scholarly journals TERMINATION OF ACQUIRED IMMUNOLOGICAL TOLERANCE TO PROTEIN ANTIGENS FOLLOWING IMMUNIZATION WITH ALTERED PROTEIN ANTIGENS

1962 ◽  
Vol 116 (6) ◽  
pp. 913-928 ◽  
Author(s):  
William O. Weigle
Keyword(s):  
Antibody Production ◽  
Clonal Selection ◽  
Immunological Tolerance ◽  
The Other ◽  
Protein Antigens ◽  
Clonal Selection Theory ◽  
Altered Protein ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant ◽  
Tolerant State

Acquired tolerance to BSA in rabbits was terminated following the injection of certain preparations of altered BSA. Injections of Freund's adjuvant containing BSA complexed to anti-BSA, heat-denatured BSA, acetyl-BSA, picryl-BSA, or arsanil-BSA failed to terminate the tolerant state. Except in an occasional tolerant rabbit, injections of these preparations failed to cause the production of precipitating antibody to the altered preparation. Similar results were obtained following injections of alum-precipitated preparations of pepsin-degraded BSA, acetyl-BSA, and picryl-BSA. Injections of Freund's adjuvant containing sulfanil-BSA terminated the tolerant state, but only small amounts of non-precipitating anti-BSA were produced. Injections of Freund's adjuvant containing picryl-acetyl-BSA terminated the tolerant state in two of six rabbits, but again, only small amounts of non-precipitating anti-BSA were produced. Injections of an alum-precipitated preparation of picryl-acetyl-BSA failed to terminate the tolerant state. On the other hand, injections of Freund's adjuvant containing arsanil-sulfanil-BSA terminated the tolerant state in eleven of eleven rabbits and caused the production of precipitating anti-BSA in all nine of the rabbits tested. The tolerant state was terminated also in six of six rabbits injected with an alum-precipitated preparation of arsanil-sulfanil-BSA. Only one of these rabbits produced precipitating anti-BSA. In addition, the injection of BGG-tolerant rabbits with arsanil-BGG, sulfanil-BGG, or arsanil-sulfanil-BGG terminated the tolerant state. These results were discussed in relation to both the clonal selection theory of antibody production and autoimmunity.

scholarly journals CYT-0853, a Novel RAD51 Inhibitor, Modulates Immunoregulatory B-Lymphocytes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2330-2330
Author(s):  
Tamar Aprahamian ◽  
ED Keniston ◽  
Jane Branca ◽  
Muneer G Hasham ◽  
Melinda Day ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Antibody Production ◽  
Cytidine Deaminase ◽  
Autoreactive B Cells ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant

Activation Induced Cytidine Deaminase (AICDA/AID) is a DNA-directed cytidine deaminase that is normally only expressed in activated B-cells to promote somatic hypermutations and immunoglobulin class switching. In cancer cells, AID causes significant genotoxic stress through DNA replication fork damage, creating a dependency upon the homologous recombination repair factor, RAD51, for survival. We have demonstrated anti-cancer activity through disruption of this axis in multiple preclinical lymphoid cancer models. Autoreactive B cells depend on RAD51 for survival and are chronically auto-stimulated and therefore continually re-express AID. It has been shown that ectopic expression of AID in autoreactive B-cells causes genome-wide DNA damage (similar to cancers). Given the role of autoreactive B cells and autoantibodies in autoimmune disorders, we hypothesize that immunomodulation of B cells via the RAD51/AID axis will remediate inflammatory disease processes. Our previous data suggests that RAD51 modulation enhances the CD73+ B cell population and reduces antibody diversity in T1D mice, indicating precise effects on AID-mediated antibody diversification. CYT-0853 is a novel RAD51 inhibitor that sensitizes cells to AID activity. Here, we assessed the in vivo effect of CYT-0853 on primary B cells and antibody production. Wild-type C57BL/6 mice were treated with 40mg/kg CYT-0853 or vehicle for five weeks. One-week post-treatment start, mice were immunized with DNP-KLH antigen mixed with Complete Freund's Adjuvant. A second booster with DNP-KLH antigen mixed with Incomplete Freund's Adjuvant was administered two weeks later. At termination, blood, spleen, and bone marrow was collected for analysis by flow cytometry. Surface expression of CD45, CD19, IgM, and IgG1 was assessed to determine white blood cell count, B cells, and pre- and post-class switch recombination (CSR), respectively. While no significant changes to B cell populations were observed in bone marrow or spleen, we demonstrate that CYT-0853 significantly decreases the median number of circulating CD45+ and IgG1 (post-CSR) B cells (61.8% vs. 31.6% and 8.7% vs. 4.4%, respectively). In addition, we observed a modest, significant increase in the amount of IgM+ (pre-CSR) B cells. These results were complemented by an associated overall significant decrease in circulating IgM levels. Of note, no adverse effects were observed in these mice over this treatment period. Based on these data and the role of B cells not only in antibody production, but also as antigen-presenting cells in multiple sclerosis, we tested our molecule in the myelin oligodendrocyte glycoprotein35-55-experimental autoimmune encephalomyelitis model of multiple sclerosis. Prophylactic treatment using 40mg/kg CYT-0853 did not affect disease activity or circulating cytokine production, however we observed a significant decrease in the spleen. Based on these results, further exploration is warranted to harness the power of CYT-0853 on the AID/RAD51 axis. This specific targeting may elicit beneficial therapeutic changes to B-lymphocyte populations and provide a novel immunomodulatory target to treat immunity and inflammation. Taken together, these data provide a foundation for continued preclinical development of CYT-0853 with applicability towards autoimmune diseases. Disclosures Aprahamian: Cyteir Therapeutics: Consultancy. Day:Cyteir Therapeutics: Employment. Mills:Cyteir Therapeutics: Employment, Equity Ownership.

Nanodiamonds in Oil Emulsions as Effective Vaccine Adjuvants and Antitumor Therapeutic Agents

2021 ◽  
Author(s):  
Hsin-Hung Lin ◽  
Chih-Yen Wang ◽  
Feng-Jen Hsieh ◽  
Fang-Zhen Liao ◽  
Yu-Kai Su ◽  
...  
Keyword(s):  
Antibody Production ◽  
High Efficiency ◽  
Effective Vaccine ◽  
Vaccine Adjuvants ◽  
Immunological Responses ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant ◽  
Oil Emulsions ◽  
New Formulation ◽  
Therapeutic Activities

Abstract Background Vaccination is an effective tool to elicit immunological responses that mediate the protection from infection or disease. Composed of mineral oil and mycobacteria pathogens, complete Freund’s adjuvant (CFA) is one of the most commonly employed adjuvants for antibody production and vaccination due to its high efficiency. However, the dead mycobacteria in CFA can cause many allergic reactions. To avoid these adverse effects, we propose here a new formulation based on the use of nanodiamonds (NDs) as biocompatible non-allergic additives in incomplete Freund’s adjuvant (IFA) instead. ResultsTested with chicken egg ovalbumin (OVA) in mouse models, the new formulation with 100-nm NDs was found to serve well as a safe and potent vaccine adjuvant that significantly enhanced the immune responses and reduced the consumption of antigens in producing the antibodies of interest. Additionally, the composites showed distinct therapeutic activities, as proven by the OVA/ND/IFA treatment which effectively inhibited the tumor progression of OVA-expressing E.G7 cells inoculated in mice and allowed the animals to survive up to 35 days post tumor-cell challenges. ConclusionsThe dual functionality of ND/IFA makes it useful as adjuvants not only to increase antibody production but also to create single-dose vaccines.

Immunity in trypanosomiasis

Parasitology ◽  
1964 ◽  
Vol 54 (3) ◽  
pp. 585-591 ◽  
Author(s):  
M. A. Soltys
Keyword(s):  
The Other ◽  
Practical Application ◽  
Freezing And Thawing ◽  
Negative Results ◽  
Other Hand ◽  
Protective Antibodies ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant ◽  
Positive Results ◽  
Better Than

Success in immunizing rabbits, rats and sheep with dead trypanosomes depends on the method of killing trypanosomes, the frequency of inoculations, and the strain used for immunization. Positive results were obtained when trypanosomes were killed by formalin or by freezing and thawing five times. Negative results were obtained when trypanosomes were killed by 56° C. for half an hour.Animals which received 10 doses of the mixture produced better results than those which received the same amount but only in 2 doses. An addition of Freund's adjuvant improved results, but 10 doses without an adjuvant were still better than 2 doses with an adjuvant. When trypanosomes were killed by 0·5% formalin, only an M variant of T. brucei, which was maintained by frequent passage in mice and was an antibody-sensitive variant, was able to produce in animals protective antibodies and resistance to a homologous ‘M’ variant, but not to an ‘R’ variant. On the other hand, if an ‘R’ variant of the same strain, which was passaged forty-eight times through rabbits and became resistant to antibodies, was killed by 0·5 % formalin and inoculated into animals, no antibodies and resistance could be demonstrated to a homologous ‘R’ variant and an ‘M’ variant.Although it is possible to produce immunity in animals with dead trypanosomes further studies, particularly in the field, are necessary to find its practical application.

scholarly journals Frank Macfarlane Burnet, 3 September 1899 - 31 August 1985

1987 ◽  
Vol 33 ◽  
pp. 99-162 ◽  
Keyword(s):  
Influenza Virus ◽  
Experimental Work ◽  
Clonal Selection ◽  
Working Life ◽  
Immunological Tolerance ◽  
Viral Diseases ◽  
Critical Importance ◽  
Complete Understanding ◽  
Clonal Selection Theory ◽  
Ecological Principles

Frank Macfarlane Burnet was the greatest biologist that Australia has produced. He spent virtually all of a long working life in Australia. His experimental work on bacteriophages and animal viruses, especially influenza virus, resulted in major discoveries concerning their nature and replication, and he was a pioneer in the application of ecological principles to viral diseases. He proposed two concepts in immunology, acquired immunological tolerance and the clonal selection theory of antibody production, that proved to be of critical importance in stimulating research and led to a more complete understanding of immune processes. In the later stages of his life he wrote about problems of ageing and cancer.

scholarly journals A STUDY OF RABBIT γ-GLOBULIN ALLOTYPY BY MEANS OF HETEROIMMUNIZATIONS

1964 ◽  
Vol 120 (4) ◽  
pp. 655-676 ◽  
Author(s):  
Paul Bornstein ◽  
Jacques Oudin
Keyword(s):  
The Other ◽  
Precipitation Reaction ◽  
Simple Diffusion ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant ◽  
Precipitation Reactions ◽  
Constant Observation

Representatives of two species, the chicken and the goat, were immunized by injection with Freund's adjuvant, of specific precipitates prepared from the antisera of rabbits with various allotypic specificities. The precipitation reactions of the resulting antisera with normal rabbit sera were studied in liquid and in gellified media. In these reactions the isotypic specificity and often one or the other of the allotypic specificities of rabbit γ-globulin were involved. It was always easier to obtain antibodies against the specificities controlled by the alleles of locus b (Ab4, Ab5, Ab6) than of locus a (Aa1, Aa2, Aa3). The precipitation reaction of antibodies against a specificity of the a series could always be inhibited by an excess (nearly always moderate) of a serum lacking this specificity. A similar inhibition of the antibodies against the specificities of the b series was often impossible, especially if the antiserum had been collected after a second injection of immunizing material. The reactions of 58 Ab4+ sera with a goat anti-Ab4 serum and of 28 Ab5+ sera with a chicken anti-AbS serum were studied in gel tubes (simple diffusion). The constant observation of two precipitation zones due respectively to two types of molecules, Ab4+ and Ab4- (or Ab5+ and Ab5-), indicated the existence of an appreciable number of Ab4- or Ab5- molecules, even in supposed homozygotes. In the latter rabbits Ab4- or Ab5- molecules are b- molecules; i.e., molecules lacking the specificities of the b series. Measurements of the distances between the two zones in the reaction of 72 sera revealed significant differences between sera of individuals of the same phenotype, as well as systematic differences not only between sera of homozygotes and of heterozygotes, but also between heterozygotes of different genotypes. These measurements were used to evaluate the ratio of concentrations of the two types of molecules detected by each of the two antisera. The occurrence of b- molecules in every one of the fairly large number of sera studied indicates a new aspect of the heterogeneity of γ-globulin. Although detected by means of allotypy, this heterogeneity is not dependent upon factors which vary with individuals. These results are discussed in connection with what is known of the structure of γ-globulin.

Sign in / Sign up

Export Citation Format

Share Document