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The Inducible Defense System: The Induction and Development of the Inducible Defence
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Michael A. Hickey, Diane Wallace Taylor
If they find them, i.e, if the TcR on the cytotoxic T cell binds specifically to the peptide being presented by the Class I molecule, they are able to directly kill the cell. Cytotoxic T cells kill their target cell by making direct membrane to membrane contact with them (Figure 8.12). Then, within the zone of contact, they release molecules called perforin which polymerize to form a hollow ring or pore in the membrane of the target cell. The cytotoxic T cells then release several serine proteases, called granzymes, directly into the abnormal cell. These proteases break down the DNA in the cell, which causes the cell to die through a process called apoptosis. The DNA in the nucleus is broken down and the cell eventually breaks up into vesicles which are phagocytosed by macrophages. Thus, virus-infected cells are killed before the viruses can complete their replication and tumor cells are killed before they divide. Because cytotoxic T cells make direct, intimate contact with the target cells and directly release perforin and granzymes into them, only abnormal cells and not innocent by standard cells are killed.
Basics of Allergy
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Rafeul Alam, Dipa K Sheth, Magdalena M Gorska
CD8 T cells have two distinct mechanisms of cytotoxicity: perforin and Fas ligand (Fig. 1.3) (Russell and Ley 2002). Perforin is a membrane pore-forming molecule, which allows release of granular enzymes directly into the cytosol of the target cell. Granzyme B induces rapid apoptosis of the target cell through caspase-dependent and caspase-independent manners.
The Role of Nanoparticles in Cancer Therapy through Apoptosis Induction
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Marveh Rahmati, Saeid Amanpour, Hadiseh Mohammadpour
When cells are infected by viruses, the perforin/granzyme apoptosis pathway is initiated by cytotoxic lymphocytes to remove the infected cells. Perforin, also known as cytoplasmic granule toxin, is a kind of protein with a pore-forming ability in mitochondrial membrane. Granzyme is a serine protease protein, which contains cytotoxic granules of cytotoxic lymphocytes (CLs). Although, Granzyme is required for triggering apoptosis, it should be delivered appropriately by perforin. In humans, there are numerous granzymes including A, B, H, K, and M, but the Granzymes A and B are the most abundant enzymes that are involved in apoptosis. This pathway is initiated when granzymes could enter into target cells. This internalization is facilitated by perforin. Granzyme B activates pro-apoptotic BH3-interacting domain death agonist Bid, leading to the activation of CASP-3. Activated CASP-3 is subsequently able to proceed with executive apoptosis. Granzyme B can also inactivate MCL-1, which is a member of the anti-apoptotic BCL-2 family [36]. The granzyme A pathway is also involved in apoptosis via activating a parallel, caspase-independent cell death pathway through single-stranded DNA damage [37].
Engaging natural killer cells for cancer therapy via NKG2D, CD16A and other receptors
Published in mAbs, 2023
Kerry A. Whalen, Kavya Rakhra, Naveen K. Mehta, Alexander Steinle, Jennifer S. Michaelson, Patrick A. Baeuerle
Among immune cells, NK cells are most closely related to cytotoxic T cells. The latter encompasses T cell subsets, including CD8+ and CD4+ T cells, gamma-delta T cells, and natural killer T (NKT) cells, all of which contain cytotoxic granules filled with cysteine proteases, called granzymes, and a pore-forming protein called perforin. NK cells, NKT cells and gamma-delta T cells belong to the innate immune system and serve as a first line of defense against pathogens, while CD8+ and CD4+ T cells are elements of the adaptive immune system, which are highly specific for pathogenic antigens, but first need to be primed, selected, and expanded in response to peptide antigen stimuli.11 Like T cells, NK cells are cytotoxic by virtue of having secretory granules filled with the same granzymes and a variant of perforin.12 Once delivered into a cytolytic synapse formed between NK cell and target cell, perforin forms a pore in the target cell membrane that enables transmembrane delivery of granzymes. Inside the target cell, granzyme B activates pro-caspases 3 and 7, eliciting programmed cell death, or apoptosis, while other granzymes such as granzyme A, H, K and M cleave numerous other protein substrates, causing target cell damage.13 Like T cells, NK cells also release inflammatory cytokines and chemokines upon activation.14
Prospects for CAR T cell immunotherapy in autoimmune diseases: clues from Lupus
Published in Expert Opinion on Biological Therapy, 2022
Marko Radic, Indira Neeli, Tony Marion
Injection of a therapeutic antibody such as Rituximab relies on pharmacodynamic parameters for complete B cell depletion (Figure 1). The antibody, usually injected intravenously, must distribute through the blood stream and reach tissues, such as the kidney interstitium or the dermis. In tissues, the antibody must attain local concentrations that are sufficient to recognize and bind to B cell surface receptors. Upon injection, the MAb will begin to lose efficacy due to degradation, cellular uptake, or clearance from the body, each of which occurs with a typical exponential decay kinetics [41]. Further, antibodies that attach to the B cell must remain bound to their target antigen until recognized by Fc receptors on effector cells such as macrophage or natural killer cells, which initiate phagocytosis or cell killing [42]. Natural killer cells, like cytotoxic T cells, discharge granule contents that include perforin and granzymes and induce B cell death [43]. In addition, B-cell-bound IgG may trigger complement activation at the cell surface that leads to membrane disruption and cell lysis [44]. B cell depletion by an IgG, like Rituximab, will therefore be effective if at least one of these mechanisms is engaged in time before the MAb availability decreases below its effective nadir.
Immunotoxins and nanobody-based immunotoxins: review and update
Published in Journal of Drug Targeting, 2021
Mohammad Reza Khirehgesh, Jafar Sharifi, Fatemeh Safari, Bahman Akbari
For further deimmunising, human endogenous cytotoxic enzymes such as Granzyme B and RNase have been used in IT development. Granzyme B secretes from activated cytotoxic T-cells and natural killer cells. Translocation of Granzyme B into target cells leads to apoptosis induction [121–124]. Another strategy to reducing the immunogenicity of ITs is PEGylation, attaching polyethylene glycol to the target molecules. However, ITs PEGylation leads to reduced binding affinity and increased size [125,126]. Vascular leak syndrome (VLS) is one of the common side effects and dose-limiting toxicity of ITs. VLS is characterised by increased vascular permeability accompanied by extravasation of fluids and proteins, resulting in interstitial edoema and organ failure [127]. The conserved motif exists in RTA, PE and IL2 that induces VLS via binding to the endothelial cells [128]. Removing the motif may prevent VLS induction in IT therapy.