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Ann Neurol. 2012 Oct 11. doi: 10.1002/ana.23784. [Epub ahead of print]
Diminished Th17 (not Th1) responses underlie multiple sclerosis disease
abrogation after hematopoietic stem cell transplantation.
Darlington PJ, Touil T, Doucet JS, Gaucher D, Zeidan J, Gauchat D, Corsini R, Kim
HJ, Duddy M, Jalili F, Arbour N, Kebir H, Chen J, Arnold DL, Bowman M, Antel J,
Prat A, Freedman MS, Atkins H, Sekaly R, Cheynier R, Bar-Or A; for the Canadian
MS/BMT Study Group.
Neuroimmunology Unit, Montreal Neurological Institute, McGill University,
Montreal, Quebec, Canada.
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 hematopoietic 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.
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 chemoablation and HSCT. ANN NEUROL 2012;
Diminished Th17 (not Th1) responses underlie multiple sclerosis disease
abrogation after hematopoietic stem cell transplantation.
Darlington PJ, Touil T, Doucet JS, Gaucher D, Zeidan J, Gauchat D, Corsini R, Kim
HJ, Duddy M, Jalili F, Arbour N, Kebir H, Chen J, Arnold DL, Bowman M, Antel J,
Prat A, Freedman MS, Atkins H, Sekaly R, Cheynier R, Bar-Or A; for the Canadian
MS/BMT Study Group.
Neuroimmunology Unit, Montreal Neurological Institute, McGill University,
Montreal, Quebec, Canada.
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 hematopoietic 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.
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 chemoablation and HSCT. ANN NEUROL 2012;
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