules are still unconfirmed. Our earlier study suggests that the serum level of the 70- to 80-kDa form of CD44 (sCD44) parallels the clinical treatment response in patients with lymphoma. In the present study we investigated the origin and the function of sCD44 in non-Hodgkin's lymphoma. Both peripheral blood and tumor lymphocytes were able to shed soluble CD44 in cell culture. In a SCID mouse model, transplanted Burkitt lymphoma (Namalwa) cells transfected with human CD44 shed soluble CD44. In binding studies sCD44 was able to adhere to hyaluronate and fibronectin, and moreover, sCD44 was able to block the binding of hyaluronate to CD44 on the cell surface and to block the binding of lymphocytes to high endothelial venules, suggesting that sCD44 retains its biological activity although it does not contain the cytoplasmic tail. In conclusion, sCD44 is biologically active and is at least partially shed by lymphoma cells in non-Hodgkin's lymphoma patients.
Kinetics of cytokine production in experimental systemic lupus erythematosus: involvement of T helper cell 1/T helper cell 2-type cytokines in disease.
Authors: Segal R , Bermas B L , Dayan M , Kalush F , Shearer G M , Mozes E 
Published: December 2022

Abstract
We followed cytokine production from induction through disease progression in a murine model of experimental systemic lupus erythematosus (SLE). SLE was induced by immunization with the human monoclonal anti-DNA Ab that bears the common Id designated 16/6 Id. BALB/c and C3H.SW mice that are susceptible to SLE induction and C57BL/6 mice that are resistant were immunized with the 16/6 Id. Cytokine production was tested periodically for 7 mo. Increased production of IL-2 and IFN-gamma, the Th1-type cytokines, was detected in BALB/c and C3H.SW mice 2 to 4 mo following immunization. IL-4 and IL-10, the Th2-type cytokines predominated later in disease course, and peaked 5 mo following disease induction. At this stage the Th1 type cytokines dropped to levels below those observed in controls. IL-4 production also dropped rapidly to very low levels, while IL-10 production decreased but remained above control levels. The ratio of IgG2a/IgG1 of DNA and 16/6 Id-specific Abs peaked at 2 mo following disease induction and decreased later, in concordance with the higher production of Th2-type cytokines. Thus, the development of experimental SLE in mice involves two stages: increased production of Th1-type, followed by increased induction of Th2-type cytokines. High levels of the proinflammatory cytokines, TNF-alpha and IL-1, were maintained throughout disease course. No significant changes were detected in the cytokine profile of C57BL/6 immunocytes following immunization with the 16/6 Id, supporting the possible role of the cytokine network in SLE.
CD3+ CD8+ CTL activity within the human female reproductive tract: influence of stage of the menstrual cycle and menopause.
Authors: White H D , Crassi K M , Givan A L , Stern J E , Gonzalez J L , Memoli V A , Green W R , Wira C R 
Published: December 2022

Abstract
The human female reproductive tract (RT) has been analyzed by others with respect to NK cell cytolytic activity, but not CD3+ T cell (CTL) cytolytic activity. Here, we describe the cytolytic capacity of mucosal CD3+ T cells both longitudinally within the RT (Fallopian tube, uterine endometrium, endocervix, ectocervix, and vaginal mucosa) and temporally throughout the menstrual cycle, using a redirected lysis assay system. Cytolysis by CD3+ CD8+ T cells is found throughout the RT and appears to be hormonally regulated, since in the uterine endometrium, the capacity for CD3+ T cell cytolytic activity is present during the proliferative phase of the menstrual cycle and absent during the subsequent secretory (postovulatory) phase. In contrast, in postmenopausal women the entire RT, including the uterus, retains the capacity for strong CD3+ T cell cytolytic activity. These findings suggest that the high levels of estradiol and progesterone present during days 14 to 28 of the menstrual cycle down-regulate CTL activity in the uterus. As a consequence, the absence of this activity may allow implantation of a semiallogeneic embryo that would otherwise be rejected. Further, these studies indicate that CTL activity is regulated differentially in different regions of the RT, persisting in the cervix and vagina throughout the menstrual cycle.
A Study of Vital Staining with Trypan Blue in Shock in Rabbits and Guinea Pigs
Authors: Ramsdell Susan Griffith 
Published: December 2022

Summary
For the rabbit, the tissues of importance in the absorption of trypan blue from the circulation during shock were found to be the skin, the mucous membranes, the blood vessels and the liver. For the guinea pig, the only tissue of importance was the skin.
Since the appearance of the dye in the tissues is assumed to be only an indication of an edema, we may conclude that such a change can play no significant part in acute shock in the guinea pig, and that in the rabbit its effects are only indirect, producing the toxic rather than the acute syndrome usually manifested by this animal. But this is not to say that the first effect of an antigen-antibody reaction is not upon the capillary endothelium. Possibly the ensuing permeability is the first step in a stimulation of the smooth musculature so great, in the guinea pig, as to obscure the less spectacular oedema, especially since this last depends for its manifestation in a large measure both upon the time factor and a special type of tissue—rich in capillaries and connective tissue, which finds its highest development only in the skin.
Blood Groups in Peru, Santo Domingo, Yucatan and among the Mexicans at the Blue Ridge Prison Farm in Texas
Authors: Moss W. L. , Kennedy James A. 
Published: December 2022

Abstract
Introduction. During the last decade considerable interest has been manifest in determining the percentage distribution among the four blood groups of the population in the various countries of the world.
Geneticists have been active in collecting this data and have attempted to apply it to the investigation of racial origins and relationships.
It is generally accepted that the blood groups are hereditary characteristics, probably transmitted according to the Mendelian laws although there is not exact agreement as to the theories of the genetic formulae of the four groups.
During the world war Hirschfeld and Hirschfeld (1) determined the percentage of the four groups in 16 different peoples, examining approximately 500 individuals in each of the following nationalities: English, French, Italians, Germans, Austrians, Serbs, Greeks, Bulgarians, Arabs, Turks, Russians, Jews, Malagasies, Negroes (Senegal), Annamese, and Indians.
Inhibition of JAK3 and STAT6 Tyrosine Phosphorylation by the Immunosuppressive Drug Leflunomide Leads to a Block in IgG1 Production
Authors: Siemasko Karyn , Chong Anita S-F. , Jäck Hans-Martin , Gong Haihua , Williams James W. , Finnegan Alison 
Published: December 2022

AbstractLeflunomide is an immunosuppressive drug capable of inhibiting T and B cell responses in vivo. A number of studies demonstrate that leflunomide functions both as a pyrimidine synthesis inhibitor and as a tyrosine kinase inhibitor. We previously reported that leflunomide inhibits LPS-stimulated B cell proliferation, cell cycle progression, and IgM secretion. This inhibition can be reversed by the addition of exogenous uridine, suggesting that leflunomide functions as a pyrimidine synthesis inhibitor in B cells. We report here that while the addition of uridine restored proliferation and IgM secretion to leflunomide-treated LPS-stimulated B cells, as determined by metabolic labeling and immunoprecipitation, it did not completely restore secretion of IgG Ab. We hypothesized that leflunomide inhibits LPS-induced IgG secretion by inhibiting tyrosine kinase activity required for isotype switch. We tested this hypothesis in a well-defined model of isotype switch, LPS plus IL-4 induction of IgG1. Leflunomide inhibited IgG1 secretion in this model in a dose-dependent manner. The signal transduction pathway utilized by IL-4 to induce IgG1 involves tyrosine phosphorylation of the IL-4 receptor, JAK1, JAK3, and STAT6 proteins induced by IL-4 binding to the IL-4R. Leflunomide diminished the tyrosine phosphorylation of JAK3 and STAT6 in the absence or presence of uridine. In gel mobility shift studies, STAT6 binding to the STAT6 DNA binding site in the IgG1 promoter decreased in the presence of leflunomide or leflunomide plus uridine. Taken together, these data suggest that leflunomide acts as a tyrosine kinase inhibitor to block IgG1 production.
Lack of Orally Induced Systemic Unresponsiveness in IFN-γ Knockout Mice
Authors: Kweon Mi-Na , Fujihashi Kohtaro , VanCott John L. , Higuchi Kazuo , Yamamoto Masafumi , McGhee Jerry R. , Kiyono Hiroshi 
Published: December 2022

AbstractSplenic T cells isolated from BALB/c mice that had been mucosally tolerized by oral administration of 25 mg of OVA revealed selective increases in IFN-γ production with impaired levels of IL-2, IL-4, IL-5, and IL-10. These mice possessed reduced splenic OVA-specific T cell proliferative and delayed-type hypersensitivity responses when compared with nontolerized controls. Further, OVA-specific IgG Ab responses in serum and the numbers of IgG Ab-forming cells in spleen were significantly diminished following systemic challenge with OVA in CFA. When IFN-γ-deficient (IFN-γ−/−) mice of the same genetic background were given an oral dose of 25 mg of OVA before systemic immunization, no reduction in OVA-specific IgG Ab responses in serum and spleen was seen. Furthermore, the serum IgG Ab responses were restricted to IgG1 and IgG2b subclasses. Interestingly, although IFN-γ−/− mice displayed a partial diminishment of T cell proliferative and delayed-type hypersensitivity responses to OVA, significant responses were still present when compared with the low responses noted in IFN-γ+/+ mice. In addition, OVA-specific T cells from IFN-γ−/− mice produced Th2-type cytokines (e.g., IL-4), which provided help for systemic OVA-specific serum IgG1 and IgG2b Ab responses. These findings clearly indicate a central role for IFN-γ in the induction and maintenance of mucosally induced tolerance.
Early Intrathymic Precursor Cells Acquire a CD4low Phenotype
Authors: Michie Alison M. , Carlyle James R. , Zúñiga-Pflücker Juan Carlos 
Published: December 2022

AbstractCD4low cells are a population of lymphoid lineage-restricted progenitor cells representing the earliest precursors present in the adult thymus. Paradoxically, thymic progenitors with a similar phenotype in fetal mice and adult RAG-2-deficient (RAG-2−/−) mice lack this characteristic low-level expression of CD4. We now show that radiation-induced differentiation of CD4+CD8+ double positive thymocytes in RAG-2−/− mice results in the appearance of low levels of CD4 on thymocytes that are phenotypically identical to CD4low progenitor cells present in the normal adult thymus. This suggests that CD4 surface expression can be passively transferred from double positive cells to early progenitor thymocytes. Analysis of mixed bone marrow chimeras, reconstituted with hematopoietic stem cells from both CD4−/− (CD45.2) and CD4wt (CD45.1) congenic mice, revealed a CD4low phenotype on cells derived from CD4−/− bone marrow cells. Furthermore, these CD4−/−-derived “CD4low” progenitors were capable of reconstituting lymphocyte-depleted fetal thymi, with all thymocytes displaying a CD4−/− phenotype. This directly demonstrates that genetically CD4-deficient thymic progenitor cells can passively acquire a CD4low phenotype. Moreover, CD4 expression on CD4low progenitor thymocytes is sensitive to mild acid treatment, indicating that CD4 may not exist as an integral cell surface molecule on this thymocyte population. Our findings demonstrate that low-level CD4 surface expression can be passively acquired by intrathymic progenitor cells from the surrounding thymic microenvironment, suggesting that other cell surface molecules expressed at low levels may also result from an acquired phenotype.
Enhanced Generation of Specific Tumor-Reactive CTL In Vitro by Selected Melan-A/MART-1 Immunodominant Peptide Analogues
Authors: Valmori Danila , Fonteneau Jean-François , Lizana Concepción Marañón , Gervois Nadine , Liénard Danielle , Rimoldi Donata , Jongeneel Victor , Jotereau Francine , Cerottini Jean-Charles , Romero Pedro 
Published: December 2022

AbstractThe Melan-A/MART-1 gene, which is expressed by normal melanocytes as well as by most fresh melanoma samples and melanoma cell lines, codes for Ags recognized by tumor-reactive CTL. HLA-A*0201-restricted Melan-A-specific CTL recognize primarily the Melan-A27-35 (AAGIGILTV) and the Melan-A26-35 (EAAGIGILTV) peptides. The sequences of these two peptides are not necessarily optimal as far as binding to HLA-A*0201 is concerned, since both lack one of the dominant anchor amino acid residues (leucine or methionine) at position 2. In this study we introduced single amino acid substitutions in either one of the two natural peptide sequences with the aim of improving peptide binding to HLA-A*0201 and/or recognition by specific CTL. Surprisingly, analogues of the Melan-A27-35 peptide, which bound more efficiently than the natural nonapeptide to HLA-A*0201, were poorly recognized by tumor-reactive CTL. In contrast, among the Melan-A26-35 peptide analogues tested, the peptide ELAGIGILTV was not only able to display stable binding to HLA-A2.1 but was also recognized more efficiently than the natural peptide by two short-term cultured tumor-infiltrated lymph node cell cultures as well as by five of five tumor-reactive CTL clones. Moreover, in vitro generation of tumor-reactive CTL by stimulation of PBMC from HLA-A*0201 melanoma patients with this particular peptide analogue was much more efficient than that observed with either one of the two natural peptides. These results suggest that the Melan-A26-35 peptide analogue ELAGIGILTV may be more immunogenic than the natural peptides in HLA-A*0201 melanoma patients and should thus be considered as a candidate for future peptide-based vaccine trials.
Structure-Function Study of the Extracellular Domain of the Human IFN-α Receptor (hIFNAR1) Using Blocking Monoclonal Antibodies: The Role of Domains 1 and 2
Authors: Lu Ji , Chuntharapai Anan , Beck Joanne , Bass Steve , Ow Arlene , De Vos Abraham M. , Gibbs Verna , Kim K. Jin 
Published: December 2022

AbstractWe have performed a structure-function analysis of extracellular domain regions of the human IFN-α receptor (hIFNAR1) using mAbs generated by immunizing mice with a soluble hIFNAR1-IgG. Five mAbs described in this study recognize different epitopes as determined by a competitive binding ELISA and by alanine substitution mutant analyses of the hIFNAR1-IgG. Two mAbs, 2E1 and 4A7, are able to block IFN-stimulated gene factor 3 (ISGF3) formation and inhibit the antiviral cytopathic effect induced by several IFN-α (IFN-α2/1, -α1, -α2, -α5, and -α8). None of these anti-IFNAR1 mAbs were able to block activity of IFN-β. mAb 4A7 binds to a domain 1-hIFNAR1-IgG but not to a domain 2-hIFNAR1-IgG, which suggests that its binding region is located in domain 1. The binding of the most potent blocking mAb, 2E1, requires the presence of domain 1 and domain 2. The most critical residue for 2E1 binding is a lysine residue at position 249, which is in domain 2. These findings suggest that both domain 1 and domain 2 are necessary to form a functional receptor and that a region in domain 2 is important. IFN-β recognizes regions of the hIFNAR complex that are distinct from those important for the IFN-α.
Involvement of Extracellular Signal-Regulated Kinase Module in HIV-Mediated CD4 Signals Controlling Activation of Nuclear Factor-κB and AP-1 Transcription Factors
Authors: Briant Laurence , Robert-Hebmann Véronique , Sivan Virginie , Brunet Anne , Pouysségur Jacques , Devaux Christian 
Published: December 2022

AbstractAlthough the molecular mechanisms by which the HIV-1 triggers either T cell activation, anergy, or apoptosis remain poorly understood, it is well established that the interaction of HIV-1 envelope glycoproteins with cell surface CD4 delivers signals to the target cell, resulting in activation of transcription factors such as NF-κB and AP-1. In this study, we report the first evidence indicating that kinases MEK-1 (MAP kinase/Erk kinase) and ERK-1 (extracellular signal-regulated kinase) act as intermediates in the cascade of events that regulate NF-κB and AP-1 activation upon HIV-1 binding to cell surface CD4. We found that CEM cells transfected with dominant negative forms of MEK-1 or ERK-1 do not display NF-κB activation after HIV-1 binding to CD4. In contrast, NF-κB activation was observed in these cells after PMA stimulation. Although the different cell lines studied expressed similar amounts of CD4 and p56lck, HIV-1 replication and HIV-1-induced apoptosis were slightly delayed in cells expressing dominant negative forms of MEK-1 or ERK-1 compared with parental CEM cells and cells expressing a constitutively active mutant form of MEK-1 or wild-type ERK-1. In light of recently published data, we propose that a positive signal initiated following oligomerization of CD4 by the virus is likely to involve a recruitment of active forms of p56lck, Raf-1, MEK-1, and ERK-1, before AP-1 and NF-κB activation.