bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sirolimus, Post–Transplant Cyclophosphamide, and CTLA4-Ig Maintain Stable Mixed Chimerism In a Mismatched Murine Model
Authors: Fisher Cameron , Xu Xin , Phang Oswald , Fitzhugh Courtney , Olkhanud Purevdorj B 
Published: January 2023

Abstract
Hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with sickle cell disease (SCD). We sought to extend our haploidentical HSCT regimen with nonmyeloablative conditioning. The objective of our study was to assess the ability of the immunosuppressive agent CTLA4-Ig to induce mixed chimerism in the haploidentical HSCT setting when combined with sirolimus, post-transplant cyclophosphamide (PT-Cy), or both.
We used a mismatched mouse model with BALB/c donors and C57BL/6 recipients. Recipient mice received 200 cGy TBI on day of the transplant and were conditioned with or without sirolimus, PT-Cy, and/or CTLA4-Ig.
Our data show that when CTLA4-Ig alone or CTLA4-Ig/PT-Cy are given, donor cells are not detected. However, mixed chimerism is maintained in mice who received either sirolimus/PT-Cy or sirolimus/PT-Cy given together with CTLA4-Ig over 60 days. Additionally our data indicate a significant increase in recovery of donor cells within CD8 T-cell, CD19 B-cell, and CD11b myeloid cell populations in groups conditioned with sirolimus/PT-Cy, or sirolimus/PT-Cy/CTLA4-Ig as compared to groups conditioned with CTLA4-Ig (p=0.003; p=0.002; p=0.049) alone or CTLA4-Ig/PT-Cy (p=0.001; p&lt;0.0001; p=0.001) at 30 days, respectively.
These data demonstrate that sirolimus in combination with PT-Cy and CTLA4-Ig is synergistic in an MHC-mismatched mouse model. The novel tri-drug group establishes mixed chimerism while conditioning with CTLA4-Ig alone or CTLA4-Ig/PT-Cy does not. The data also identify induction of stable mixed chimerism in specific cellular subpopulations within the sirolimus/PT-Cy and sirolimus/PT-Cy/CTLA4-Ig groups, indicating that these cells may play an important role in HCST.
Characterization of human preformed antibodies to non-SLA xenoantigens on RBC from genetically-engineering pigs
Authors: Wang Zheng-Yu , Martens Gregory , Tector Matthew , Tector A. Joseph 
Published: January 2023

Abstract

BACKGROUND
Genetic engineering pig models of pig-to-human xenotransplantation may overcome a growing shortage of available solid organs. Development of pigs deficient in galactose α1,3 galactose and N-glycolylneuraminic acid have significantly improved cell survival when challenged by human antibody and complement in vitro. The b4GalNT2 glycosyltransferase may also synthesize xenoantigens in pigs. In this study, we used RBC, as a cell model, to assess human antibody-mediated response to non-SLA xenoantigens of pigs deficient in these carbohydrate-modifying genes.

MATHODS AND MATERIALS
RBC were isolated from wild type pigs and pigs deficient in GGTA1/CMAH knockout (DKO) and GGTA1/CMAH/β4GalNT2 knockout (TKO). Human ABO sera were purchased from Valley Biomedical. Human ABO RBC were isolated from healthy people. Total antibody binding was assessed by hemagglutination assay; human IgG or IgM binding to RBC was characterized by flow cytometry; opsonized RBC phagocytosis by THP-1 macrophages was analyzed using confocal microscope.

RESULTS
Phenotype of TKO RBC was characterized by flow cytometry. Silencing the three genes reduced hemagglutination levels of TKO RBC compared with that of DKO RBC by all three human blood-type A, O, and AB sera but except blood-type B sera, and decreased both of IgG and IgM binding to TKO RBC compared with DKO RBC. Confocal image data showed that phagocytosis of opsonized TKO RBC was lower than that of opsonized DKO RBC by THP-1 cells.

DISCUSSION
Non-SLA xenoantigenicity of pig RBC can be disrupted using gene engineering tools, which greatly reduced the humoral barrier to xenotransplantation
AhR activation plays a detrimental role in airway epithelial injury after transplantation
Authors: Zhang Ruochan , Ochando Jordi , Li Liwu , Ding Yaozhong , Xu Jiangnan 
Published: January 2023

Abstract
Patients with tracheal tumors, trauma, infection, congenital malformations or injury after prolonged intubation may require partial or complete tracheal resection, and tracheal transplantation will be necessary when the length of resected trachea is longer than 30% in children or 50% in adults. Currently, obliterative bronchiolitis (OB) is a major obstacle that affects allograft function and survival after tracheal transplantation. Th17 polarization and inflammatory cytokine expression is crucially involved in airway transplant rejection, and activation of aryl hydrocarbon receptor (AhR) could modulate Th17 differentiation and inflammatory cytokine production. However, the role of AhR signal pathway in airway epithelial injury, a leading factor of OB development, after transplantation remains unclear. In this study, we performed murine orthotopic tracheal transplants in C57BL/6 wild type mice using BALB/c donors. The levels of IFNγ, IL-6 and IL-17 expression were significantly elevated in allografts, and the airway pseudostratified epithelia changed into flat epithelia with inflammation and fibroblast proliferation in submucosa tissue. Allografts of recipients administered with AhR antagonist (CH-223191) displayed inhibition of IL-17 and IFNγ, and some airway epithelial protection. Significant lamina fibrosis and higher levels of inflammatory cytokine production was observed in allografts of recipients administered with AhR agonist (FICZ). Together, our results demonstrate that AhR activation plays a detrimental role in airway epithelial injury after transplantation, pointing to a new therapeutic avenue for benefitting airway allograft survival through manipulating AhR pathway.
PD-L1/CD80 interaction differentially regulates CD8+ T cell metabolism, survival and GVHD capacity in the presence or absence of PD-1
Authors: Cassady Kaniel , Song Qingxiao , Zhang Yuankun , Martin Paul J. , Ann David , Riggs Arthur D. , Zeng Defu 
Published: January 2023

Abstract
Purified alloreactive CD8+ T cells induce no acute GVHD, but the mechanisms remain unknown. PD-L1 interacts with PD-1 and CD80. Here we show that, sorted C57BL/6 donor CD8+ T cells (1.25 ×106) expanded in wild-type MHC-mismatched BALB/c recipients but induced no acute GVHD. In PD-L1−/− recipients, donor CD8+ T cells expanded and induced lethal acute GVHD. PD-1−/−CD8+ T cells induced lethal acute GVHD in wild-type recipients. Blockade of PD-L1/CD80 interactions on days 0 and 2 prevented expansion of wild-type and PD-1−/− CD8+ T cells in wild type recipients and prevented acute GVHD caused by PD-1−/− CD8+ T cells. On the other hand, blockade of PD-L1/CD80 interaction after CD8+ T activation on day 5 caused lethal acute GVHD in wild-type recipients that usually have no acute GVHD. Naïve CD8+ T cells express much higher levels of CD80 than PD-1, whereas activated CD8+ T cells express higher levels of PD-1 than CD80. PD-L1/CD80 interaction augmented glycolysis in naïve WT and PD-1−/− CD8+T cells. This interaction was associated with increased phosphorylation of PLC-γ and activation of the AKT/mTOR pathway in a CD28-dependent manner. This interaction increased mitochondrial numbers and volume and augmented ROS production and apoptosis at the peak of CD8+ T cell activation, such that CD8+T cells did not over-expand to cause GVHD. Conversely, blockade of PD-L1/CD80 after CD8+ T activation in the presence of high PD-1 expression led to increased mitophagy, reduced apoptosis and overexpansion of CD8+ T cells, resulting in lethal GVHD. These results indicate that PD-L1/ CD80 interaction is dependent on PD-1 expression to differentially regulate glycolysis and mitophagy as well as expansion, survival and acute GVHD capacity of alloreactive CD8+ T cells.
Studies in Anaphylaxis
Authors: Weil Richard 
Published: January 2023

Abstract
The investigation of the effects of simultaneous intravenous injections of antigen and antibody occupies one of the most interesting and important chapters in anaphylaxis. About ten years ago Otto (1) first showed that passive sensitization is invariably accompanied by a latent period of several hours duration. He interpreted the latent interval simply as the period of time required by the cells to appropriate the introduced antibody, and drew the fundamental inference that the anaphylactic response could not take place except through the mediation of cellular antibody. This theory, which is quite in harmony with Besredka's views, was at first very generally accepted. The discovery of anaphylatoxin, however, gave rise to a rival and altogether irreconcilable theory of anaphylaxis. When it was found that the incubation of antigen with immune serum in the test tube gave rise to violent poisons, it seemed natural to infer that the same poisons would be produced when antigen was injected into the sensitized animals.
Studies in Protein Intoxication
Authors: Harris Boughton T. 
Published: January 2023

Abstract
The literature contains but few references to vascular lesions in acute anaphylaxis, and, so far as I can find, only one reference (7) to vascular lesions produced by repeated injections of foreign proteins. Gay and Southard (1) studying the lesions produced in guinea pigs in acute anaphylaxis, report finding fatty changes in capillary endothelium which they interpret as being the cause of the hemorrhages which are so constantly found in acute anaphylaxis. Rosenau and Anderson (2) were unable to find these lesions in acute anaphylaxis, but Longcope (3) and others mention finding them frequently. Longcope (3), (4), (5) in studying the histologic results of repeated injections of foreign proteins in various animals, found marked, and in some cases, even severe lesions in the parenchymatous cells of heart, liver, and kidney, with varying degrees of fibrosis, but, aside from perivascular infiltration, found no arterial lesions.
Fate of the Foreign Protein in the Acute Anaphylactic Reaction
Authors: Manwaring W. H. , Kusama Yoshio , Crowe Harold E. 
Published: January 2023

Summary
Perfusions of isolated organs and tissues with dilute foreign proteins furnish no evidence of a measurable destruction of the foreign protein by the blood serum, nor of an appreciable destruction or binding of the foreign protein by the fixed tissues during the acute anaphylactic reaction.
Anaphylaxis
Authors: Sherwood Noble P. , Stoland O. O. 
Published: January 2023

Summary and Conclusion
Our results indicate that in heart-lung perfusion experiments on normal and sensitized dogs, the phenomena consisting of a 50 to 75 per cent reduction in rate of flow of perfusion fluid, the development of a rubbery consistency of the lungs and the appearance of a tracheal exudate, all in four to seven minutes are not peculiar to the sensitized dog as judged by the blood pressure and coagulation time phenomena. While these do not correlate with other and at present accepted criteria of sensitization, yet a quantitative study of our data suggests that a probable change in permeability in heart-lung tissue, perhaps independent of anaphylaxis, does frequently result from the injection of horse serum in a dog. Experiments in passive sensitization show that marked variation exists in either ability to take up antibody or refractoriness to the shocking dose of antigen. This observation indicates that negative results on a single recipient are not an accurate criterion of deficiency or absence of antibodies in the donor's blood.
Isohemagglutination: The Work of Jan Janský with a Critical Analysis
Authors: Kennedy James A. 
Published: January 2023

Summary and Conclusions
Janský's classification is based upon 3160 “cross-agglutinations” in which he utilized sera from 30 (32) individuals and corpuscles from 99. These “cross-agglutinations” are reproduced from his work, appearing herein as table 1. A more orderly arrangement of his “cross-agglutinations” has been made by me and appears as table 2. Janský's classification is based upon the 30 (32) individuals whose sera he used in the “cross-agglutinations.” This is reproduced as table 3 and shows: Group I, 12 individuals; Group II, 10; Group III, 6; and Group IV, 2. In table 4, I have given the result of my analysis of his series of “cross-agglutinations.” It is evident that Janský failed to realize that, in addition to grouping the sera that he was using in his work, he was also grouping the other individuals whose corpuscles only he employed. This is clearly shown in table 2. Consequently his results should have been Group I, 40 individuals; Group II, 38; Group III, 20; and Group IV, 2; with a racial index of 1.8. It seems more logical to me to assume that the irregularity shown by the blood of individual 7524 F. B. is due to a low isoagglutinin “b” titer which has been made ineffective by dilution, very short incubation period and possibly temperature of incubation. This is contrary to the interpretation of Guthrie and Huck (15). The blood of individual 7627 Š. J. is exceptional. However, due to the fact that Janský did not include the serum of this individual's blood in his series, one is hardly justified in drawing any definite conclusions regarding it.
Production of Potent Antitetanic Serum
Authors: Predtechensky S. N. 
Published: January 2023

Summary
A method for producing a potent antitetanus serum in horses is described. A ground-immunity was obtained by a few injections of toxin and antitoxin; then the horses rested during three or four months and, after that, they were immunized with doses of toxin doubled each time. The content of antitoxin in the serums reached 1500 units per cubic centimeter and even more.
Diphtheria Antibodies in the Urine of a Child After Intramuscular Injection of Antitoxic Horse Globulin
Authors: Neill James M. , Gaspari Emidio L. , Sugg John Y. 
Published: January 2023

Summary
Tests for diphtheria antibodies were made upon the urine of a child with a mistaken diagnosis of diphtheria who had received intramuscular injections of a large amount of the usual therapeutic antitoxic horse globulin. The presence of the antitoxin antibody was proved both by the capacity of the urine to neutralize the toxin in vitro, and also by in vivo neutralization of toxin injected subcutaneously in guinea pigs several hours subsequent to the intravenous injection of the urine.
Therapeutic antitoxin solutions contain not only the antitoxin antibody, but also diphtheria antibodies of the antibacterial sort, recognizable by agglutination of a degraded strain of diphtheria bacilli; a certain amount of these antibacterial antibodies were also contained in the urine of the child who had received the therapeutic solution.
No serum protein was detected in the urine either by the usual chemical tests or by anaphylaxis tests. The failure to detect the globulin in the urine was not considered evidence of a separation of the antitoxin from the globulin with which it was originally injected, because both the chemical and anaphylaxis tests proved unable to detect the globulin in dilutions of therapeutic antitoxic globulin equivalent in antitoxin concentration to that found in the child's urine.
The Influence of Hypersensitiveness to Horse Serum on the Duration of Local Passive Antitoxic Immunity in Man
Authors: Hooker Sanford B. , Follensby Edna M. 
Published: January 2023

Summary
Previous experimental work on this subject has been here reviewed.
The duration of a local passive immunity produced by injecting scarlatinal antitoxin into the skin was compared in human subjects who were separable into 3 groups according to their endermal reactivity to horse serum. Those who responded negatively or with a reaction of the delayed type, usually retained an effective portion of the test dose of antitoxin for more than twenty-four hours; the immediate reactors disposed of antitoxin so much more rapidly that in less than four hours an equally effective portion was no longer demonstrable.
That this accelerated disposal of antitoxin is specifically dependent upon the allergic state seems highly probable; certain evidences that were not directly conformable to this hypothesis have been discussed.
Extirpation of the Antigenic Depot and Antibody Production
Authors: Roberts Edward F. 
Published: January 2023

Abstract
Within the past decade, the whole subject of the antigen-antibody complex has been approached in an entirely new way and the astounding results obtained have threatened to overthrow many of the earlier concepts. Excision of the area of antigen deposition has raised the question whether or not antigen needs to come in contact with the antibody-producing tissues and if not, what the nature of the stimulus might be.
The pioneer in this field of investigation was Oshikawa (11). He not only confirmed the observation of Friedberger and Girgoloff (8) that transplants of organs of immune animals stimulate antibody production in animals of the same species, but he also added his own observation to the effect that antibody production proceeded perfectly well in the rabbit whose area of antigen deposition (ear) was excised. A small antigenic dose and short intervals between injection and extirpation were found to be instrumental in assuring a good antibody response.
The Speed of Flocculation of Diphtheria Toxin
Authors: Bunney William E. , Kiamil Mumtaz 
Published: January 2023

Summary
A toxin which on acidification yields a slight precipitate flocculating slowly in the Ramon test can be made to yield a rapidly flocculating precipitate by the addition to the toxin of a protein foreign to the diphtheria bacillus but precipitating at the same pH as the toxin itself.
STIM1 contributes to mast cell functional response via MrgprX2
Authors: Occhiuto Christopher J. , Kammala Ananth Kumar , Subramanian Hariharan 
Published: January 2023

Abstract
Mast cells are inflammatory immune cells whose activation is critically regulated by intracellular Ca2+ concentrations. MrgprX2 is a G-protein coupled receptor (GPCR) expressed on mast cells that has been implicated in pseudo-allergic reactions in humans. Though it is known that MrgprX2 activation leads to an increase in intracellular Ca2+ levels, the Ca2+ mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports have demonstrated that the stromal interaction molecule 1 (STIM1) calcium sensor regulates GPCR-mediated Ca2+ responses in mast cells. Therefore, the objective of this study was to determine whether STIM1 contributed to MrgprX2 activation in mast cells. We treated human mast cells with the STIM1 inhibitor SKF 96365 (SKF) prior to MrgprX2 stimulation. As a complementary approach, we also silenced the expression of STIM1. Inhibition or deletion of STIM1 expression resulted in blunted Ca2+mobilization to two different MrgprX2 agonists; Cortistatin-14 and Cathelicidin LL-37. Accordingly, degranulation and inflammatory cytokine production were also attenuated. An in vivo mouse-paw edema model utilizing SKF for inflammation prevention further supplemented the in vitro data suggesting that STIM1 also regulated Ca2+ responses in the mouse ortholog of the human receptor (MrgprB2). Thus, MrgprX2 activation is dependent upon STIM1, and employing STIM1 inhibitors could be a potential strategy to alleviate pseudo-allergic reactions.
IL-6 potentiates FcɛRI-induced PGD2 biosynthesis from human skin mast cells by a STAT3-dependent mechanism.
Authors: McHale Cody C. , Gomez Gregorio 
Published: January 2023

Abstract
Mast cells are tissue resident immune cells that cause allergies. The agents responsible for allergic reactions are pre-formed mediators like histamine and inflammatory lipids such as Prostaglandin D2 (PGD2) that are rapidly biosynthesized following crosslinking of FcɛRI with allergen. In humans, increased IL-6 levels are consistently correlated with allergic diseases like asthma and urticaria in which mast cells play a vital role. However, the exact role of IL-6 in allergic disease is not known. In this study, we show that human in situ-matured skin mast cells (huSMCs) express functional membrane-bound receptors for IL-6, and demonstrate our novel finding that IL-6 potentiates FcɛRI-induced PGD2 biosynthesis. Treatment of huSMCs with IL-6 alone induced the phosphorylation of STAT3 at the activating tyrosine 705, and the expression of SOCS3 and VEGF mRNA. IL-6 alone did not induce PGD2 secretion, but significantly and dose-dependently enhanced PGD2 secretion from FcɛRI-activated huSMCs. Accordingly, IL-6 enhanced the FcɛRI-induced expression of COX-2, which is directly involved in PGD2 biosynthesis. In addition, phosphorylation of STAT3 at both tyrosine 705 and serine 727, which is required for maximal transcriptional activity, was increased in huSMCs treated with IL-6 + FcɛRI crosslinking. Moreover, the IL-6-mediated increase in FcɛRI-induced COX-2 expression was inhibited with C188-9, the small molecule inhibitor of STAT3 tyrosine phosphorylation. Together, these data demonstrate that IL-6 potentiates FcɛRI-induced PGD2 biosynthesis from huSMCs by a STAT3-dependent mechanism. Thus, we hypothesize that IL-6 contributes to allergic disease by enhancing the production of inflammatory PGD2 from mature mast cells.
Mast cell corticotropin releasing factor receptor CRF2 regulates mast cell function in response to psychological and immunological stress
Authors: Moeser Adam James , D’Costa Susan , Ayyadurai Saru , Mackey Emily , Wilson Neco 
Published: January 2023

Abstract
Psychological stress is a significant risk factor in a number of inflammatory and allergic diseases. We have previously demonstrated that CRF1 receptors expressed on mast cells (MCs) can potentiate psychological stress-induced MC degranulation intestinal permeability, and IgE-mediated anaphylaxis. In this study, we investigated the role of the CRF2 receptors in regulating MC activation in response to psychological and immunological stress. CRF2-deficient (CRF2−/−) bone marrow derived MCs exhibited enhanced IgE-and c48/80-mediated mast cell degranulation, determined by β-hex and histamine release. Heightened degranulation in CRF2−/− MCs were mediated by enhanced intracellular Ca2+ mobilization from endoplasmic reticulum stores. Similar results were obtained with human LAD2 mast cells treated with the CRF2 antagonist Astressin 2B. In vitro findings translated to in vivo studies as MC-deficient KitW-sh/W-sh mice systemically engrafted with CRF2−/− BMMCs exhibited a 3-fold increase in serum histamine levels and intestinal permeability following acute restraint stress or passive systemic anaphylaxis. Contrasting effects of CRF2 were observed with de novo synthesized mediator release as IL-4, IL-6, MCP-1 and prostaglandin D2 release were reduced (by ~40–50%) in CRF2−/− BMMCs following stimulation with IgE-antigen, LPS and IL-33. In summary, these data show that CRF2 signaling inhibits MC degranulation and associated pathophysiology induced by acute psychological stress and IgE-mediated anaphylaxis, while enhancing the release of de novo synthesized mediators. Therefore, targeting CRF2 may represent a novel therapeutic approach for preventing stress-related allergic and inflammatory disease flares.