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).