5. T CELLS AS THERAPEUTIC TARGET
The modulation of T cell-mediated immune response is of particular
interest in diseases such as MS, where successful first-line
immunotherapies and monoclonal antibody therapies, such as Natalizumab,
are used to treat patients with severe symptoms (Warnke et al., 2010).
Natalizumab targets the α4β1 integrin on T cells, preventing them from
binding to VCAM1 on BBB endothelial cells and entering the CNS. This is
demonstrated by the marked decrease in various T cell populations in the
CSF of MS patients treated with natalizumab compared to controls (Stuve
et al., 2006). However, treatment with this antibody in these patients
can result in various immune deficiencies, such as opportunistic
infections and leukoencephalopathies (Warnke, Olsson & Hartung, 2015).
The sphingosine 1-phosphate receptors (S1PRs) S1PR1, S1PR3, S1PR4, and
S1PR5 are expressed in many cell types, including lymphocytes and
endothelial cells. They play a crucial role in regulating biological
processes, such as lymphocyte trafficking and vascular permeability. The
use of S1PR modulators, such as Fingolimod, Siponimod, Ozanimod, or
Ponesimod, which are approved for the treatment of MS, helps to reduce
the trafficking of immune cells to the CNS (Mapunda, Tibar, Regragui &
Engelhardt, 2022). However, due to the multifactorial nature of this
autoimmune disease, it is important to continue searching for new
autoantigens to provide more targeted and effective treatments with
minimal side effects.
The regulation of the immune response can also be of interest in
diseases other than those with a clear immunological component. In the
case of AIS, preclinical approaches aim to alleviate its adverse
effects, such as using monoclonal antibodies like anti-VLA4, which
blocks CD49d (Liesz et al., 2011) or FTY720/Fingolimod, an agonist of
S1P1 receptors (Salas-Perdomo et al., 2019). These aim to prevent immune
cells from infiltrating the CNS. Regulators of immune homeostasis, such
as Vitamin D and Resveratrol, which regulate PPARγ function (Matsuura,
Egi, Yuki, Horikawa, Satoh & Akira, 2011), as well as modulators of the
intestinal microbiota (Dou, Rong, Zhao, Zhang & Lv, 2019), like sodium
butyrate and valproic acid, have been shown to reduce infarct size and a
decrease in cognitive impairment.
The regulation of T cell-mediated responses in AD is not well explored
compared to other pathologies. While some preliminary studies have
investigated the use of monoclonal antibodies against Aβ peptides and
phosphorylated Tau protein (Wisniewski & Goni, 2015), and early-stage
clinical trials aimed at restoring the suppressive activity of Treg
cells by expanding them ex vivo (Faridar et al., 2020), a deeper
understanding is needed to effectively implement these therapies. The
APOE protein is an important modulator of T cell response and a powerful
risk factor in AD, making it an interesting target for regulating
abnormal T cell activation in this pathology.
The contribution of T cells to the development of PD has been well
established, leading to the development of numerous neuroprotective
therapies that show a T cell-mediated mechanism (Table 2). Specifically,
increasing the number or function of Tregs has been shown to be
effective in providing neuroprotection in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model
of PD. The recognition of the immune response’s role in PD opens up new
opportunities for diagnosis and treatment. Identifying individuals with
HLA alleles that increase their risk for specific α-synuclein-specific T
cells could lead to early diagnosis and treatment. Additionally, these
clonal T cells could be used as early biomarkers of disease, identifying
self-protein autoimmunity before motor symptoms develop. One promising
avenue of treatment is Sargramostim, a granulocyte-macrophage
colony-stimulating factor, which has been used to treat patients
receiving bone marrow transplants or undergoing cancer treatment, by
promoting myeloid recovery and inducing Treg responses. Results from a
phase I clinical trial show that patients receiving the drug showed
improvement after 6-8 weeks of treatment, with increased numbers and
function of Tregs compared to patients receiving a placebo. Additional
clinical research will shed light on the potential of immunomodulatory
drugs for the treatment of PD (Garretti, Agalliu, Lindestam Arlehamn,
Sette & Sulzer, 2019).