bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant-free in vivo targeting. Antigen delivery by alpha 2-macroglobulin enhances antibody formation.
Authors: Chu C T , Oury T D , Enghild J J , Pizzo S V 
Published: December 2022

Abstract
The proteinase "inhibitor" alpha 2-macroglobulin (alpha 2M) is able to entrap and form covalent linkages with diverse proteins during a transient proteinase-activated state. These complexes are rapidly endocytosed after binding to receptors present on macrophages and other cells. We have previously shown that compared to free hen egg lysozyme (HEL), alpha 2M-complexed HEL undergoes enhanced macrophage uptake, processing, and presentation to T hybridoma clones in vitro. Inasmuch as it is not clear whether T hybridoma responses accurately reflect primary immune responses in vivo, we studied antibody production in rabbits using two Ag complexed with either human alpha 2M (H alpha 2M) or a homologous protein purified from rabbit plasma, alpha 1-macroglobulin (R alpha 1M). Pathogen-free NZW rabbits received s.c. injections with adjuvant-free preparations of free HEL or porcine pancreatic elastase (PPE), H alpha 2M-HEL-PPE complexes, R alpha 1M-HEL-PPE complexes, or mixtures of the uncomplexed proteins. Complexing the Ag to alpha 2M resulted in 10 to 500-fold higher IgG titers compared to uncomplexed controls. Injection of Ag complexed to either H alpha 2M or R alpha 1M resulted in levels of anti-HEL IgG comparable to those elicited by emulsification in CFA. Inasmuch as inflammatory proteinases such as neutrophil elastase can initiate covalent complex formation with alpha 2M, we propose that "proteinase-activated" alpha 2M may mediate receptor-enhanced Ag uptake by macrophages, resulting in augmented Ag processing and antibody production.
Structural requirements for peptides that stimulate a subset of gamma delta T cells.
Authors: Fu Y X , Vollmer M , Kalataradi H , Heyborne K , Reardon C , Miles C , O'Brien R , Born W 
Published: December 2022

Abstract
Hybridomas representing the V gamma 1-positive subset of murine gamma delta T cells secrete lymphokines in response to synthetic peptides representing a short segment of the mycobacterial 60-kDa heat shock protein (HSP-60). Here we show the TCR dependency of this response by transfection of productively rearranged TCR genes derived from an HSP-60 reactive gamma delta T cell hybridoma. We also have defined structural requirements for the stimulatory peptide. The smallest HSP-60 peptide capable of stimulating these hybridomas is seven amino acids long, representing positions 181-187, and having the sequence FGLQLEL. Amino acid-substituted derivatives of this peptide, and another containing the same core, p180-190, revealed amino acids essential for stimulatory activity. Phenylalanine in position 181 and leucine in position 183 seem to be required for stimulation of all HSP-60 reactive cells, whereas others are only required by some. Clonal differences in the responses to these peptides provide indirect evidence for cognate TCR-peptide interactions. The smallest stimulatory peptide, p181-187, represents an area not well conserved among HSP-60 molecules of other species, and stimulates a mycobacteria-specific response unlike the earlier observed cross-reactive responses of the same hybridomas with longer HSP-60 peptides derived from mycobacteria and other species (our manuscript in preparation). We propose that the TCR-dependent multiclonal gamma delta T cell response to HSP-60 peptides and derivatives, which in some ways resembles superantigen responses and in other ways resembles responses to conventional Ag, may be a separate, third type of Ag response by T cells.
Heterosubtypic immunity to influenza type A virus in mice. Effector mechanisms and their longevity.
Authors: Liang S , Mozdzanowska K , Palladino G , Gerhard W 
Published: December 2022

Abstract
Immunity that cross-reacts between influenza type A viruses of distinct subtypes is called hetero(sub)typic (Het-I). We have studied Het-I by challenging PR8-immune mice with the heterosubtypic virus X31. Het-I did not prevent infection by X31 but, at its height, strongly aided in recovery. The nature of the effector mechanisms involved was investigated by simultaneous challenge with X31 and an immunologically unrelated influenza type B virus and by depleting individual lymphocyte subsets in PR8-immune mice before challenge. The study showed the following: 1) The effector mechanisms were intimately associated with immune recognition events. 2) In the nose, depletion of CD8+ or CD4+ T cells led to partial reduction of Het-I, and simultaneous depletion of both T cell subsets abrogated Het-I almost completely. This T cell-mediated immunity was short lived and had disappeared 4 to 5 mo after induction. 3) In trachea and lung, depletion of CD8+ T cells led to a partial reduction of Het-I, whereas depletion of CD4+ T cells was without significant effect. The CD8-mediated component appeared short lived, whereas the residual immunity (in CD4/8-depleted mice) was long lived and persisted past 7 mos after induction. 4) Depletion of NK cells did not significantly reduce the strength of Het-I in either nose or lung. In conclusion, the study shows that Het-I in this system is mediated by a complex combination of immune mechanisms that differ, in part, between upper and lower respiratory tract.
A peptide antigen antagonist prevents the differentiation of T cell receptor transgenic thymocytes.
Authors: Spain L M , Jorgensen J L , Davis M M , Berg L J 
Published: December 2022

Abstract
The developmental fate of an immature T cell is determined in the thymus. Depending on the specificity of its TCR, a thymocyte receives signals to either die or differentiate. We have used fetal thymic organ cultures derived from TCR transgenic mice to examine the role of MHC/peptide ligands in T cell selection. Single amino acid substituted peptide analogues of the Ag recognized by the transgenic TCR were examined for their ability to enhance or interfere with positive selection. We have identified a nonstimulatory peptide analogue that interferes with the differentiation of transgenic CD4+8+ thymocytes into CD4+8- cells. We also show that this peptide, substituted in a TCR contact residue, is a competitive antagonist for activation of the T cell hybridoma expressing the same TCR. These observations demonstrate a novel mechanism for tolerance induction in the thymus.
Natural antibody and complement-mediated antigen processing and presentation by B lymphocytes.
Authors: Thornton B P , Vĕtvicka V , Ross G D 
Published: December 2022

Abstract
Normal immune responses to primary protein Ags (those not seen previously by the immune system) have been shown to require C3 and the C3 receptor CR2 (CD21). This investigation tested the hypothesis that natural Abs to the primary protein Ag keyhole limpet hemocyanin (KLH) exist in normal serum and will form immune complexes (IC) that activate C and generate bound iC3b/C3dg, thereby promoting B cell CR2-dependent Ag processing. Both IgM and IgG anti-KLH were detectable in sera from 11 normal donors. IC generated with fresh serum bore iC3b and bound to CR1 (CD35), CR2, and CR3 (CD11b/CD18). Further treatment of IC with serum containing rCR1 formed IC-bearing C3dg that bound only to CR2. When ICs were mixed with B lymphoblastoid cell clones, CR2-dependent processing of the KLH occurred that was dependent on bound C3dg and CR2. Processing occurred regardless of whether the B cells bore KLH-specific surface Ig, although the efficiency of processing was greater with KLH-specific B cells. Both KLH-specific and nonspecific B cell clones presented KLH to KLH-specific T cells. The binding of KLH IC by normal B lymphocytes induced expression of the B7/BB1 Ag (CD80), the required co-stimulatory ligand for T cell CD28. Blocking experiments indicated that although bound C3 and CR2 were required to mediate IC binding to B cells, induction of CD80 expression required the secondary ligation of IC-associated IgG to B cell FcRII (CD32). These data support the hypothesis that responses to primary protein Ags involve IgG natural Abs and C3 that mediate Ag processing and presentation via B cell CR2 and FcRII.
Coordinate regulation of multiple human lymphokine genes by Oct-1 and potentially novel 45 and 43 kDa polypeptides.
Authors: Kaushansky K , Shoemaker S G , O'Rork C A , McCarty J M 
Published: December 2022

Abstract
The hematologic response to inflammation is critically dependent on the release of a family of glycoproteins termed CSFs. Central to this process is the coordinated T lymphocyte production of three of these proteins, granulocyte macrophage-CSF (GM-CSF), IL-3, and IL-5. In the course of our studies of the transcriptional regulation of IL-3 expression we noted that the same or similar proteins that bound to the downstream-activating region of the human IL-3 gene were also captured using DNA probes derived from sequences present in the GM-CSF and IL-5 genes. In this study, DNA-protein cross-linking techniques and reporter gene analyses were used to define the nuclear proteins that mediate transcriptional enhancement of these genes at one cis-acting site. These studies establish that Oct-1, a member of the POU family of transcription factors, binds to regions of the GM-CSF, IL-3, and IL-5 promoters and contributes to basal T cell gene transcription. In addition, although the c-jun proto-oncogene product was detected in stimulated human T cells, two additional T cell-specific proteins (45 and 43 kDa) bind to the GM-CSF, IL-3, and IL-5 promoters and are functionally and immunologically distinct from c-jun or OAP40 (jun-D). These proteins contribute to transcriptional enhancement of the IL-3 and GM-CSF genes in stimulated T cells. Together, these data suggest that the coordinate regulation of several lymphokine genes is based on responses to shared proteins. These studies further our understanding of the networks of transcriptionally active proteins responsible for the host response to inflammatory stimuli.
Expression cloning and characterization of a human IL-10 receptor.
Authors: Liu Y , Wei S H , Ho A S , de Waal Malefyt R , Moore K W 
Published: December 2022

Abstract
cDNA clones encoding a human IL-10R (hIL-10R) from a Burkitt lymphoma cell line, BJAB, express a 90 to 110 kDa polypeptide in COS7 cells that binds hIL-10 specifically. The predicted amino acid sequence of hIL-10R is 60% identical and 73% similar to mouse IL-10R (mIL-10R). rIL-10R expressed in an IL-3-dependent mouse pro-B cell line (Ba/F3) binds hIL-10 with high affinity (200 to 250 pM), and the transfected cells exhibit a proliferative response to hIL-10. Mouse IL-10 does not bind to hIL-10R, and hIL-10R-expressing Ba/F3 cells do not respond to the mouse cytokine, observations consistent with the known species specificity of IL-10. Expression of hIL-10R mRNA seems to be restricted mainly to human hemopoietic cells and cell lines. In a number of human T cell clones, expression of hIL-10R mRNA is down-regulated after activation of the cells with anti-CD3 Ab and phorbol ester. The hIL-10R gene is on human chromosome 11. Like mIL-10R, hIL-10R is structurally related to IFNR. Because IL-10 inhibits macrophage activation by IFN-gamma, this relationship suggests possible shared receptor or signal transduction pathway components.
Administration of anti-granulocyte mAb RB6-8C5 impairs the resistance of mice to Listeria monocytogenes infection.
Authors: Czuprynski C J , Brown J F , Maroushek N , Wagner R D , Steinberg H 
Published: December 2022

Abstract
Mice injected i.p. with RB6-8C5 mAb experienced a profound depletion of neutrophils in the bloodstream and spleen and significant impairment of their resistance to experimental infection with Listeria monocytogenes. Control mice survived i.v. inoculation with 5 x 10(4) L. monocytogenes; whereas, most RB6-8C5 mAb-treated mice inoculated i.v. with as few as 10 L. monocytogenes died within 6 days. RB6-8C5 mAb treatment was particularly deleterious when given within the first 24 h after i.v. inoculation with L. monocytogenes; however, some adverse effect was observed even when administration was delayed until 3 or 5 days after bacterial inoculation. Histopathologic examination of the livers of RB6-8C5 mAb-treated mice revealed necrotic foci that were characterized by few inflammatory cells and massive numbers of Gram-positive bacteria within hepatocytes. Additional evidence that the effects of RB6-8C5 mAb administration were chiefly due to neutrophil depletion include: 1) the effects of RB6-8C5 mAb treatment occurred more rapidly than what is generally seen in mice treated with anti-T cell mAbs, 2) similar results were observed with normal and scid mice, 3) RB6-8C5 mAb administration did not diminish delayed-type hypersensitivity nor the ability of spleen cells from immunized mice to transfer resistance, and 4) natural killer cell activity was unaffected by RB6-8C5 mAb administration. The results of this study provide additional evidence in support of the importance of neutrophils in the early stage of innate resistance to murine listeriosis.
A role for nonspecific (cyclosporin A) or specific (monoclonal antibodies to ICAM-1, LFA-1, and IL-10) immunomodulation in the prolongation of skin allografts after antigen-specific pretransplant immunization or transfusion.
Authors: Gorczynski R M , Wojcik D 
Published: December 2022

Abstract
C3H/HEJ mice given pretransplant immunization via the portal vein with irradiated B10.BR spleen cells or non-irradiated B10.BR peripheral blood leukocytes showed delayed rejection of B10.BR but not BALB.K skin grafts. No increased graft survival was seen if pretransplant immunization was given by the lateral tail vein. Addition of a single treatment with cyclosporin A after pretransplant immunization via the portal vein led to indefinite graft survival in over 70% of recipients. As reported earlier, increased graft survival in vivo was correlated with preferential production of IL-4 (from Th2 type cells) rather than IL-2 from lymphocytes stimulated in vitro. When mice were given pretransplant transfusion via the lateral tail vein and a combination of anti-LFA-1 and anti-ICAM-1 mAbs, increased graft survival was again seen. In addition, in vivo injection of anti-IL-10 mAbs (but not anti-IFN-gamma or anti-IL-4 mAbs) abolished the delayed rejection seen when mice received pretransplant immunization via the portal vein. In all cases, delayed graft rejection in vivo was correlated with preferential activation of Th2-type cells, as assessed by lymphokine production from cells harvested from treated mice and activated in vitro.
Human cutaneous allergic late-phase response is inhibited by soluble IL-1 receptor.
Authors: Mullarkey M F , Leiferman K M , Peters M S , Caro I , Roux E R , Hanna R K , Rubin A S , Jacobs C A 
Published: December 2022

Abstract
The late-phase allergic reaction (LPR) occurs 4 to 8 h after allergen exposure and probably causes the symptoms of chronic allergic disease. To determine the effects of soluble IL-1 receptor on the cutaneous LPR, we performed a prospective, randomized, double-blind, placebo-controlled study on 15 allergic subjects. Intradermal injections of allergen were placed on subjects' forearms, followed by immediate subcutaneous injections at the same site of either 1, 10, 25, 50, or 100 micrograms of rhu IL-1R to three subjects in each dosage group. Placebo was given to matched allergen-injected sites on the contralateral arm. Erythema, induration, and itching were recorded for each site. Sites were biopsied at 8 h for immunohistologic evaluations. Rhu IL-1R significantly reduced the clinical reaction at all concentrations. At 1 and 10 micrograms, measurements of LPR were significantly less (p &lt; 0.05) than at placebo sites at several time points from 2 to 8 h. At higher concentrations, LPR was suppressed at rhu IL-1R and placebo sites, suggesting a systemic effect of rhu IL-1R. Histologic evaluation and indirect immunofluorescence for eosinophil granule major basic protein, neutrophil elastase, and mast cell tryptase showed no statistical differences between rhu IL-1R and placebo sites or among doses. IL-1 plays an important role in the generation of allergic LPR. While microgram quantities of rhu IL-1R inhibited the clinical signs and symptoms of LPR, its effects on the allergic inflammatory infiltrate are yet to be defined. In this short term trial, rhu IL-1R was neither immunogenic nor toxic.
Production of interleukin-1 receptor antagonist, inflammatory chemotactic proteins, and prostaglandin E by rheumatoid and osteoarthritic synoviocytes--regulation by IFN-gamma and IL-4.
Authors: Seitz M , Loetscher P , Dewald B , Towbin H , Ceska M , Baggiolini M 
Published: December 2022

Abstract
This study analyzes the effects of the T cell cytokines IL-4 and IFN-gamma on the spontaneous and stimulated production of IL-8, MCP-1, IL-1 receptor antagonist (IL-1ra), and PGE by synoviocytes from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Cells from both sources constitutively released IL-8 and MCP-1, but no IL-1ra or PGE. Stimulation with IL-1 beta or TNF-alpha massively increased chemokine production and induced the generation of PGE and low amounts of IL-1ra. The constitutive or cytokine-stimulated release of IL-8 was inhibited by IFN-gamma, but not by IL-4. The constitutive or IL-1 beta-stimulated release of MCP-1, by contrast, was markedly enhanced by IL-4 and IFN-gamma. Both cytokines, however, had only borderline effects on the release stimulated by TNF-alpha. The yield of IL-1ra was strongly enhanced by IFN-gamma in all cases, whereas the effect of IL-4 was pronounced only in IL-1 beta-stimulated OA synoviocytes. IL-4, on the other hand, markedly decreased the release of PGE, which was less susceptible to IFN-gamma. The observed effects on chemokines, IL-1ra expression, and PGE release by synoviocytes suggest that IFN-gamma and IL-4 are important regulatory elements in the inflamed synovium and may exert anti-inflammatory effects.
Evidence for a direct physical interaction of membrane IgM, IgD, and IgG with the B29 gene product.
Authors: Lankester A C , van Schijndel G M , Frommé J , Cordell J L , van Lier R A , van Noesel C J 
Published: December 2022

Abstract
The B cell Ag-receptor complex is composed of membrane immunoglobulin (mIg) and the mb-1/B29 heterodimer. In order to obtain insight into the architecture of the B cell receptor complex, we have looked for conditions that disrupt all disulfide bridges in the complex without affecting the noncovalent interaction between the mIg heavy chain and one or both members of the associated heterodimer. We show that in the presence of the reducing agent beta-mercaptoethanol the m mu, m delta, and m gamma heavy chains remain selectively associated with the B29 members. Our findings implied that if isotype-related differences exist between the mIg-associated dimers, they may reside in B29 and not, as initially suggested, in mb-1. However, sequence analyses of B29 gene transcripts from B cells expressing mIgM, mIgD, or mIgG only revealed no differences in their nucleotide composition. Thus, in spite of their close physical interaction with mIg heavy chain classes, which are significantly distinct in the C-terminal regions, no isotype-specific forms of B29 seem to exist.
IL-2 reverses human T cell unresponsiveness induced by thymic epithelium in SCID-hu mice.
Authors: Schols D , Vandekerckhove B , Jones D , Roncarolo M G 
Published: December 2022

Abstract
In this study we investigated the mechanism responsible for the unresponsiveness of thymus-reactive T cells obtained from severe combined immunodeficient (SCID) mice constructed with human fetal liver (FL) stem cells from donor A and an allogeneic human fetal thymus (FT) from donor B (A/B SCID-hu mice). These A/B SCID-hu mice have a human thymus containing B cells, macrophages, and dendritic cells from FL donor A but thymic epithelial cells from FT donor B. The repertoire of human T cells developing in this chimeric thymus is depleted of T cells specific for the HLA Ags of the FL donor, whereas T cells reactive against the HLA Ags expressed by the FT donor are still present. However, these thymocytes failed to proliferate and expressed low levels of the activation markers CD25, CD71, and HLA-DR after stimulation with the EBV-LCL of the FT donor in primary MLRs. This unresponsiveness could be completely reversed by IL-2. Restoration of T cell responsiveness was Ag specific and a unique property of IL-2. The T cells produced very low levels of IL-2 when stimulated with the HLA Ags of FT donor B, whereas they secreted normal levels of IL-2 after activation by third party alloantigens. Low IL-2 production was also observed at the clonal level. CD4+ T cell clones from A/B SCID-hu mice, specific for the HLA Ags of B, produced significantly less IL-2 and granulocyte macrophage-CSF than control CD4+ T cell clones. However, these T cell clones synthesized normal levels of IL-2 and granulocyte macrophage-CSF after stimulation with combinations of PMA/Calo or PMA/anti-CD3 mAb. Thus, T cells that differentiate in a chimeric thymus containing allogeneic host thymic epithelium are rendered tolerant to the HLA Ags expressed by the thymic epithelial cells. This tolerance results in the presence of T cells that do not proliferate properly after Ag-specific stimulation. This lack of proliferation is primarily related to their inability to produce sufficient levels of IL-2 and can be restored by exogenous IL-2.
Effect of antibody valency on interaction with cell-surface expressed HIV-1 and viral neutralization.
Authors: Cavacini L A , Emes C L , Power J , Duval M , Posner M R 
Published: December 2022

Abstract
F(ab) and F(ab')2 fragments of the human mAb, F105, were compared to intact IgG1 for binding to the CD4 binding site of HIV-1/gp120 on the surface of infected cells and viral neutralization. F105 IgG1 and F(ab')2 bound to IIIB, MN, and RF infected cells and neutralized these strains in an identical fashion, whereas strain-specific differences were observed in F(ab) activity. Although F105 F(ab) bound with equivalent affinity to IIIB-infected cells, there was a 4- to 10-fold decrease in the neutralization of IIIB by monovalent F(ab) compared to the bivalent molecules. F105 F(ab) demonstrated both diminished binding and neutralization of the MN strain and failed to bind or neutralize the RF strain. When cooperativity of V3 loop antibody (V3ab) with F105 IgG and fragments was examined, the binding of F105 IgG and F(ab')2 to IIIB-, MN-, or RF-infected cells was modestly enhanced by V3ab; viral neutralization was substantially enhanced by the combination of V3ab and F105 IgG and F(ab')2. The combination of F105 F(ab) with V3ab also resulted in significant cooperative neutralization of IIIB and MN, but the lack of F105 F(ab) binding and neutralization of RF was unaltered by V3ab. These results suggest that bivalent interaction may be important in binding and neutralization of virus, and support the notion that this interaction may depend on conformational changes in oligomeric gp120 on intact virions and cell surface rather than on affinity or steric effects.