China
Africa
Explore chapters and articles related to this topic
Immunologic Tolerance
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Clonal deletion appears to require some TCR-MHC interaction. It is hypothesized that T cells which have “high affinity” for self MHC are deleted since they are likely to generate harmful autoimmunity. On the other hand, cells with “low affinity” for self MHC, or MHC and peptide, are positively selected. The role of peptide in selective mechanisms is yet to be determined. It would seem likely that peptides are important beyond simply maintaining the structural integrity of MHC molecules. However, a plausible mechanism which accounts for observed data has not yet been developed. It has been speculated that antigen processing of self could have great influence on tolerance, since tolerance could only be expected to epitopes actually presented. Tolerance to a particular epitope of a self protein may be bypassed if other epitopes not presented in the thymus are presented in the periphery. It has been suggested that peptides which mimic foreign antigens are generated in the thymus via mistranscription of DNA and mistranslation of mRNA. This would provide a suitable substrate for positive selection with little risk of promoting autoimmunity.
Lupus erythematosus syndrome induced by drugs
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
T-cell immune responses require presentation of the antigen on the class II molecules of the major histocompatibility complex (MHC) expressed on antigen presenting cells, and most drugs are ignored by this peptide-based immune recognition machinery. However, if a drug or its metabolite can form a stable bond to self-molecules, a combined epitope generated by the drug–self-protein complex could be endocytosed, processed and presented on the MHC for recognition by receptors on T-cells. Presentation of a drug on the MHC could also occur by binding directly to the MHC through a non-covalent association.48 B-cell receptors would be able to interact with drug-altered macromolecules directly. Alternatively, B-cells within the microenvironment of a drug-specific T-cell response might become activated by cytokine-mediated bystander mechanisms.
Immunotherapy of Chronic Myeloid Leukemia
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
Bocchia Monica, Lauria Francesco
Another candidate for a peptide vaccine approach in CML is the Wilm’s tumor protein (WT-1)—a self protein overexpressed in most human leukemias, including CML and some solid tumors, but rarely present in normal cells (28). Recent studies have identified WT-1-specific CTLs in CML patients (29). Importantly, in vitro models have demonstrated that WT-1-specific CTLs deplete leukemic but not normal CD34+ stem cells (30) suggesting that they may be effective in eradicating the quiescent stem cells present in MRD. Additionally, intravenous injection of human T cells transduced with a WT-1 T-cell receptor into NOD/SCID mice harbouring human leukemia cells resulted in leukemia elimination (31).
The use of biologics in the treatment of autoimmune liver disease
Published in Expert Opinion on Investigational Drugs, 2020
Christopher Chang, Atsushi Tanaka, Christopher Bowlus, M. Eric Gershwin
There are, however, four mechanisms that have been proposed that can play a role in disruption of tolerance. These include molecular mimicry [3], bystander activation [4], epitope spreading, and viral persistence. Molecular mimicry occurs when there are similarities between self and foreign proteins. This leads to autoreactive T and B cells erroneously recognizing the self-protein as dangerous and mounting an immunological response to it. Bystander activation is a process by which T cells can be activated in the absence of normal T cell receptor stimulation, thus bypassing the normal immunoregulatory checkpoints. Epitopes are sites on the surface of an antigen to which antibody binds. Epitope spreading involves the ability of the immune system to respond to epitopes that are distinct from and non-cross reactive with the dominant epitope. It is generally the secondary cryptic epitopes that lead to the development of autoimmunity. These phenomena are not mutually exclusive and any of them or combination of them can lead to autoimmunity. Biological modifiers are usually in the form of a monoclonal antibody or fusion protein which is designed to target some of the pathways involved in the pathogenesis of autoimmunity.
De novo generation of specific human IgGs by in vitro immunization using autologous proteins containing immunogenic p-nitrophenylalanine
Published in mAbs, 2019
Yue Tong, Xu Fang, Hong Tian, Shengwei Zhong, Liang Jin, Xiangdong Gao, Wenbing Yao
We acknowledge that the antigen-specific B cell-response has obvious individual difference in our in vitro immunization system. In addition, sensitivity of naïve CD4+ T cells against antigen sensitization differs between donors. This is probably due to the great variety of human genetic background. Schultz et al.15 found that introduction of pNO2Phe at a particular site in self-antigens breaks tolerance in the context of a specific MHC. Moreover, Holmdahl et al.16 reported pNO2Phe-containing variants showed different immunogenicity in mice on different MHC II backgrounds. To clarify this issue, we plan to investigate more thoroughly the human MHC II locus restricted to pNO2Phe-containing self-antigens, leading to a more consistent and efficient antigen-specific B-cell response in our system. We can also introduce pNO2Phe into potential T cell epitopes through the analysis of bioinformatics software. Further, we can use genetic incorporation of pNO2Phe into more sites on a self-protein, creating a higher potency antigen with more universal immunogenicity.
Challenges related to the immunogenicity of parenteral recombinant proteins: Underlying mechanisms and new approaches to overcome it
Published in International Reviews of Immunology, 2018
Fatemeh Faraji, Zahra Karjoo, Maryam Vakili Moghaddam, Sahel Heidari, Reza Zolfaghari Emameh, Reza Falak
To show the differences between wild-type and modified epitopes in term of the immunogenicity, the transgenic mice strains are immunized with combination of peptide epitope and adjuvant. There is a direct correlation between T-cell responses in infected human individuals and T-cell responses in immunized HLA transgenic mice.67,68 Therefore, available HLA transgenic mice are now commonly used to evaluate and optimize human epitope driven vaccines in pre-clinical researches.54 Stewart et al.69 analysed the immunogenicity of an adjuvant on the wild and mutated type (containing one amino acid substitution) of recombinant human-tissue plasminogen activator (rhtPA) in transgenic mice. The results revealed that the adjuvant did not boost the immune reaction to the self-protein, while triggered a robust immune response to the mutated type of protein in mice. In this model, adjuvant just induced the classical immune responses.1