Monday, 17 February 2014

T-cell reconstitution after autologous stem cell transplant in patients with MS

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A new study by the Immune Tolerance Network (ITN) reveals that CD4+ and CD8+ lymphocytes exhibit different reconstitution patterns following autologous stem cell transplantation.

The study was carried out on 24 patients with relapsing, remitting multiple sclerosis (MS) received high-dose immunosuppression followed by a transplant of their own stem cells to potentially reprogram the immune system so that it stops attacking the brain and spinal cord.

The study, appearing in today's Journal of Clinical Investigation, quantified and characterized T cell populations following this aggressive regimen to understand how the reconstituting immune system is related to patient outcomes.

ITN investigators used a high-throughput, deep-sequencing technology (Adaptive Biotechnologies, ImmunoSEQTM Platform) to analyze the T cell receptor (TCR) sequences in CD4+ and CD8+ cells to compare the repertoire at baseline pre-transplant, two months post-transplant and 12 months post-transplant.

Using this approach, alongside conventional flow cytometry, the investigators found that CD4+ and CD8+ lymphocytes exhibit different reconstitution patterns following transplantation. The scientists observed that the dominant CD8+ T cell clones present at baseline were 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 findings also suggest the possibility that differences in repertoire diversity early in the reconstitution process might be associated with clinical outcomes. Nineteen patients who responded to treatment had a more diverse repertoire two months following transplant compared to four patients who did not respond. 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 immune tolerance.

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 provides a previously unseen in-depth analysis of how the immune system reconstitutes itself following immune-depleting therapy.

ITN is a research consortium sponsored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. ITN develops and conducts clinical and mechanistic studies of immune tolerance therapies designed to prevent disease-causing immune responses, without compromising the natural protective properties of the immune system. 

- Paolo A. Muraro1, Harlan Robins2, Sachin Malhotra, Michael Howell, Deborah Phippard, Cindy Desmarais, Alessandra de Paula Alves Sousa, Linda M. Griffith, Noha Lim, Richard A. Nash, Laurence A. Turka (2013). T cell repertoire following autologous stem cell transplantation for multiple sclerosis Journal of Clinical Investigation DOI: 10.1172/JCI71691

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