Epub: Darlington PJ et al. Diminished Th17 (not Th1) responses underlie MS disease abrogation after HSCT Annal Neurol 2012 DOI: 10.1002/ana.23784.
Objective: To define changes in phenotype and functional responses of reconstituting T cells in patients with aggressive MS treated with ablative chemotherapy and autologous hematopoietic stem cell transplantation (HSCT).
Methods: Clinical and brain MRI 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, while thymic function was assessed using T cell receptor excision-circle (TREC) analyses as well as flow cytometry measurements of CD31+ recent thymic emigrants (RTE). Functional assays were performed to track CNS-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 two years of immune monitoring following treatment was associated with sustained decrease in naïve T cells, in spite of restoration of both thymic function and release of RTE 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 pre-ablation myelin reactive T cells. In contrast, the post-therapy T-cell repertoire exhibited a significantly diminished capacity for Th17 responses.
Interpretation: 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 chemo-ablation and HSCT.
We have talked about TH1 and TH17 cells in a previous educational post, this study reports on T cell responses to myelin after replacement of the immune system. This treatment prevents further relapsing disease further showing that relapsing disease is driven by the effects of the immune system. That myelin-reactive Th17 did not return indicates that this is the important T cell subset as reported to be the case in animal studies. Therefore therapies to target the Th17 subset may be beneicial, there is some supportive data on this based on recent trials in MS.