Mahita Nuthalapati

Background: Following a TBI, the processes which result in prolonged cognitive and behavioral deficits, along with progression of the chronic neurodegeneration remain unclear. According to the CDC, these injuries often go unreported, untreated, and are particularly concerning for younger patients susceptible to experiencing chronic neurologic deficits which can progress into disabilities. It is well-recognized in the literature for the chronic impairments to be a result of prolonged neuroinflammation in the months after the injury.¹

Objective: This study explores three avenues of treatment, T-cell knockout, inflammatory marker modulation, and T-reg cell amplification.

Search Method: An online search in the PubMed database published within the last 5 years with the following key words: “immune response”, “TBI”, “adaptive immune response”.

Results: Cytotoxic T-cell knockout experiments demonstrate reduced pathology at 8 and 32 weeks as measured by myelin vacuolization and improved neurologic outcomes compared to WT or CD4+ knockout mice.¹ Injection of CD8+ neutralizing monoclonal antibodies 4 weeks after injury also yields improved cognitive and behavioral outcomes, therefore this treatment model can be applicable to human TBI therapy.¹  ST2 receptor knockout group displayed increased severity of injury marked by lesion size and behavioral deficits compared to WT CCI mice.² Amplifying the IL-33/ST2 response displays anti-inflammatory properties, alleviating chronic TBI effects.² Interfering with the IL-33/ST2 axis displayed decreased amounts of IL-10 and TGF-beta, both anti-inflammatory markers.² It is important to note the IL-33 concentrations were elevated in the CNS and systemically ², therefore targeting this pathway may have undesired effects in a human model. Knockout other than CD8+ T-cells yielded the same or poorer results than the non-treated TBI group.¹ The results strongly suggest that B-cells and autoantibodies play a role in neuroprotection and modulate pro-inflammatory activity. ¹ WT and CD4+ knockout TBI group exhibited lower circulating IL-13 levels compared to uninjured mice whereas increasing IL-13/ST2 stimulation exhibited improved outcomes measures be anti-inflammatory markers and lesion size.² The above pathway was noted to have increased T-reg cell activity, making it a component of neuroprotection and potential target for improved TBI outcomes.² T-Reg cells harvested from umbilical cord blood were injected and studied at several dosages. Higher doses exhibited lower levels of IFN-gamma, lower microglial activation, and improved BBB permeability.⁴ These results became significant between the 7 and 30 day time points, reflecting the long-term TBI effects related to immune associated neurodegeneration.⁴ This study displayed the potential to increase the functions of T-reg cells to improve neuroprotection post-TBI.⁴   Cordyceps treatment group displayed improved anti-inflammatory markers, lower microglial and macrophage activation, less white matter atrophy, and improved BBB compared to non-treatment group.⁵ Treatment group also had a lower concentration of pro-inflammatory markers such as IL-10.⁵

Conclusion: Overall, current treatment for TBI is grossly limited to conservative management of the patient’s symptoms There is obvious pre-clinical evidence which needs to be adapted into human Clinical Trials, however, many proposed trials have been withdrawn or incomplete. Regarding the previously discussed mechanisms, the modulation of immune response needs to be better contained to the CNS, or treatment protocols need to consider isolation in order to prevent iatrogenic illnesses.

Works Cited:

1. Daglas M, Draxler DF, Ho H, et al. Activated CD8(+) T Cells Cause Long-Term Neurological Impairment after Traumatic Brain Injury in Mice. Cell Rep . Oct 29 2019;29(5):1178-1191 e6. doi:10.1016/ j.celrep.2 019.09.046
2. Xie D, Miao W, Xu F, et al. IL-33/ST2 Axis Protects Against Traumatic Brain Injury Through Enhancing the Function of Regulatory T Cells. Front Immunol . 2022;13:860772. doi:10.3389/fimmu.2022.860772
3. Buenaventura RG, Harvey AC, Burns MP, Main BS. Traumatic brain injury induces an adaptive immune response in the meningeal transcriptome that is amplified by aging. Front Neurosci . 2023;17:1210175. doi:10.3389/fnins.2023.1210175
4. Caplan HW, Prabhakara KS, Kumar A, et al. Human cord blood-derived regulatory T-cell therapy modulates the central and peripheral immune response after traumatic brain injury. Stem Cells Transl Med . Aug 2020;9(8):903-916. doi:10.1002/sctm.19-0444
5. Wei P, Wang K, Luo C, et al. Cordycepin confers long-term neuroprotection via inhibiting neutrophil infiltration and neuroinflammation after traumatic brain injury. J Neuroinflammation . Jun 15 2021;18(1):137. doi:10.1186/s12974-021-02188-x