The promise of autologous stem cell transplantation in patients with autoimmune disease is that the newly reconstituted immune system will be reset in a way that no longer favors autoimmunity. The ITN’s HALT-MS study (High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis) used high-dose immunosuppression followed by an autologous stem cell transplant in 24 relapsing, remitting multiple sclerosis (MS) patients in an attempt to reconstitute a healthy immune system. To better understand the post-HSC transplanted immune system, ITN investigators used a high-throughput, deep-sequencing technology (Adaptive Biotechnologies, ImmunoSEQTM Platform) to compare the T cell repertoire at baseline, 2 months post-transplant, and 12 months post-transplant. This is one of the first studies to quantitatively compare the baseline T cell repertoire with the reconstituted repertoire following autologous stem-cell transplant, and has provided a heretofore unseen in-depth analysis of how the immune system reconstitutes itself following lympho-ablative therapy. The results are published today online in the Journal of Clinical Investigation.
The investigators found that CD4+ and CD8+ lymphocytes exhibit different reconstitution patterns following transplantation. The dominant CD8+ T cell clones present at baseline were found to be expanded at 12 months post-transplant, suggesting these clones were not effectively eradicated during treatment. In contrast, the dominant CD4+ T cell clones present at baseline were undetectable at 12 months, and the reconstituted CD4+ T cell repertoire was predominantly comprised of new clones.
The results also suggested the possibility that differences in repertoire diversity early in the reconstitution process might be associated with clinical outcomes. Patients who responded to treatment (n=19) had a more diverse repertoire at 2 months following transplant compared to those who did not respond (n=4). Despite the low number of non-responders, these comparisons approached statistical significance and point to the possibility that complexity in the T cell compartment may be important for establishing tolerance.
Overall this work demonstrates with detail the effects of autologous stem cell transplantation on T cell reconstitution, and that repertoire diversity following reconstitution may have implications for disease outcomes.