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Gene & Protein in Disease Review of CAR-T in ADs

nephritis, can greatly affect the quality of life and safety receptor (CAR)-T therapy as a therapeutic strategy for
of affected individuals. 8,9 ADs.
ADs can be categorized into organ-specific ADs and 2. CAR-T cell therapy molecular mechanism
systemic ADs, depending on the extent of the associated
tissue damage. Organ-specific ADs involve the immune and development
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system attacking specific organs or tissues in the body, for The conventional clinical therapies for ADs include
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example, Type 1 diabetes (T1D), MG, RA, inflammatory glucocorticoids, non-steroidal anti-inflammatory drugs,
bowel disease (IBD), and multiple sclerosis (MS). In broad-spectrum immunosuppressants, and biological
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contrast, systemic ADs affect multiple areas of the body and agents. However, as these common treatments lack
6
include conditions such as SLE and Sjögren’s syndrome. 13 specificity, patients often experience disease relapses and
The development of ADs is driven by autoreactive T require lifelong medication, which can lead to systemic
cells and B lymphocytes that secrete autoantibodies. immunosuppression and an increased risk of infection
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During AD development, B lymphocytes generate and cancer. Recently, novel medications such as TNF
autoantibodies that target their tissues and organs, leading inhibitors, B cell-depleting agents, T cell co-stimulatory
to inflammation, tissue damage, and organ dysfunction. blockade inhibitors, anti-interleukin-6 (IL-6) agents,
For instance, in SLE, autoantibodies produced by B anti-IL-1 agents, and protein kinase inhibitors have
lymphocytes cause harm to various tissues and organs in been developed for localized treatment (biologics).
the body, including the skin, joints, and kidneys. 15 Notably, monoclonal antibodies targeting various B cell
subtypes and other abnormal cells in ADs have also been
Another significant factor in the development of ADs developed. 20,21 For example, rituximab, targeting CD20, has
is the involvement of autoreactive T cells. Specifically, demonstrated efficacy across various ADs. The half-life of
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T lymphocytes, a type of immune cell, typically regulate monoclonal antibodies varies depending on the dosage
and coordinate immune responses. However, in ADs, and frequency of administration. Typically, this half-life
autoreactive T lymphocytes may malfunction, mistakenly falls within the range of 1.6 – 20 days and may require
recognizing and attacking their tissues, leading to damage multiple doses during treatment to achieve the desired
and inflammation. An example of self-reactive T therapeutic effect, 22,23 which greatly limits the application
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lymphocyte-mediated AD is RA, in which T lymphocytes of monoclonal antibodies in ADs. In contrast, CAR-T cell
attack joint tissue, causing inflammation and pain. 18
therapy recognizes target antigens within the patient’s body,
The abnormal activity and dysfunction of B triggering their activation and subsequent amplification,
lymphocytes secreting autoantibodies, along with thereby enhancing their anti-disease efficacy. Importantly,
autoreactive T lymphocytes, are significant contributors to CAR-T cells exhibit good tissue penetration and a longer
the development of ADs. At present, treatment methods therapeutic effect, making them a promising avenue for the
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targeting B and T lymphocytes, including the use of management of ADs.
immunosuppressants, immunomodulators, and therapies
targeting specific cell surface markers, are being extensively 2.1. Composition of CAR-T cells
researched. CAR-T cells have CAR antigen binding selectivity and
Several mechanisms could be related to the development T cell cytotoxicity. They can grow extensively when coupled
of ADs: (i) Epitope spreading, wherein the immune with target cells and exhibit cytotoxic effects through
response switches from targeting primary epitopes to the release of granzymes and perforins. CAR T-cells can
targeting secondary epitopes or creating new epitopes on also trigger apoptosis within targeted cells by activating
antigen-presenting cells (APCs); (ii) bystander activation, apoptotic signaling pathways. Furthermore, cytokines
characterized by T cell receptor (TCR)-independent from CAR-T cells can stimulate various immune cells,
activation of autoreactive T cells; (iii) persistent viral resulting in synergistic effects that speed up the clearance
infections, in which the immune system is stimulated by of harmful cells. 24
the continuous presence of viral antigens; (iv) molecular The CAR comprises four parts: (i) the extracellular
mimicry, which occurs because of shared immune epitopes antigen-binding domain, (ii) the hinge region,
or sequence similarity, leading to cross-reactivity between (iii) the transmembrane domain, and (iv) the intracellular
host and pathogen; and (v) genetic factors. co-stimulatory domain. The extracellular antigen binding
The purpose of this study is to provide a foundation domain is a single-chain fragment variable (scFv)
for treatment improvements by conducting a systematic generated by a peptide link between the variable heavy
review of advancements in the field of chimeric antigen and variable light chains. This domain binds to the target

Volume 3 Issue 2 (2024) 2 doi: 10.36922/gpd.2851