OBJECTIVE: To define changes in phenotype and functional responses of reconstituting T cells in patients with aggressive multiple sclerosis (MS) treated with ablative chemotherapy and autologous haematopoietic stem cell transplantation (HSCT).
METHODS: Clinical and brain magnetic resonance imaging measures of disease activity were monitored serially in patients participating in the Canadian MS HSCT Study. Reconstitution kinetics of immune-cell subsets were determined by flow cytometry, whereas thymic function was assessed using T-cell receptor excision circle analyses as well as flow cytometry measurements of CD31+ recent thymic emigrants (RTEs). Functional assays were performed to track central nervous system-autoreactive antigen-specific T-cell responses, and the relative capacity to generate Th1, Th17, or Th1/17 T-cell responses.
RESULTS: Complete abrogation of new clinical relapses and new focal inflammatory brain lesions throughout the 2 years of immune monitoring following treatment was associated with sustained decrease in naive T cells, in spite of restoration of both thymic function and release of RTEs during reconstitution. Re-emergence as well as in vivo expansion of autoreactive T cells to multiple myelin targets was evident in all patients studied. The reconstituted myelin-specific T cells exhibited the same Th1 and Th2 responses as preablation myelin-reactive T cells. In contrast, the post-therapy T-cell repertoire exhibited a significantly diminished capacity for Th17 responses.
: Our results indicate that diminished Th17 and Th1/17 responses, rather than Th1 responses, are particularly relevant to the abrogation of new relapsing disease activity observed in this cohort of patients with aggressive MS following chemoablation and HSCT.
Haematopoeitic stem cell transplantation involves ablation of the immune response and then replacement of the recipients immune system, using in this case the donors own stem cells. This made the recipient. This is yet further clear evidence that the drivers of relapses in MS is due to the actions of the immune system.
New T cells develop from cells that are found in the thymus and they re-arrange their T cell receptors during this process. Recent T cells that leave the thymus gland express CD31-also express platelet cell adhesion molecule. In adult humans this gland usually becomes smaller as we have made most of the T cells and following immune ablation there were reduced production of T cells from the thymus. When the type of cells made in people following immune ablation it was found that there were similar levels of myelin-reactive Th1 (gamma interferon producers) and Th2 (intereluking four producers) cells as before therapy, however their were less Th17 (produce interleukin 17 and express interleukin 23 receptor). Implicating Th17 as a pivotal cell in MS relapse. Whilst the first question is, are myelin-reactive cells important? This study suggests yes and secondly it implicates Th17 and supports current dogma, so therapy against this subset of cells may be advantageous. Some companies have already developed interleukin 17-based therapies that could attack this cell type.