bluuebunny/crossref_metadata_2025_split huggingface dataset:
Granzyme B-Induced Loss of Mitochondrial Inner Membrane Potential (ΔΨm) and Cytochrome c Release Are Caspase Independent
Authors: Heibein Jeffrey A. , Barry Michele , Motyka Bruce , Bleackley R. Chris 
Published: December 2022

Abstract
CTLs kill targets by inducing them to die through apoptosis. A number of morphological and biochemical events are now recognized as characteristic features of the apoptotic program. Among these, the disruption of the inner mitochondrial transmembrane potential (ΔΨm) and the release of cytochrome c into the cytoplasm appear to be early events in many systems, leading to the activation of caspase-3 and, subsequently, nuclear apoptosis. We show here that, in Jurkat targets treated in vitro with purified granzyme B and perforin or granzyme B and adenovirus, ΔΨm collapse, reactive oxygen species production, and cytochrome c release from mitochondria were observed. Loss of ΔΨm was also detected in an in vivo system where green fluorescent protein-expressing targets were attacked by a cytotoxic T cell line that kills predominantly through the granzyme pathway. DNA fragmentation, phosphatidylserine externalization, and reactive oxygen species production were inhibited in the presence of the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (zDEVD-fmk) in our in vitro system. Importantly, in either the in vitro or in vivo systems, these inhibitors at concentrations up to 100 μM did not prevent ΔΨm collapse. In addition, cytochrome c release was observed in the in vitro system in the absence or presence of zVAD-fmk. Thus the granzyme B-dependent killing pathway in Jurkat targets involves mitochondrial alterations that occur independently of caspases.
Differential Requirements for CD4 in TCR-Ligand Interactions
Authors: Vidal Karine , Daniel Claude , Hill Mark , Littman Dan R. , Allen Paul M. 
Published: December 2022

AbstractThe coreceptor molecule, CD4, plays an integral part in T cell activation; it is involved in both extracellular Ag recognition and intracellular signaling. We wanted to examine the functional role of CD4 in the recognition of agonist and altered peptide ligands (APLs). We generated two CD4-deficient T cell lines expressing well-characterized TCRs specific for Hb(64–76)/I-Ek. Although the responsiveness of the T cell lines to the agonist peptide was differently affected by the loss of CD4 expression, the recognition of APLs was in both cases dramatically reduced. Nearly full responsiveness to the agonist peptide was achieved by expression of a CD4 variant that did not associate with p56lck; however, the stimulation by APLs was only partially restored. Importantly, the expression of a CD4 variant in which domains interacting with MHC class II molecules have been mutated failed to restore the reactivity to all ligands. CD4-deficient T cells were able to be antagonized by APLs, indicating that CD4 was not required for antagonism. Overall, these findings support the concepts that CD4 is an integral part of the initial formation of the immunological synapse, and that the requirement for different CD4 functions in T cell activation varies depending upon the potency of the ligand.
The Th1/Th2 Nature of Concurrent Immune Responses to Unrelated Antigens Can Be Independent
Authors: Ismail Nahed , Bretscher Peter A. 
Published: December 2022

AbstractWe tested the independence hypothesis, namely that the Th1/Th2 nature of concurrent immune responses, generated in the same secondary lymphoid organ to non-cross-reacting Ags, can be independently determined. Some infectious agents and some adjuvants contain modulatory molecules that affect the Th1/Th2 nature of immune responses in a non-Ag-specific manner. We therefore excluded infectious agents as Ags and the use of adjuvants to generate immune responses. We first show that the dose of xenogeneic RBC administered i.v. determines the Th1/Th2 nature of the splenic immune response. Low doses generate a virtually exclusive Th1 response, whereas a higher dose induces either a mixed Th1/Th2 or a predominantly Th2 response, and stimulates the production of specific Abs. We immunized individual mice simultaneously with a low dose of one kind of xenogeneic RBC and with a higher dose of another non-cross-reacting xenogeneic RBC and assessed the Th1/Th2 nature of the immune responses generated in the spleen to each kind of RBC. The Th1/Th2 nature of the response to each RBC in doubly immunized mice was indistinguishable from that of the corresponding immune response in singly immunized mice. We discuss the significance of our findings for understanding immune class regulation, and the possible reasons why such independence is not always seen.
Thymocyte Antigens Do Not Induce Tolerance in the CD4+ T Cell Compartment
Authors: Jhaver Kanchan G. , Chandler Phillip , Simpson Elizabeth , Mellor Andrew L. 
Published: December 2022

Abstract
Thymocytes fail to tolerize the developing T cell repertoire to self MHC class I (MHC I) Ags because transgenic (CD2Kb) mice expressing H-2Kb solely in lymphoid cell lineages reject skin grafts mismatched only for H-2Kb. In this study, we examined why thymocytes fail to tolerize the T cell repertoire to self MHC I Ags. The ability of CD2Kb mice to reject H-2Kb skin grafts was age dependent because CD2Kb mice older than 20 wk accepted skin grafts. T cells from younger CD2Kb mice proliferated, but did not develop cytotoxic functions in vitro in response to H-2Kb. Proliferative responses were dominated by H-2Kb-specific, CD4+ T cells rather than CD8+ T cells. Representative CD4+ T cell clones from CD2Kb mice were MHC II restricted and recognized processed H-2Kb. TCR transgenic mice were generated from one CD4+ T cell clone (361) to monitor development of H-2Kb-specific immature thymocytes when all thymic cells or lymphoid cell lineages only expressed H-2Kb. Thymocyte precursors were not eliminated and mice were not tolerant to H-2Kb when Tg361 TCR transgenic mice were intercrossed with CD2Kb mice. In contrast, all thymocyte precursors were eliminated efficiently in thymic microenvironments in which all cells expressed H-2Kb. We conclude that self MHC I Ags expressed exclusively in thymocytes do not induce T cell tolerance because presentation of processed self MHC I Ags on self MHC II molecules fails to induce negative selection of CD4+ T cell precursors. This suggests that some self Ags are effectively compartmentalized and cannot induce self-tolerance in the T cell repertoire.
T Cell Infiltration into Class II MHC-Disparate Allografts and Acute Rejection Is Dependent on the IFN-γ-Induced Chemokine Mig
Authors: Koga Shoji , Auerbach Michael B. , Engeman Tara M. , Novick Andrew C. , Toma Hiroshi , Fairchild Robert L. 
Published: December 2022

AbstractDirect evidence that cytokines with chemoattractant properties for leukocytes, chemokines, recruit alloantigen-primed T cells into transplanted allografts has been lacking. We present evidence that neutralization of a single chemokine inhibits T cell infiltration into class II MHC-disparate murine allografts and acute rejection. The chemokines IFN-γ-inducible protein-10 and monokine induced by IFN-γ (Mig) are expressed in allogeneic skin grafts during the late stages of acute rejection. Survival of class II MHC-disparate B6.H-2bm12 allografts is prolonged from day 14 to day 55 posttransplant when C57BL/6 recipients are given a short course treatment with an antiserum to Mig. This treatment also inhibits T cell and macrophage infiltration into the allografts. B6.H-2bm12 allografts are also not rejected by IFN-γ−/− C57BL/6 recipients. Injection of Mig directly into B6.H-2bm12 grafts on IFN-γ-deficient recipients restores T cell infiltration and rejection. Therefore, the inability of IFN-γ-deficient recipients to reject the class II MHC-disparate allografts is due to the lack of intraallograft Mig production and alloantigen-primed T cell recruitment to the graft. These results indicate for the first time the potential utility of chemokine neutralization strategies in preventing T cell infiltration into allografts and abrogating acute rejection.
In Vivo Evidence That Caspase-3 Is Required for Fas-Mediated Apoptosis of Hepatocytes
Authors: Woo Minna , Hakem Anne , Elia Andrew J. , Hakem Razqallah , Duncan Gordon S. , Patterson Bruce J. , Mak Tak W. 
Published: December 2022

AbstractCaspase-3 is essential for Fas-mediated apoptosis in vitro. We investigated the role of caspase-3 in Fas-mediated cell death in vivo by injecting caspase-3-deficient mice with agonistic anti-Fas Ab. Wild-type controls died rapidly of fulminant hepatitis, whereas the survival of caspase-3−/− mice was increased due to a delay in hepatocyte cell death. Bcl-2 expression in the liver was dramatically decreased in wild-type mice following anti-Fas injection, but was unchanged in caspase-3−/− mice. Hepatocytes from anti-Fas-injected wild-type, but not caspase-3−/−, mice released cytochrome c into the cytoplasm. Western blotting confirmed the lack of caspase-3-mediated cleavage of Bcl-2. Presumably the presence of intact Bcl-2 in caspase-3−/− hepatocytes prevents the release of cytochrome c from the mitochondria, a required step for the mitochondrial death pathway. We also show by Western blot that Bcl-xL, caspase-9, caspase-8, and Bid are processed by caspase-3 in injected wild-type mice but that this processing does not occur in caspase-3−/− mice. This study thus provides novel in vivo evidence that caspase-3, conventionally known for its downstream effector function in apoptosis, also modifies Bcl-2 and other upstream proteins involved in the regulation of Fas-mediated apoptosis.
Systematic Mutagenesis of TCR Complementarity-Determining Region 3 Residues: A Single Conservative Substitution Dramatically Improves Response to Both Multiple HLA-DR Alleles and Peptide Variants
Authors: Brawley James V. , Concannon Patrick 
Published: December 2022

AbstractTo define the relative contributions of HLA and peptide contacts with TCR complementarity-determining region (CDR) 3 residues in T cell recognition, systematic mutagenesis and domain swapping was conducted on two highly similar TCRs that both respond to the influenza hemagglutinin (HA) peptide, HA307–319, but with different HLA restrictions. Despite the primary sequence similarity of these TCRs, exchange of as little as two CDR3 residues between them completely abrogated responsiveness. At position 95 within CDR3α, various substitutions still allowed for some degree of recognition. One modest substitution, alanine for glycine (essentially the addition of a methyl group), significantly broadened the specificity of the TCR. Transfectants expressing this mutant TCR responded strongly in the context of multiple HLA-DR alleles and to HA peptide variants with substitutions at each TCR contact residue. These results suggest that the conformations of CDR3 loops are crucial to TCR specificity and that it may not be reliable to extrapolate from primary sequence similarities in TCRs to similarities in specificity. The ease with which a broad specificity is induced in this mutant TCR has implications for the mechanisms and frequency of alloreactivity and promiscuity in T cell responses.
Neutrophil Dysfunctions, IL-8, and Soluble L-Selectin Plasma Levels in Rapidly Progressive Versus Adult and Localized Juvenile Periodontitis: Variations According to Disease Severity and Microbial Flora
Authors: Gainet Jean , Dang Pham M. C. , Chollet-Martin Sylvie , Brion Monique , Sixou Michel , Hakim Jacques , Gougerot-Pocidalo Marie-Anne , Elbim Carole 
Published: December 2022

AbstractWe used flow cytometry to analyze the expression of adhesion molecules and the oxidative burst of whole-blood polymorphonuclear neutrophils (PMN) from 26 patients with periodontitis. Three different clinical entities were studied: adult periodontitis (AP), localized juvenile periodontitis (LJP), and rapidly progressive periodontitis (RPP). Unstimulated PMN from the patients showed reduced Lewis x, sialyl-Lewis x, and L-selectin expression relative to those from healthy control subjects. These alterations were present whatever the severity of periodontal disease. However, PMN from RPP patients showed increased basal H2O2 production and decreased L-selectin shedding. These latter impairments, which correlated with increased IL-8 plasma levels, could contribute to initial vascular damage. In addition, decreased IL-8 priming of H2O2 production by PMN from RPP patients could account for a lower bactericidal capacity of PMN, leading to the large number of bacteria in the subgingival region of RPP patients. Soluble L-selectin plasma levels were also decreased in the RPP group, indicating more severe or diffuse endothelial damage. These abnormalities were not found in the patients with less destructive forms of periodontitis (AP and LJP). Porphyromonas gingivalis, a bacterial pathogen known to increase IL-8 production by PMN, was found in the periodontal pockets of RPP patients only. These results show links among PMN abnormalities, the clinical form of periodontitis, and the gingival bacterial flora.
Tissue Specificity of E- and P-Selectin Ligands in Th1-Mediated Chronic Inflammation
Authors: Chu Alvina , Hong Kenneth , Berg Ellen L. , Ehrhardt Rolf O. 
Published: December 2022

AbstractThe demonstrated role of E- and P-selectin ligands in the recruitment of Th1 cells raises the question of tissue specificity determination by pathogenic T cells. We took advantage of the fact that chronic Th1-mediated inflammation in the scid/scid CD4+CD45RBhigh T cell transfer model can occur at multiple tissue sites, resembling inflammatory bowel disease in the colon and psoriasis in the skin. We show that the majority of infiltrating effector T cells from psoriatic skin expresses high levels of functional P-selectin ligand (87 ± 3%), detected by P-selectin-Ig (PIg), while a significantly smaller subset of T cells from colitic lesions expresses this ligand (24 ± 2%). Similarly, E-selectin ligand is preferentially expressed on CD4+ T cells infiltrating the skin (24 ± 2%), but only on very few CD4+ T cells infiltrating the colon (CIT; 1.3 ± 0.8%). In contrast, CD4+ T cells infiltrating the skin express α4β7 at a significantly lower level than CIT (mean fluorescence intensity, 28 vs 61, respectively), although, interestingly, αEβ7 was expressed at high levels on both populations. Analysis of the disease-inducing potential of PIg+ and PIg− CD4+ CIT cells revealed that both populations not only express similar levels of the gut-homing molecule α4β7 (mean fluorescence intensity, 50 vs 56, respectively), but do not differ in their capacity to express IFN-γ. Furthermore, CIT depleted of cells expressing functional P-selectin ligand were able to induce colitis upon transfer, suggesting that induction of colitis in this model may be independent of E- and P-selectin. These results indicate that adhesion molecule expression and the homing pattern of inflammatory T cells are regulated by the local environment independently of their inflammatory capacity.
Photochemical Treatment with S-59 Psoralen and Ultraviolet A Light to Control the Fate of Naive or Primed T Lymphocytes In Vivo After Allogeneic Bone Marrow Transplantation
Authors: Truitt Robert L. , Johnson Bryon D. , Hanke Carrie , Talib Sohel , Hearst John E. 
Published: December 2022

Abstract
Donor leukocyte infusions after allogeneic bone marrow transplantation can provide a curative graft-vs-leukemia (GVL) effect, but there is a significant risk of graft-vs-host (GVH) disease. A simple and effective method for controlling the fate of naive or primed T-lymphocytes in vivo without eliminating their beneficial properties is needed. In this report, photochemical treatment (PCT) ex vivo with a synthetic psoralen (S-59) and UVA light was evaluated as a pharmacological approach to limiting the proliferation and GVH potential of naive and primed donor T cells in vivo. S-59 rapidly intercalates into and cross-links DNA on UVA illumination. The effects of PCT on T cells were found to be both S-59 and UVA dose dependent. With selected PCT regimens, treated T cells still expressed activation markers (CD25 and CD69) and secreted IL-2 on activation, but they showed limited proliferative capacity in vitro and in vivo. Clonal expansion of CTL in MLR was reduced after PCT, but short term lytic activity of primed CTL was not affected. In a murine model of MHC-mismatched bone marrow transplantation, the addition of PCT-treated T cells to T-depleted bone marrow facilitated donor engraftment and complete chimerism without causing acute or chronic graft-vs-host disease. Allospecific GVL reactivity was reduced but not eliminated after PCT treatment. In an MHC-matched model using host-presensitized donor T cells, PCT significantly reduced GVH-associated mortality without eliminating GVL reactivity. Thus, PCT ex vivo offers a simple, rapid, and inexpensive method by which to control the fate of naive and primed T cells in vivo.
The Reticulo-Endothelial System and Antibody Production
Authors: Roberts Edward F. 
Published: December 2022

Abstract
In a previous study (5) consideration was given to the influence of a reticulo-endothelial blockade upon the appearance of antibody in the circulating blood of the rabbit injected with antigens of various types. India ink, diluted in distilled H2O and filtered, was found to qualify as a suitable blockading agent since the carbon particles were intensely phagocytized and the mechanical barrier thus effected persisted for a considerable length of time. Various types of antigen were employed singly and in combination. Most significant of all, the study revealed that the results derived from a given experiment of this kind might suggest an interpretation in a definite direction whereas the results secured in a second experiment, carried out under almost identical conditions, could only be interpreted in an entirely different way. Moreover, the disagreement in results of duplicate experiments was not surpassed by the varied observations of workers who, compared one with the other, conducted their experiments under far more dissimilar conditions.
Schick Test as Applied to the Selection of Horses for the Production of Diphtheria Antitoxin
Authors: Nishimura H. 
Published: December 2022

Abstract
That horses possessing natural antitoxin in their blood produce antitoxin readily is well known by workers (Hitchens and Tingley, Hida, Glenny, Wadsworth, Sordelli, Ramon, etc.) in this field. Park and Zingher pointed out that persons yielding negative Schick tests respond to toxin-antitoxin injections with the production of antitoxin more readily than those who react in a positive manner.
In the selection of such naturally immune horses for the purpose of immunization a trial bleeding is usually taken and the serum is tested for natural antitoxin by Römer's cutaneous method or Ehrlich's subcutaneous method. Hitchens and Tingley injected 0.2 cc. diphtheria toxin, equaling 3 m.l.d.'s for 250 gram guinea pigs, into the conjunctiva of one eye of horses under examination for the purposes of immunization, and found that many yielded negative tests read at the end of forty-eight hours, indicating the presence of natural diphtheria-antitoxin in the blood of normal horses.
The Toxicity of Human Serum for the Guinea Pig As Affected by Absorption of Agglutinins
Authors: Davidsohn I. , Ramsdell Susan Griffith 
Published: December 2022

Summary
Sera from persons treated with immune sera and showing a toxicity of the heterophilic type for the guinea pig, when treated with the red cells of this animal for the removal of agglutinins do not lose such toxicity. When the same sera are absorbed in the same way with sheep cells, as a heterophilic antigen, the toxicity is usually but not always completely, removed thereby. The experiments further indicate the heterophilic nature of the antibodies concerned in the toxicity. But there is also the possibility that, in these cases, sheep cells constitute an incomplete antigen; or else that another factor, as yet unidentified, is contained in such sera.
On the Anticomplementary Action of Pancreatic Extracts
Authors: Grove Ella F. 
Published: December 2022

Summary
The anticomplementary action of the pancreatic extract known as pangestin is exhibited in a narrow quantitative zone, the larger quantities causing progressively less inhibition. This zone phenomenon is not present in the digestive activity of this preparation. This finding shows that the inhibition of complement by pancreatic extracts is not due to digestion of a component of complement.
Studies on the “Toxins” of Hemolytic Streptococci
Authors: Ando K. , Ozaki K. 
Published: December 2022

Summary and Conclusions
Skin reactions to the nucleoprotein of streptococcus seem to indicate a somewhat nonspecific allergic state of the individuals tested with this substance which seems to be common at least to various streptococci, and are not an indication of a specific relationship with certain streptococci. The fact that the allergy to the N.P. runs parallel to the immunity to the essential toxin is due to the structure of Streptococcus scarlatinae of which the N.P. and the essential toxin are the two components. But that both are not necessarily parallel to each other seems to depend upon the fact that nucloproteins are widely common to various sorts of streptococci while only a limited variety of streptococci can produce essential toxin and that the rapidity of development of immunity to the essential toxin and of allergy to the N.P. does not run parallel to each other. An explanation of many data reported by various authors on the Dick test contrary to the Dicks' theory may be found in the fact that the ordinary Dick toxin (culture filtrate) in addition to the essential toxin contains N.P. which is also capable of evoking allergic reactions on human skins. The culture filtrate which contains a considerable amount of N.P. seems to have given results inconsistent with the toxin-antitoxin theory. For the standardization of the Dick toxin for the Dick test it is not sufficient to determine its skin units, but the nucleoprotein content of it must be considered. In this respect, the Washington standard toxin was very satisfactory, but the use of the purified toxin free fron N.P. is most reasonable. In order to determine skin units of ordinary culture filtrate very young children with strongly positive reaction to the scarlatinal toxin are preferred, as they scarcely have a positive reaction to the nucleoproteins. If we utilize weak positive reactors and place the importance on the percentage of positive reactors, this will likely lead us into error, owing to the positive reactions to the N.P. The divergence of the results reported by many authors on the age distribution of positive reactors seems to depend upon the different content of nucleoproteins in the filtrate used.
The Minimum Blanching Dose and the Unit Value of Scarlatinal Antitoxin Determined by the Skin-Test Method on the White Pig
Authors: Ando K. , Futagi Y. 
Published: December 2022

Abstract
Wadsworth, Cruickshank, O'Brien, Wylie, etc., pointed out the practical difficulties met with in the titration of scarlet fever antitoxin by means of the Schultz-Charlton blanching test. But Friedemann recommends to the clinician the application of this method in selecting serum to be used. They inject two serums to be used in serial dilution intracutaneously into the rash of one and the same patient, at the same time, and compare their endpoint of positive reaction. In the Government Hospital for Infectious Diseases at Dairen the same method has been used as a routine for the same purpose since some years ago.
It was our earnest desire to compare the value determined by the blanching test and the unitage determined by the skin-test method on the white pig.