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Radiation Protection: Ribonucleic acid (RNA) Antiradiation vaccine or messenger
RNA (mRNA) Antiradiation vaccine.
Dmitri Popov
MD (Russia), PhD.
Advanced Medical Technologies and Systems Inc. Canada.
intervaccine@yahoo.com
Exposure to ionizing radiation (IR) causes severe injuries to the human body, and
normal tissue toxicity also limits the further application of cancer radiotherapy.
However, current clinically used radioprotective agents are difficult to produce
satisfactory effects. [10]
Toll-Like receptor (TLR) is a kind of pattern recognition receptor (PRR) that has
been extensively studied for radioprotection in recent years. Several TLR family
members are closely related to radioprotection. In cultured cells, TLR2, TLR5 or
TLR9 agonist was proved to inhibit radiation-induced apoptosis and increase cell
survival. [10]
TLR5 ligand CBLB502 was reported to alleviate bone marrow and intestinal
injuries in mice and rhesus monkeys. Activation of TLR4 by its agonist LPS can
protect bone marrow damage and lower mice mortality after irradiation. TLR9
ligand also exhibited protective effects on mid jejunum. [10]
Moreover, some kinds of TLR agonists, such as TLR2/6 co-agonist CBLB613,
were reported to be more effective in radioprotection than single TLR agonist.
[10].
In conclusion, TLRs and their ligands provide novel strategies for radiation
protection in nuclear accidents as well as protection of normal tissues during
cancer radiotherapy. [10]
Radiation therapy can enhance the expression of tumor-associated antigens, induce
immune-mediated targeting of tumor stroma, and diminish regulatory T cell
activity. Recent evidence suggests that radiation therapy may also activate
effectors of innate immunity through TLR-dependent mechanisms, thereby
augmenting the adaptive immune response to cancer. [11]
Although non-immune cells can potentially absorb vaccine mRNA, manufacture
spikes, and display spikes on their surfaces, dendritic cells absorb the mRNA
globules much more readily. [12]
Implications for Ribonucleic acid (RNA) Antiradiation vaccine or Messenger
RNA (mRNA) Antiradiation vaccine.
A ribonucleic acid (RNA) Antiradiation vaccine or messenger RNA (mRNA)
Antiradiation vaccine is a type of novel vaccine that uses a copy of a natural
molecule called messenger RNA (mRNA) to produce an immune response or
immunomodulate an immune response or suppress immune response.
The vaccine transfects molecules of synthetic RNA into immunity cells. Once
inside the immune cells, the vaccine's RNA functions as mRNA, causing the cells
to build non-self, proteins that would abnormally to be produced by irradiated
cells, or by a cancer cell. [2]
These protein molecules stimulate an adaptive immune response which teaches the
body how to identify and gradually destroy the irradiated cells with non-repairable
DNA or cancer cells. [12,13]
Usually, the delivery of mRNA is achieved by a co-formulation of the molecule
into lipid nanoparticles which protect the RNA strands and helps their absorption
into the cells.
Technology contain new, mRNA vaccines introduce a short-lived [8, 9,10]
synthetically created fragment of the RNA sequence of a non-self, radiation
induced antigen into the vaccinated individual. These mRNA fragments are taken
up by dendritic cells – a type of immune system cell – by phagocytosis. [8,9,10,11]
The dendritic cells use their own internal machinery (ribosomes) to read the
mRNA and produce the self-antigens that the mRNA encodes before destroying the
mRNA.[4]
Vaccines based on mRNA have dominated the headlines during the COVID-19
pandemic owing to their high efficacy and unprecedented speed of development
and manufacture.
In a recent paper in Science, U. Sahin, who led the development of a COVID-19
mRNA vaccine, and coauthors have now harnessed this vaccine technology to
suppress, rather than prime, antigen-specific immune responses [4,5,8,9]
Working with mouse models of multiple sclerosis, authors show that immunization
with a modified mRNA encoding a self-antigen and delivered in a non-
inflammatory lipoplex carrier leads to a dampening of autoimmunity through the
activation of antigen-specific regulatory T cells. [8,9]
Although further research is needed to assess the clinical potential of the
strategy, a successful tolerizing vaccination approach could transform the treatment
of Acute Radiation Syndromes and Chronic Radiation Disease. [8,9]
The ideal treatment for an autoimmune disease should specifically target
autoreactive cells, without the need for systemic immune suppression. Various
approaches to antigen- specific tolerization of autoreactive T cells have been
studied, with limited success. [7,8,9]
The authors had previously developed liposomal formulations of mRNA vaccines
(mRNA- LPX) that are optimized for the systemic delivery of mRNA- encoded
antigens to lymphoid tissue- resident CD11c+antigen- presenting cells (APCs).
Normally, mRNA vaccination induces strong T helper 1 (TH1) responses via the
activation of Toll- like receptors (TLRs). [9]
However, mRNA that contains1- methyl-pseudo-uridine (m1Ψ) instead of uracil
has strongly reduced inflammatory properties, because the modification abrogates
binding to TLR7. The authors hypothesized that vaccination with m1Ψ- modified
mRNA (m1Ψ mRNA- LPX) may allow for antigen- presentation by CD11c+
APCs in a non- inflammatory context and thereby induce antigen- specific
tolerance. [9]
Unlike vaccination with mRNA- LPX, m1Ψ mRNA- LPX did not induce
inflammatory cytokines or activate immune cells and allowed for higher and
prolonged antigen expression. [9]
Authors used modified mRNA and modified mRNA was tested in the experimental
autoimmune encephalomyelitis (EAE) model of multiple sclerosis. [9]
In this model, pathology is induced by immunizing mice with a peptide derived
from myelin oligodendrocyte glycoprotein (MOG35–55). [9]
Mice that were vaccinated with MOG35–55-encoding m1Ψ mRNA on days 7
and 10 after immunization with MOG35–55, were completely protected from
disease development. [9]
Vaccination of mice with established disease prevented further disease
Progression and in some cases even reverted pathology. [9]
The authors found that the treatment induced de novo FOXP3+ regulatory T (Treg)
cells and enhanced the expression of exhaustion markers such as PD1 and CTLA4
on antigen- specific CD4+ T cells. [9]
Importantly, it was also effective in models of EAE induced with a
different protein epitope (PLP139–151), indicating that the vaccination can
induce bystander tolerance. [9]
However, it did not affect immune responses to completely unrelated antigens.
A detailed analysis by single- cell sequencing showed that the m1Ψ mRNA vaccine
induces the specific suppression of disease- promoting TH1, TH17 and TH1/TH17
cells by effector Treg cells, rather than the deletion of autoreactive cells. [9]
This suppression appeared to be mediated by co- inhibitory molecules, as treatment
with PD1- targeted or CTLA4- targeted checkpoint inhibitors almost completely
abolished the protective effect of the vaccine. [9]
Although, in this example MOG35–55-encoding m1Ψ mRNA specific for peptide
derived from myelin oligodendrocyte glycoprotein (MOG35–55) induce specific
tolerogenic immune effect to particular auto-antigens, similar effects could be
achieved to auto-antigens isolated from cell-membranes of normal or irradiated
cells. [8]
DNA and RNA stimulate the mammalian innate immune system through activation
of Toll-like receptors (TLRs). DNA containing methylated CpG motifs, however, is
not stimulatory. Selected nucleosides in naturally occurring RNA are also
methylated or otherwise modified, but the immunomodulatory effects of these
alterations remain untested. [7]
Because multiple sclerosis is driven by several autoantigens, successful immune
tolerizing interventions in patients might require T reg cells that not only suppress
cognate autoreactive T cells but also mediate bystander suppression of autoreactive
T cells bearing other antigen specificities. [8]
Authors show that RNA signals through human TLR3, TLR7, and TLR8, but
incorporation of modified nucleosides m5C, m6A, m5U, s2U, or pseudo-uridine
ablates activity. [8]
Dendritic cells (DCs) exposed to such modified RNA express significantly less
cytokines and activation markers than those treated with unmodified RNA. [7,8,9]
DCs and TLR-expressing cells are potently activated by bacterial and
mitochondrial RNA, but not by mammalian total RNA, which is abundant in
modified nucleosides. Authors conclude that nucleoside modifications suppress the
potential of RNA to activate DCs. The innate immune system may therefore detect
RNA lacking nucleoside modification as a means of selectively responding to
bacteria or necrotic tissue. [7,8,9]
We considering for Antiradiation RNA vaccine several prospective peptides which
play the role of molecule inhibitors (SMIs), which are synthetic or naturally
derived biologically active agents with the activity to inhibit TLR signal
transduction. [16,17,18,19]
Their lipophilic packaging and small size allow them to cross cell membranes and
act on specific intracellular adapter proteins or compartments along
the TLR signaling pathways. [16,17,18,19]
References.
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radiation-induced normal tissue toxicity and implications for future clinical trials.
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5. Christina Krienke et al. A noninflammatory mRNA vaccine for treatment of
experimental autoimmune encephalomyelitis. Science. 08 Jan 2021:
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16. V Maliev, D Popov, R C Casey, J A Jones. Mechanisms of action for an anti-
radiation vaccine in reducing the biological impact of high dose and dose-rate, low-
linear energy transfer radiation exposure. Radiats. Biol. Radioecol. May-Jun
2007;47(3):286-91.
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Molecular Mechanisms of Action, Radiomimetic Properties and Possible
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vaccine in reducing the biological impact of high-dose gamma irradiation.
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linear energy transfer radiation exposure. Research Gate. February 2020.
DOI: 10.13140/RG.2.2.18158.77126 Project: Radiation Protection: Desensitization to
Radiation.