The development of anti-PD-1 antibody-induced spinal cord injury in bone marrow transplant C57BL/6 <i>Rag1^-/-</i> mouse model

<b>Aims:</b> This paper was to scrutinize the toxicity mechanism of anti-programmed death 1 (anti-PD-1) therapy-caused spinal cord injury (SCI). <b>Methods:</b> Bone marrow transplant <i>Rag1^−/−</i> mice were used to establish SCI model. <b>Results:</b> Anti-PD-1 results in SCI via CD8⁺ T-cells activation, while excessive activation of CD8⁺ T-cells further aggravated SCI. Both anti-PD-1 and the activation of CD8⁺ T-cells induced the expression of apoptosis-related perforin, GrB and FasL, but suppressed PI-9 level. The opposite results were observed in the effects of neuroserpin on these factors. CD8⁺ T-cells activation induced neurotoxicity via upregulation perforin, GrB and FasL and inhibiting PI-9. Additionally, neuroserpin suppressed CD8⁺ T-cells activation via perforin/GrB/PI-9/FasL pathways. <b>Conclusion:</b> These results may provide theoretical foundation for the clinical treatment of SCI caused by anti-PD-1. In the process of treating cancer, immune checkpoint inhibitors such as anti-programmed death 1 (anti-PD-1) therapy, as a form of immunotherapy, have developed rapidly and changed the way to manage cancers significantly. However, some cancer patients who receive immune checkpoint blockade treatment suffer from severe adverse effects including spinal cord injury (SCI). This article for the first time constructed a bone marrow transplant mouse model to explore the toxicity mechanism of anti-PD-1 therapy-caused SCI. We found that anti-PD-1 therapy can induce the activation of immune cells, while immune cell activation further promotes self-destruction of nerve cells by regulating cell death pathways. The mechanism of anti-PD-1 therapy-caused SCI is to activate of immune cells through regulating cell death pathways, thereby inducing self-destruction of nerve cells. These findings provide theoretical foundation for the clinical treatment of SCI caused by anti-PD-1 therapy. The ratio of CD3⁺CD8⁺ T-cells was significantly increased in three randomly selected bone marrow transplant <i>Rag1^−/−</i> mice. Basso Mouse Scale for Locomotion score in the spinal cord injury (SCI) model group was lowered significantly and further decreased in SCI exacerbation group. While was restored in the SCI treatment group. Anti-programmed death 1 (anti-PD-1) therapy could induce the activation of CD8⁺ T-cells, while administration of neuroserpin suppressed CD8⁺ T-cells activation. Anti-PD-1 therapy or naive CD8⁺ T-cells combination with anti-PD-1 therapy increases the levels of perforin, FasL and GrB, but decreases PI-9 level, while treatment with neuroserpin reverses the expression of these factors. Some limitations of this research remain exist such as confirming the number of T- and B-cells in <i>Rag1</i>^-/- mice and measuring the percentages of other immune cells except for CD8⁺ T-cells. Even so, this study also provides a theoretical basis for the clinical treatment of anti-PD-1 therapy-induced SCI to a certain extent.