bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue-resident memory CD4+ T cells play a dominant role in the initiation of antitumor immunity
Authors: Zhang Hui , Zhu Zhaohui , Modrak Samantha , Little Alex 
Published: January 2023

Abstract
Tumor immunology has been studied extensively. Tumor immunology-based cancer immunotherapy has become one of the most promising approaches for cancer treatment. However, one of the fundamental aspects of tumor immunology – the initiation of antitumor immunity – is not fully understood. Compared to that of CD8+ T cells, the effect of CD4+ T cells on antitumor immunity has not been fully appreciated. Using a gene knockout (KO) mouse model – these mice are deficient in TCRa repertoire, specifically lacking iNKT and MAIT cells - we found that the deficiency in TCRa repertoire diversity did not affect the antitumor immunity, at least to melanoma and breast cancer. However, after acquiring thymocytes or splenocytes from wild-type mice, these KO mice exhibited greatly enhanced and long-lasting antitumor immunity. This enhanced antitumor immunity depended on CD4+ T cells, especially tissue-resident memory (TRM) CD4+ T cells, but not iNKT or CD8+ T cells. We also present evidence that CD4+ TRM cells initiate antitumor immunity through IFN-g, and the process is dependent on NK cells but not macrophages. The CD4+ TRM/NK axis appears to control tumor formation and development by eliminating tumor cells and modulating the tumor microenvironment. Taken together, our results demonstrated that CD4+ TRM cells play a dominant role in the initiation of antitumor immunity.
Supported by Washington State University Start-up funds
Recombinant protein mimicking the antigenic structure of the envelope protein of dengue virus enhances antigen-specific virus-neutralizing immune response induction
Authors: Jang Yong-Suk , Kim Ju , Lim Tae-Young , Park Jisang , Kim JunYoung , Cho SooHyeon 
Published: January 2023

Abstract
Dengue virus (DENV) comprises four serotypes in the family Flaviviridae and infects approximately 390 million people worldwide every year. So far, there is no effective therapy available for dengue diseases other than supportive care. Therefore, the development of safe and effective vaccines is critical. Most of DENV vaccines are primarily based on the envelope proteins prM and E, which are believed to induce protective immune responses in humans. Particularly, the DENV E protein and its envelope domain III (EDIII) have been investigated as candidate antigens for recombinant subunit vaccine. However, most EDIII-based antigens do not display quaternary structure of DENV E protein which is essential to induce virus neutralizing immune responses. We developed the Recombinant of DENV-2 Envelope Domain (r2ED) as an antigen, which mimics the antigenic structure of E protein on the surface of DENV. We tested the ability of r2ED to boost antigen-specific immune response induction in vivo. As a result, we observed that r2ED elicited antigen-specific and neutralizing antibody responses and T cell-mediated immune responses higher than EDIII alone in mice. In addition, antigen-specific antibody and T cell responses were maintained in an enhanced level at 6 months after the last immunization in r2ED-immunized mice, suggesting the sustained immune memory responses for a long time. These results are helpful to develop the improved subunit vaccine for inducing an effective and long-lasting immune response against DENV infection.
This work was supported by the NRF funded by the Ministry of Education No. 2017R1A6A1A03015876 and the Ministry of Science and ICT No. 2020K1A4A7A02095058. J. Park, J. Kim, and S. Cho were supported by the BK21 FOUR program in the Department of Bioactive Material Sciences.
Peripheral co-immunization with CCL27 drives robust mucosal responses to SARS-CoV-2 synDNA antigens and provides heterologous protection against Delta variant challenge
Authors: Gary Ebony Nicole , Tursi Nicholas J , Warner Bryce , Parzych Elizabeth , Ali Ali , Kobasa Darwyn , Patel Ami , Kulp Daniel , Weiner David B 
Published: January 2023

Abstract
SARS-CoV-2, which causes COVID-19 has caused a global pandemic which has claimed over 5 million lives to date. Emerging variants of concern and waning vaccine-induced immunity continually challenge viral control measures. We previously reported on the immunogenicity of a DNA vaccine encoding the spike glycoprotein of SARS-CoV-2, however directing vaccine-induced humoral and cell-mediated responses to mucosal surfaces such as the respiratory mucosa remains a challenge. We immunized mice with synthetic DNA (synDNA) plasmids expressing the wild-type SARS-CoV-2 spike protein (pS) alone, or with the DNA-encoded molecular adjuvant cutaneous T cell-attracting chemokine (pCTACK) Mice co-immunized with pS and pCTACK had increased spike-specific IFNy T cell responses compared to those receiving pS alone. While groups had similar levels of spike receptor binding domain (RBD)-specific IgG in their serum, in the mucosa, co-immunization with pCTACK enhanced RBD-specific IgA and only the cecal extract from pCTACK co-immunized animals neutralized pseudotyped viruses. When ACE2 transgenic mice were immunized, rested, and challenged with the heterologous SARS-CoV-2 Delta variant, co-immunization with pCTACK supported 100% survival while immunization with wild-type spike DNA antigens supported 60% survival. Importantly 100% of pCTACK co-immunized animals were protected from infection-induced weight loss. These studies demonstrate that chemokine adjuvants can direct vaccine-induced responses to specific immunological sites and that such responses can have significant impact on heterologous challenge outcomes and support the continued study of molecular chemokine adjuvants in the context of SARS-CoV-2 vaccines.
We would like to thank the Animal Facility staff at the Wistar Institute and the Public Health agency of Canada for providing care to the animals used in these studies and for additional financial support. We would also like to thank the flow cytometry core facility at the Wistar Institute. This work was supported by NIH NCI award T32 CA09171 (ENG) and NIH NIAID award T32-AI-055400 (EMP) with additional support from CEPI/Inovio Pharmaceuticals.
B cell receptor repertoire dynamics and convergent evolution following SARS-CoV-2 vaccination
Authors: Fraley Elizabeth Ross , Khanal Santosh , LeMaster Cas , Pierce Stephen , Pastinen Tomi , Bradley Todd 
Published: January 2023

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel betacoronavirus causing Coronavirus disease 2019 (COVID-19). B cell receptors (BCRs) are expressed at the surface of the B cell and are secreted as soluble antibodies. These antibodies can block viral infection by neutralizing the virus, are critical for resolution of SARS-CoV-2 infection, and may be correlates of protection for COVID-19 vaccines. We have previously shown that SARS-CoV-2 immunization elicits a robust antibody response that is significantly higher in individuals who recovered from COVID-19. Moreover, recovered individuals had slower antibody decay in their levels seven months after vaccination. Here, we sequenced the BCR repertoire of individuals undergoing vaccination by SARS-CoV-2 mRNA vaccine (Pfizer, BNT162b2) with (seropositive) or without (seronegative) previous laboratory confirmed COVID-19 infection. We identified genetic differences in the BCR repertoire between groups including V gene usage, CD3R length, percentage of somatic hypermutation, and clonotype diversity. We then focused our analyses to vaccine-expanded clonotypes in both groups to further analyze the differences in BCR repertoire on candidate SARS-CoV-2-specific clonotypes. We determined the frequency of pre-existing clones present after infection that were engaged by the vaccine in the seropositive group. Moreover, in both groups we identified clonotypes that were shared among individuals that could be a result of convergent evolution. Defining the characteristics and evolution of the BCR repertoire during vaccination of individuals with different histories of viral infection will aid in understanding SARS-CoV-2 humoral response dynamics.
OX40 boosts and sustains humoral and cellular immune responses to SARS-CoV2 spike protein and RNA vaccinations
Authors: Duhen Rebekka A , Beymer Michael , Jensen Shawn , Abbina Srinivas , Abraham Suraj , Thomas Anitha , Hu Hong-Ming , Fox Bernard A , Weinberg Andrew D 
Published: January 2023

Abstract
To prevent SARS-CoV-2 infections and generate long-lasting immunity, vaccines need to generate both, a strong humoral immune response as well as viral-specific CD4 and CD8 T cells. Previous results from our lab have shown that immunization in the presence of an agonist antibody targeting OX40 led to higher antibody titers and increased numbers of antigen-specific CD4 and CD8 T cells. Using the same strategy, we explored the effect of OX40 co-stimulation in the prime and boost together with the SARS-CoV-2 spike protein + adjuvant in C57Bl/6 mice. Our results show that OX40 engagement led to a significant increase in long-lived antibody responses when compared to mice that did not receive additional co-stimulation. In addition, spike protein and peptide-specific proliferation were greatly increased for both CD4 and CD8 T cells, with augmented secretion of IFN-γ, TNF-α and IL-2. Booster immunizations (7 months post prime) did not lead to anergy, but instead further increased the antibody and T cell responses. In initial experiments, the self-amplifying RNA (saRNA) vaccination generated lower antibody titers, independent of OX40 co-stimulation. However, the saRNA vaccine did induce a robust expansion of antigen-specific CD8 T cells, that expressed high levels of GrzmB, which was further increased by OX40 administration. The strong immune responses and the differential effects of the protein and saRNA vaccines suggest that heterologous prime-boost approaches, as currently approved in adults, might be beneficial in boosting different arms of the anti-viral immune response against SARS-CoV2, with OX40 agonists enhancing both approaches. Further studies in animals will aid defining the effects and benefits of this approach.
Method for Increasing and Prolonging the Production of Antitoxins in Horses
Authors: Ramon G. , Lemétayer E. 
Published: January 2023

Abstract
When horses are immunized by the injection of increasing doses of diphtheria toxin or anatoxin, the serum of the animals comes to contain increasing quantities of antitoxin. At the end of a period varying with different factors referring to the antigen or the animal, the antitoxic power of the serum reaches a certain degree which appears to be the highest degree which it is possible to attain under any conditions. As soon as this maximum is reached, therefore, it is considered preferable, by certain laboratories, to bleed the animals completely. In other laboratories, the practice is to allow a period of about eight days to elapse following the last injection of the antigen and then bleed the animal in two fractions of 6 to 8 liters each, done a few days apart. This double bleeding is repeated every month.
Anaphylaxis to Diphtheria Toxin
Authors: Neill James M. , Sugg John Y. , Richardson Lurline V. 
Published: January 2023

Abstract
Previously reported experiments (1, 2, 3) on anaphylaxis apparently due to the toxin or toxoid antigen were made upon actively sensitized (antitoxic immune) animals. The results had indicated that while other diphtheria antigens participated to some extent, the major part of the anaphylaxis could be assigned to the toxin or toxoid antigen, provided one used both for the immunization and for the intravenous test minimal amounts of unheated filtrate in which toxin or toxoid was the dominant antigen, and selected for intravenous test the individual guinea pigs that had been “earliest” in antitoxin production. Passive sensitization possesses certain advantages over active sensitization in the distinction of reactions due to toxin-antitoxin from reactions due to other diphtheria antigen-antibody combinations, for with the passive method it is possible to examine each of the sensitizing sera for antibodies other than antitoxin and, when desired, to remove the other antibodies by absorption of the antisera before using them for sensitization.
The Effect of Concentration and of Various Tissue Constituents on the Virulence of the Poliomyelitis Virus
Authors: Jungeblut Claus W. 
Published: January 2023

Summary and Conclusions
Titration of poliomyelitis virus cord suspensions of varying percentages shows there is a particular concentration with maximum virulence below which the dilutions become progressively less infective and above which virulence is likewise diminished. Berkefeld-filtrates of virus cord suspensions are at times more virulent than corresponding unfiltered suspensions, although exceptions do occur. Neither normal monkey cord nor normal monkey brain when added in vitro to virus filtrates, has any appreciable effect on the virulence of the virus. The results with convalescent cord are too irregular to indicate clearly the presence of a neutralizing principle in the immune tissue. Normal monkey testicle added to virus filtrates in vitro frequently produces a conspicuous diminution of virulence of the virus in the supernatant fluid. The extent of this antagonistic effect varies with different monkey testicles. Normal rabbit testicle, under similar conditions, seems slightly to enhance the virulence of the virus.
AL008 Enhances Myeloid Antitumor Function by Inhibiting SIRPα Signaling and Activating Fc Receptors
Authors: Yang Jingping , Deresa Isaiah , Ho Wei-Hsien , Long Hua , Maslyar Daniel , Rosenthal Arnon , Liang Spencer C , Pincetic Andrew 
Published: January 2023

Abstract
Antagonizing the CD47–signal regulatory protein (SIRP)α pathway, a critical myeloid checkpoint, promotes antitumor immunity. In this study, we describe the development of AL008, a pan-allelic, SIRPα-specific Ab that triggers the degradation of SIRPα and, concurrently, stimulates FcγR activation of myeloid cells through an engineered Fc domain. AL008 showed superior enhancement of phagocytosis of tumor cells opsonized with antitumor Ag Abs compared with another SIRPα Ab tested. Unlike ligand-blocking SIRPα Abs, AL008 demonstrated single-agent activity by increasing tumor cell engulfment by human monocyte-derived macrophages even in the absence of opsonizing agents. This effect was due to enhanced Fc function, as blocking FcγR2A abrogated AL008-mediated phagocytic activity. AL008 also promoted human monocyte-derived dendritic cell–mediated T cell proliferation. In humanized mouse models, AL008 induced internalization of SIRPα and increased expression of CD86 and HLA-DR on human tumor-associated macrophages, confirming that the mechanism of action is retained in vivo. Monotherapy treatment with AL008 significantly reduced tumor growth in humanized mice implanted with human MDA-MB-231 tumor cells. AL008 also significantly potentiated the effects of T cell checkpoint blockade with anti–programmed death ligand-1 in syngeneic tumor models. This dual and specific mechanism of AL008, to our knowledge, provides a novel therapeutic strategy for targeting myeloid cells for immune activation.
Agglutination Reactions in Rheumatoid Arthritis
Authors: Dawson Martin H. , Olmstead Miriam , Jost Elizabeth L. 
Published: January 2023

Summary
A comparative study of precipitins and agglutinins against Streptococcus hemolyticus has been made in the sera of 71 cases of rheumatoid arthritis and in 79 cases of other diseases. The results indicate that there is a close approximation, but not an absolute agreement, in the capacity of rheumatoid arthritis sera to agglutinate strains of Streptococcus hemolyticus and to precipitate various group-specific fractions of this organism. With certain exceptions, to which special reference is made, the control sera examined did not show the presence of either agglutinins or precipitins in significantly high dilutions. These findings offer suggestive evidence in favor of the hypothesis that the disease rheumatoid arthritis is associated with infection by Streptococcus hemolyticus.
Age and Antibody Production
Authors: Baumgartner Leona 
Published: January 2023

Summary
Differences in the antibody production of animals of different ages indicate that there is a curve of development in the ability of such animals to produce antisera and that during the course of this immunologic maturation process there is also a change in the quality of the antisera elaborated. This hypothesis is substantiated by the following observations drawn from a series of studies with 79 antisera produced by active immunization of rabbits. The “avidity” of fresh antisera agglutinating B. enteritidis produced in 22 “adult” animals was greater than that of antisera produced in 22 “young” animals.The “avidity” of fresh antisera agglutinating B. enteritidis produced by 22 “adult” animals was only a little greater than that of antisera produced by 19 “aged” animals.The trend of the differences in these three groups of animals seemed to be the same if—The antigen used in immunization were administered intraperitoneally or intravenously.The total amount of antigen administered to each animal were the same, or was based upon the weight of the animal.The antisera were tested after a fourteen-day period of immunization or after a thirty-one-day period.Thyroid were added or omitted from the diet of the animals.These “avidity” differences were not dependent upon the titer of the sera.The quantity of antibody produced by “young” animals was less than that produced by “adults.” There was some evidence that “aged” animals were less able to produce antibody than were the “adults.”Certain applications of the statistical method to immunologic reactions were made. It is suggested that a definite value lies in the further use of similar methods in other immunologic studies.
Studies on the Chemical Nature of Shwartzman-Active Substances
Authors: Apitz Kurt 
Published: January 2023

Summary and Conclusions
Shwartzman-active substances are contained in two different chemical fractions of bacterial substances. The so-called “nucleoprotein” fraction is always found to be Shwartzman-active; it is derived from bacterial autolysis or extraction. Its potency is increased in alkaline solution. Most of the potency of agar-washings is connected with an alcohol-precipitable biuret-negative fraction. The appearance of these Shwartzman-active substances does not depend on autolytic processes, but is metabolic in character. The Shwartzman-active substances of the last described fraction are highly unstable, precipitable with small volumes of alcohol and not identical with type-specific carbohydrates. The Shwartzman-active factor of filtered washings is slowly dialyzable and resists trypsin digestion.
The Effect of Heterologous Bacterial Products Upon Tuberculous Animals
Authors: Freund Jules 
Published: January 2023

Abstract
It has long been known that tuberculous animals respond with focal and systemic reactions to injurious agents not related to tubercle bacilli. In human beings non-specific focal and systemic reactions can be observed when tuberculosis is associated with certain infectious diseases, when tuberculous patients are injected with foreign proteins (heterotherapy) or metal salts. Mollgard and others (1) observed severe systemic and focal reactions after the injection of a gold salt (sanocrysin) in tuberculous man and animals. Lewis, Menkin and others (2) found that dyes and metal salts accumulate in tubercles in larger amounts than in normal tissues. Dienes (3) reported that in tuberculous guinea pigs that had been sensitized to egg white a very small amount of this protein produces hemorrhages in tissues containing tubercles and “tuberculin” death.
Observations by Sanarelli (4) on rabbits infected with cholera vibrios afforded a new approach to the problem of the specificity of focal and systemic reactions.
The Nature of a Virucidal Substance in “Normal” Human Serum as Compared with the Trypanocidal and Bactericidal Substances
Authors: Strong Paul S. 
Published: January 2023

Abstract
In a previous communication (Culbertson and Strong, 1935) it was reported that a considerable community of characteristics was found between the trypanocidal and bactericidal properties of normal human serum. It seemed of interest to determine whether this relationship could be carried to the virucidal substance in human serum. The purpose of the present paper therefore, is to discuss in some detail the nature of the principle in human serum active against a presumed herpes virus and its possible relationship with the bactericidal and trypanocidal substances. The “W”2 virus was used in this work since it gives constant, unmistakable skin lesions in rabbits. It is usually neutralized by human serums which neutralize herpes virus, an observation first made by Gay and Holden. In the present study, the relation of the virucidal substance to alexin (complement), its thermostability, absorbability, antigenicity and the nature of the serum-virus complex are considered.
Studies on the Activity of Cephalin as It Relates to the Coagulative and Complementary Properties of the Blood
Authors: Wadsworth Augustus , Maltaner Frank , Maltaner Elizabeth 
Published: January 2023

Summary
Experiments are recorded demonstrating the quantitative relations between cephalin, protein, and hydrochloric acid or calcium chloride in: (a) the precipitation of the cephalin-protein complex from serum; (b) the restoration of the coagulative (thrombin) activity of serum; (c) the acceleration of the coagulation of oxalated plasma; (d) the inhibition and reactivation of complement.
In all of these reactions an excess of cephalin or protein inhibited the reaction, whereas optimum activity occurred when the quantities of cephalin and ionized calcium or acid were present in amounts approximating their chemical equivalents. Under these conditions the inhibition of complement was complete and irreversible. With an excess of cephalin or protein, the inhibition of complement was reversible, complete activity being restored by the addition of an amount of calcium chloride approximating or moderately in excess of the chemical equivalent of the cephalin present.
Complement reversibly inactivated by cephalin was reactivated by ammonia-, zymin-, or heat-inactivated serum and also by the heated or unheated albumin but not by the euglobulin fraction of serum: the reactivation was associated with fractions containing the ionized calcium of serum.
Complement inactivated by both zymin and ammonia and then heated also reactivated the cephalin-treated complement. Conversely, both ammonia- and zymin-inactivated complement was reactivated by heated cephalin-inactivated complement. Neither cephalin nor calcium chloride was found effective in reactivating ammonia- or zymin-inactivated complement.
Removal of calcium from fresh serum, by preliminary precipitation of the euglobulins with carbon dioxide and subsequent dialysis of the albumin fraction with dilute acid, resulted in a diminution not only in the complement activity but also in the reactivating activity for cephalin-inactivated complement. Partial reactivation of both activities occurred on the addition of calcium chloride.
Finally, experiments are recorded demonstrating: That the complement and coagulative activity of plasma inactivated by treatment with magnesium hydroxide was reactivated by heated serum or the fractions thereof or by the addition of a definite concentration of hydrochloric acid;That the complementary activity of the prothrombin solutions prepared by adsorption of plasma with magnesium hydroxide and of the albumin and euglobulin fractions of serum bore no constant relation to their coagulative (prothrombin) activity;That these prothrombin solutions, prepared with magnesium hydroxide, like those prepared with tricalcium phosphate or by the saturation of plasma with sodium chloride, contained fibrinogen.