bluuebunny/crossref_metadata_2025_split huggingface dataset:
H-2 allele-specific protection from NK cell lysis in vitro for lymphoblasts but not tumor targets. Protection mediated by alpha 1/alpha 2 domains.
Authors: Sentman C L , Olsson M Y , Salcedo M , Höglund P , Lendahl U , Käre K 
Published: December 2022

Abstract
In vivo murine NK cells are known to mediate graft rejection in allogenic as well as in "F1 anti-parental" situations. We have studied an in vitro system based on rIL-2-activated spleen cells and Con A lymphoblast targets in relation to the genetics of F1 hybrid resistance and NK cell activity. We demonstrate that NK cells in this in vitro model are regulated by MHC class I genes in an allele-specific manner at the level of the effector and the target. Using rIL-2-activated effector cells from nude C57BL/6 (B6) and BALB/c mice, we observed no killing of MHC syngeneic lymphoblasts. However, B6 as well as BALB/c lymphoblasts were killed by effector cells from allogeneic nude mice as well as by cells from (BALB/c x B6)F1 hybrids. Experiments that used D8 mice (which carry an H-2Dd transgene on B6 background) and beta 2-m-/- mice demonstrated a direct role for MHC class I molecules at the effector as well as at the target cell level: H-2Dd transgenic effector cells with the typical NK phenotype 3A4+/CD8- killed B6 blasts, but expression of the corresponding H-2Dd transgene in the target lymphoblasts protected them from killing. By using transgenic mice carrying exon shuffled MHC class I transgenes, the protective effect of the H-2Dd molecule was mapped to the alpha 1/alpha 2 domains. MHC class I-deficient lymphoblasts from beta 2-m-/- mice were killed by effectors from all strains of mice, including those matched for MHC. The H-2 class I allele-specific protection in this in vitro assay was observed for lymphoblasts but not for tumor cells, despite the fact that these tumor cells are protected in an allele-specific manner in vivo.
Cytokeratin peptide SFGSGFGGGY mimics N-acetyl-beta-D-glucosamine in reaction with antibodies and lectins, and induces in vivo anti-carbohydrate antibody response.
Authors: Shikhman A R , Greenspan N S , Cunningham M W 
Published: December 2022

Abstract
Recently, we found that human anti-GlcNAc mAbs reacted with keratin from human skin and recognized specific peptide epitopes of human cytokeratin 14. Our data demonstrate that anti-keratin Ab responses in mice might be driven by Ags bearing terminal O-linked GlcNAc residues. To determine if mouse anti-GlcNAc mAbs recognized peptide epitopes of keratin, several mouse anti-GlcNAc mAbs were reacted with a panel of overlapping synthetic decapeptides of the entire amino acid sequence of human cytokeratin 14 in the ELISA. Results of the ELISA demonstrated that three mAbs, HGAC 54, HGAC 78, and 101.4.1, expressed maximal binding activity to keratin peptide B1 with the amino acid sequence SFGSGFGGGY. In addition, we found that mouse anti-cytokeratin 14 mAb CKB-1 recognized the same peptide and expressed anti-GlcNAc activity as well. Keratin peptide B1 was shown to react not only with anti-GlcNAc mAbs but also with several lectins such as wheat germ agglutinin, Datura stramonium lectin, Lycopersicon esculentum lectin, Solanum tuberosum lectin, and lectin from Wisteria floribunda. Reaction of the lectins with solid-phase keratin peptide B1 was inhibited by soluble GlcNAc and was not inhibited by glucose demonstrating specificity of binding. Using a panel of 24 synthetic keratin B1 peptides, each with a single amino acid substitution, we found that aromatic-aromatic and hydrophobic interactions were the major driving forces in the stabilization of the peptide-protein complexes. Finally, we demonstrated that immunization of BALB/c mice with peptide B1 conjugated to BSA induced an anti-GlcNAc Ab response. Results of our experiments indicated that certain peptides may express functional activity similar to GlcNAc and induce in vivo anti-carbohydrate Ab responses.
A decapeptide (Gln-Asp-Leu-Thr-Met-Lys-Tyr-Gln-Ile-Phe) from human melanoma is recognized by CTL in melanoma patients.
Authors: Morioka N , Kikumoto Y , Hoon D S , Morton D L , Irie R F 
Published: December 2022

Abstract
The decapeptide 810 (QDLTMKYQIF) contains the antigenic epitope (KYQI) recognized by human mAb L92. This sequence is found in a 43-kDa protein associated with human melanoma M14. We examined the expression of 810 in human cells and its involvement in the cellular immune responses of melanoma patients. Nineteen stage III melanoma patients and 19 normal donors were studied for their responses to 810. All patients were immunized in vivo with an allogeneic melanoma cell vaccine. PBMC cytotoxicity was tested on autologous EBV-transformed B lymphoblastoid cell lines (BCL) pulsed with 810 and autologous melanomas. Proliferative responses of PBMC to 810 were evaluated by using [3H]Tdr incorporation assays. Western blotting revealed that the 43-kDa protein was not specific to melanoma but was common to various cells. However, the percentage of cytotoxicity of PBMC against autologous 810-pulsed BCL was significantly greater in melanoma patients than in normal controls (p &lt; 0.005). Cytotoxicity was increased after melanoma cell vaccine immunization in 15 patients (78%). Proliferative responses to 810 were observed only in melanoma patients and were enhanced in 12 patients (63%) after vaccination. Restimulation of PBMC from vaccinated patients with 810 increased cytotoxicity against both autologous 810-pulsed BCL and melanomas. These targets were lysed by CD8+ T lymphocytes in an HLA class I-restricted manner. HLA-A2 and -A11 seemed to serve as the 810-presenting molecule. Our findings indicate that 810 may function as an epitope for CTL on human melanoma and can be used as a vaccine.
Captopril inhibits neutrophil synthesis of leukotriene B4 in vitro and in vivo.
Authors: Shindo K , Baker J R , Munafo D A , Bigby T D 
Published: December 2022

Abstract
The aim of this investigation was to determine the effects of metalloproteinase inhibitors on leukotriene (LT) A4 hydrolase in human neutrophil cytosol and to examine the effects of captopril on intact neutrophils in vitro and in vivo. Cytosolic fractions were assayed for LTA4 hydrolase and 5-lipoxygenase activity in the presence or absence of inhibitors. Only bestatin, 1,10-O-phenanthroline, captopril and fosinoprilat demonstrated significant effects. The IC50 of captopril and fosinoprilat for LTA4 hydrolase activity were 500 microM and 1 mM, respectively. No inhibition of 5-lipoxygenase activity in cytosolic fractions was detected. The effect of captopril was only minimally reversed by ZnSO4. The IC50 of captopril for inhibition of LTB4 synthesis in intact neutrophils was 63 microM. Furthermore, 5-HETE production in intact cells was diminished 25.3 +/- 8.5% in the presence of 1 mM captopril. Oral captopril inhibited stimulated LTB4 release by subsequently isolated neutrophils by 48.1 +/- 5.6% and 5-HETE release by 43.2 +/- 5.5%. Thus, captopril is an inhibitor of LTB4 synthesis in neutrophils in vitro and in vivo. However, there are differences between the potency of this drug as assessed in cytosol and intact cell studies. This study significantly extends previous reports in that it demonstrates that captopril is a more potent inhibitor of LTB4 synthesis in intact neutrophils than in cytosol and in that it demonstrates an inhibitory effect of captopril on synthesis of LTB4 by neutrophils exposed to captopril in vivo.
Differential gene expression for IL-1 receptor antagonist, IL-1, and TNF receptors and IL-1 and TNF synthesis may explain IL-1-induced resistance to infection.
Authors: Vogels M T , Mensink E J , Ye K , Boerman O C , Verschueren C M , Dinarello C A , van der Meer J W 
Published: December 2022

Abstract
IL-1 pretreatment prolongs survival in lethal infection in normal and in neutropenic mice. We investigated whether this protection occurs by interference with deleterious cytokine effects. The effect of IL-1 pretreatment on concentrations of IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha circulating in vivo and the ex vivo cytokine production capacity of macrophages was assessed in uninfected, non-neutropenic and neutropenic Swiss mice, in Swiss mice infected with Klebsiella pneumoniae (non-neutropenic mice) or Pseudomonas aeruginosa (neutropenic mice), and in neutropenic C3H/HeN and C3H/HeJ mice infected with P. aeruginosa. In Swiss and C3H/HeN mice, IL-1 pretreatment enhanced survival and reduced circulating TNF-alpha and IL-6 as well as LPS-stimulated production of IL-1 alpha and TNF-alpha. In C3H/HeJ mice, a lack of IL-1-induced protection was associated with low cytokine concentrations and production. In contrast, up-regulation of mRNA for the IL-1 receptor antagonist (IL-1Ra) was observed in several organs of IL-1-pretreated mice, suggesting that IL-1Ra could attenuate deleterious IL-1 effects. In addition, IL-1 pretreatment down-regulated steady state mRNA for the type I IL-1R and the type I TNFR in several organs at the time of infection, suggesting desensitization of target cells as an additional mechanism of IL-1-induced protection. We conclude that the IL-1-induced protection is at least partially mediated by down-regulating cytokine production, and that the induction of IL-1Ra and the desensitization of target cells by receptor down-modulation may also contribute to this phenomenon.
The carboxyl-terminal region of HIV-1 Nef protein is a cell surface domain that can interact with CD4+ T cells.
Authors: Otake K , Fujii Y , Nakaya T , Nishino Y , Zhong Q , Fujinaga K , Kameoka M , Ohki K , Ikuta K 
Published: December 2022

Abstract
Our previous studies have shown that the HIV-1 Nef Ag is expressed, at least in part, on the surface of infected cells. We demonstrated this by using membrane immunofluorescence and flow cytometry with Nef murine mAbs. To identify the domain of Nef exposed on the cell surface, epitope mapping of these and a new mAb was performed by ELISAs by using several recombinant truncated Nef fusion proteins and synthetic peptides. The results showed that mAbs F1, E7, E9, and 4H4 recognized Nef epitopes located at amino acid residues 148-157, 192-206, 158-206, and 1-33, respectively. The intensity of cell surface Nef staining was stronger with mAbs E7 and E9 than with F1, and there was no staining by 4H4, which indicates that the carboxyl-terminal region of Nef is predominantly exposed on the surface of HIV-1-infected T cell lines and PBMC. This surface Nef domain displayed high affinity for the surface of uninfected CD4+ T cells, because the binding of a soluble form of recombinant Nef protein to the cell surface was specifically blocked by the E7 and E9 mAbs or by synthetic peptides that contained the carboxyl-terminal region of Nef. In addition, syncytium formation between infected and uninfected cells also was specifically reduced by the same mAbs or peptides. Thus, the cell surface domain of Nef seems to play an important role in the interaction between HIV-1-infected and CD4+ uninfected T cells.
Adult and microfilarial stages of the filarial parasite Brugia malayi stimulate contrasting cytokine and Ig isotype responses in BALB/c mice.
Authors: Lawrence R A , Allen J E , Osborne J , Maizels R M 
Published: December 2022

Abstract
Natural infection with filarial nematode parasites shows many characteristics of a Th2 immune response. In these infections, long-lived adult worms inhabit the lymphatics, releasing laval microfilariae (Mf) into the blood stream. To compare the effect of these different developmental stages on the mammalian immune system, Mf and adult worms of either sex were implanted into BALB/c mice, in which they survive for at least 28 days. Serum Ab responses showed that whereas Mf stimulated specific Abs of all IgG subclasses, but little total IgE, adult worms stimulated only IgG1 and IgE responses. Splenocytes from implanted mice were stimulated in vitro with specific Ag or Con A and assayed for proliferation and profiles of cytokine secretion. Cells from Mf-infected mice secreted high levels of IFN-gamma (30 U/ml) throughout infection, but very little IL-4 at the early time points. By day 28 postinfection, however, splenocytes from Mf-infected mice showed some IL-4 secretion in response to specific Ag (40 U/ml). The IFN-gamma response to Mf was found to be independent of the inoculum dose in the range of 10(2) to 10(6) organisms. In contrast, splenocytes taken from adult worm-implanted mice on days 14, 21, and 28 postinfection produced high levels of IL-4 (up to 435 U/ml) and negligible amounts of IFN-gamma despite the production of large numbers of Mf by adult female worms. CD4+ cells were primarily responsible for this IL-4 production. These results demonstrate that adult filarial parasites, and females in particular, exert a rapid polarization of the immune response in a Th2-like direction, but that this effect may be modulated by the Mf stage.
Administration of anti-IFN-gamma antibody to beta 2-microglobulin-deficient mice delays influenza virus clearance but does not switch the response to a T helper cell 2 phenotype.
Authors: Sarawar S R , Sangster M , Coffman R L , Doherty P C 
Published: December 2022

Abstract
Treatment of mice that were homozygous for a beta 2-microglobulin gene disruption with a mAb that was specific for IFN-gamma delayed clearance of an influenza A virus from the respiratory tract for at least 3 days, whereas administration of an anti-IL-4 mAb had no effect. However, all mice survived and eventually cleared the virus. The anti-IFN-gamma significantly decreased both the level of class II MHC glycoprotein expression and the numbers of CD4+ lymphocytes in the inflammatory populations recovered by bronchoalveolar lavage of the pneumonic lung, whereas the total cell counts remained the same. These differences were not apparent for the regional mediastinal lymph nodes, although the frequency of lymph node B cells producing virus-specific Ab of the IgG2a subclass was greatly reduced. However, neither the anti-IFN-gamma nor anti-IL-4 treatments drastically altered the cytokine production profiles detected for freshly isolated lymphocytes by the using single cell ELISPOT assay or by ELISA of culture supernatants after in vitro restimulation with virus. Thus, neutralization of secreted IFN-gamma during the course of an influenza-specific response in beta 2-microglobulin-deficient mice that lack CD8+ T cells delays virus clearance and modifies the character of the host response, but does not cause the CD4+ subset to switch to a Th2 cytokine profile.
Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile.
Authors: Somoza N , Vargas F , Roura-Mir C , Vives-Pi M , Fernández-Figueras M T , Ariza A , Gomis R , Bragado R , Martí M , Jaraquemada D 
Published: December 2022

Abstract
Insulin-dependent diabetes mellitus (IDDM), in which only the pancreatic beta cells are destroyed by the autoimmune response, is the paradigm of organ-specific autoimmunity. As a result of a combination of factors, the number of immunohistologic/cellular/molecular studies of pancreas in IDDM is very limited. We report here studies conducted in the pancreata of two IDDM patients: one newly diagnosed (case 1) and one long standing (case 2). In case 1, we demonstrated the presence of morphologically normal viable beta cells without evidence of viral infection. In both cases the expression of the autoantigens defined by islet cell Abs and by glutamic acid decarboxylase was markedly reduced in the islet cells whereas expression of hsp60, another putative autoantigen, was normal. Over-expression of HLA class I was detected in 58% of the islets in pancreatic sections and in cultured beta cells in case 1 and also in 30% of islets in case 2 but it was not restricted to any insular cell type. In case 1, there was "inappropriate" HLA class II expression in islets cells but it was a rare finding and not beta cell specific. The analysis of the correlation between class I overexpression, residual insulin, and insulitis suggests that the first event is the increase of HLA class I expression. Of adhesion molecules, ICAM-1, VLA, VCAM, and LFA-3 were normal and only ICAM-1 was moderately overexpressed in and around the islets of case 1 insulitis, as was detected by immunofluorescence which showed that 18% of the islets of case 1 had CD8+ lymphocytes as the predominant population. Reverse transcription-PCR demonstrated moderate V beta skewing and the profile of cytokines expected in CTLs: IL-2, IL-4, IL-10, and IFN-gamma negative, perforin positive. In addition, IFN-alpha, IFN-beta, and IL-6 transcripts were detected in the case 1 pancreas, consistent with the existence of a silent viral infection. Overall, the results indicated that, differently from spontaneous animal models of diabetes, in the pancreas of IDDM patients there are no elements of the inductive phase of the autoimmune response.
Expression of functional B7 and CTLA4 on rheumatoid synovial T cells.
Authors: Verwilghen J , Lovis R , De Boer M , Linsley P S , Haines G K , Koch A E , Pope R M 
Published: December 2022

Abstract
To assess the role of B7, CTLA4, and CD28 in the pathogenesis of chronic synovitis we analyzed the expression and function of these cell surface molecules in patients with rheumatoid arthritis, osteoarthritis, and psoriatic arthritis, and in normal controls. Immunoperoxidase staining of rheumatoid synovial membranes showed reactivity of 30% of T cells with anti-B7 mAb, in contrast to osteoarthritic and normal synovial membranes, in which no such staining was seen. In addition, rheumatoid synovial fluid T cells were positive by flow cytometric analysis for B7 (mean 20%, range 0 to 96%), as measured by staining with anti-B7 mAb or the CTLA4 Ig fusion protein, whereas no B7 expression was detected on peripheral blood T cells (mean 1%). To analyze the functional importance of B7 expressed on synovial fluid T cells, we used these cells as stimulator cells in primary allogeneic MLC. Purified synovial fluid T cells were far stronger stimulator cells compared with paired peripheral blood T cells and resulted in a fivefold greater increase in allogeneic T cell proliferation. Furthermore, the proliferation induced by purified synovial T cells was markedly inhibited by addition of the CTLA4 Ig fusion protein (77%). Moreover, anti-B7 mAb (37%), anti-CTLA4 mAb (33%), and Fab fragments of anti-CD28 mAb (52%) partially inhibited the primary MLC. The expression of functional B7, together with the increased expression of MHC class II molecules, indicates that synovial T cells may serve as functional APCs and may be capable of autocrine stimulation via the CD28 activation pathway.
Functional specialization of fibronectin-binding beta 1-integrins in T lymphocyte migration.
Authors: Hauzenberger D , Klominek J , Sundqvist K G 
Published: December 2022

Abstract
We have investigated the role of alpha 4 beta 1 and alpha 5 beta 1 integrins in adhesion and migration of T lymphocytes to extracellular matrix proteins. Fibronectin, collagen type IV, and laminin promoted haptotactic and chemotactic migration of lymphoid T cell lines and 12-O-tetradecanoylphorbol 13-acetate-stimulated blood lymphocytes, as determined using a modified Boyden chamber system. Adhesion studies of the T cell lines indicated involvement of both alpha 4 beta 1 and alpha 5 beta 1 integrins in the binding to fibronectin. In contrast, migration assays demonstrated that haptotactic and chemotactic migration to fibronectin in most cases was mediated by only one of the beta 1 integrins. FACS analysis demonstrated comparable amounts of alpha 4 beta 1 and alpha 5 beta 1 on the various cell lines, indicating that utilization of the integrins for migration is not determined by their expression on the cells. Haptotactic migration toward a 120-kDa fibronectin fragment containing the RGD sequence, confirmed the selectivity of the different beta 1 integrins in directing migration. Thus, T cells using alpha 5 beta 1 for haptotaxis against fibronectin were migrating against the 120 kDa fragment whereas T cells using alpha 4 beta 1 were not. These results indicate that the response of T cells to haptotactic and chemotactic signals usually is mediated selectively via alpha 4 beta 1 or alpha 5 beta 1 although binding of fibronectin to the cells is not restricted to only one of the integrins. Cholera toxin and 8-Br-cAMP but not pertussis toxin inhibited migration of T cell lines to fibronectin. Adhesion of these cells to fibronectin was not influenced by any of the toxins. Thus, both in their integrin utilization and in their signaling pathways, adhesion and migration show substantial differences in T cells.
A novel pathway of thymus-directed T lymphocyte maturation.
Authors: Lefrançois L , Olson S 
Published: December 2022

Abstract
Recent evidence has indicated that the intestinal epithelium may be a major extrathymic site of T cell production. However, which of the multiple intestinal intraepithelial lymphocyte (IEL) subsets are extrathymic in origin has been controversial. We now report that the thymus is an integral component of IEL maturation and is required for a novel two-stage process of T cell production. Thus, in neonatally thymectomized mice TCR-gamma delta IELs were depleted and some TCR-alpha beta IELs were of an immature phenotype. Thymus grafting experiments revealed that all TCR-gamma delta and TCR-alpha beta IEL subsets could be thymus-derived, including TCR-alpha beta cells lacking Thy1 and CD8 beta. In utero anti-TCR-gamma delta mAb treatments resulted in depletion of gamma delta IEL without subsequent re-emergence of this subset in adulthood, whereas anti-TCR-alpha beta mAb treatment only marginally reduced the alpha beta IEL subset. These findings suggest that TCR-alpha beta and TCR-gamma delta IELs arose at distinct developmental stages. Overall, the results indicate that some IEL precursors are thymus-derived but require further thymic influence to mature in the periphery.
Cellular mechanisms that maintain neonatally-induced tolerance of class II alloantigens. Evidence that precursor cytotoxic T cells are present but silenced.
Authors: Matriano J A , Socarras S , Streilein J W 
Published: December 2022

Abstract
Clonal deletion of alloantigen-specific lymphocytes was the first explanation advanced to explain why neonatal mice that receive injections of alloantigenic hematopoietic cells mature into adults that accept donor-derived skin allografts indefinitely, i.e., they are immunologically tolerant. However, numerous other passive and active regulatory mechanisms have been invoked to explain neonatal transplantation tolerance. In A strain mice (A.TH, las, A.TL, lak) rendered tolerant of class II-only alloantigens, formal evidence exists demonstrating that tolerogen-reactive T cells are not eliminated. In fact, tolerogen-reactive T cells are present in peripheral lymphoid organs and can secrete lymphokines (IL-2/IL-4) when stimulated with tolerogen-bearing cells in vitro. Despite the presence of cytokines in these cultures, class II-specific T cells are usually not generated, raising the possibility that selective deletion of these cells may contribute to the tolerant state. To examine this issue, limiting dilution analysis was performed and revealed that tolerant mice possess significantly diminished precursor cytotoxic T cell frequencies. Virtually all cytotoxic T cells generated by normal A.TH mice in response to A.TL class II Ags are CD8+ cells. Moreover, the frequency of donor I-E reactive V beta 5 cells among CD4+ and CD8+ subpopulations among tolerant mice was comparable to naive mice. This suggests that the peripheral lymphoid organs of tolerant mice are functionally deleted of tolerogen-specific cytotoxic T cells and that tolerogen-specific CD8+ T cells are present in normal numbers of tolerant mice. Therefore, this circumstantial evidence implies that tolerogen-specific T cells have not been physically eliminated in class II tolerant mice. Instead, either tolerogen-specific CD8+ T cells have been rendered anergic or active suppression prevents their activation in vitro and presumably in vivo.