A group of researchers funded by the Immune Tolerance Network (ITN) revealed new insights regarding the effectiveness of immune-depleting therapy in patients with relapse-remitting multiple sclerosis. The work is detailed in the Journal of Clinical Investigations. Researchers took advantage of ImmunoSEQ, a high-throughput, deep-sequencing technology from Adaptive Biotechnologies, to analyze multiple sclerosis patients’ responses to autologous hematopoietic stem cell transplantation (HSCT). The goal of HSCT is to take an autoreactive immune system, wipe it clean, and reintroduce the patient’s own, altered cells to create a non-autoimmune compartment. Other studies that have used autologous HSCT and then evaluated cells of the “new” immune system relied on CDR3 spectratyping for T-cell receptor (TCR) clonal analysis, making it difficult to assess the before-and-after state of many patients. This study was able to use the high-throughput method to evaluate 24 patients inside of ITN’s HALT-MS phase II trial for poor-prognosis multiple sclerosis.
In the study, researchers took whole blood samples from patients and preserved their immune cells. Then, patients were given high-dose immunosuppressive therapy to eliminate their circulating T-cells. After, each patient received an infusion of his or her own preserved cells, and TCR repertoire was determined with ImmunoSEQ for three time points: pre-transplant, two months post-transplant, and twelve months post-transplant. Interestingly, the researchers found that CD4+ and CD8+ T-cells have different reconstitution patterns following transplantation. Whereas the pre-transplant CD4+ T-cells were undetectable at twelve months and were replaced by the new CD4+ T-cells, the pre-transplant CD8+ T-cells were dominant, suggesting that the CD8+ T-cells were not fully eradicated during immunosuppressive treatment. Such a response underscores the complexity of the immune system and provides insight on patterns of reconstitution.
Additionally, overall TCR diversity was associated with clinical outcome. Nineteen responders had a more diverse TCR repertoire early in the reconstitution process, and four non-responders had less diversity. From this study, the authors concluded, “These results demonstrate that TCR characterization during immunomodulatory treatment is both feasible and informative, and may enable monitoring of pathogenic or protective T-cell clones following HSCT and cellular therapies.”