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Immune reconstitution after autologous haematopoietic stem cell transplantation for aggressive relapsing-remitting MS
J. Burman, J. Fagius, T.H. Tötterman, M. Fransson, S.M. Mangsbo, A.S.I. Loskog (Uppsala, SE)
Background: Autologous hematopoietic stem cell transplantation (HSCT) has been performed for multiple sclerosis (MS) since 1995. The aim of this therapy is to achieve long term disease remission through short lasting lymphoablation followed by a rebuild of a new immune system. Most patients remain free from inflammatory disease activity, even with long follow up. At our center we have seen patients with remission up to eight years after HSCT.
The mode of action is not yet fully understood. We hypothesised that the therapeutic efficacy of HSCT is related to the removal of auto-reactive clones, and/or to the restoration of tolerance to self-antigens. In this study we compared patients treated with HSCT, natalizumab (NTZ) and healthy controls.
Aim: This study had two aims, first to describe the frequency of memory T cells, Tregs, T helper type 1 (Th1) and T helper type 17 (Th17) cells after HSCT. Second, to explore if activation of T cells from MS patients by myelin oligodendrocyte glycoprotein (MOG) could be demonstrated and that this reactivity could be reversed by HSCT.
Methods: Patients that had undergone HSCT with the BEAM protocol for very aggressive relapsing remitting MS (RRMS) (n=12), or RRMS patients treated with NTZ (n=15) as well as healthy controls (n=9) were included in this study. HSCT-treated patients had a pre-treatment annualised relapse rate (AAR) of 1.9, with an increase in the number of relapses in the year prior to HSCT, reaching ARR >10 in some cases. White blood cells from patients were analysed with flow cytometry and supernatants from T cell cultures were analysed with Luminex.
Results: HSCT treated patients had similar levels of natural Tregs (defined as CD3+CD4+Foxp3+Helios+); Th1 and Th17 cells as controls, whereas NTZ treated patients had lower frequencies of natural Tregs; and higher frequencies of Th1 and Th17 cells.
There was no impact of myelin oligodendrocyte glycoprotein (MOG) antigen on T cell proliferation in either group but central memory T cells from NTZ-treated patients were activated by MOG. No such activation could be seen in the HSCT-treated group and controls.
Compared to T cells from NTZ treated patients, cells from HSCT treated patients cultured with MOG produced more TGF-beta suggestive of a Treg response. Conversely, T cells from NTZ patients more IL-17, IL-1 and IL-10 indicating a Th17 response.
Conclusion: We found evidence for the removal of auto-reactive clones as well as development of tolerance after HSCT.
J. Burman, J. Fagius, T.H. Tötterman, M. Fransson, S.M. Mangsbo, A.S.I. Loskog (Uppsala, SE)
Background: Autologous hematopoietic stem cell transplantation (HSCT) has been performed for multiple sclerosis (MS) since 1995. The aim of this therapy is to achieve long term disease remission through short lasting lymphoablation followed by a rebuild of a new immune system. Most patients remain free from inflammatory disease activity, even with long follow up. At our center we have seen patients with remission up to eight years after HSCT.
The mode of action is not yet fully understood. We hypothesised that the therapeutic efficacy of HSCT is related to the removal of auto-reactive clones, and/or to the restoration of tolerance to self-antigens. In this study we compared patients treated with HSCT, natalizumab (NTZ) and healthy controls.
Aim: This study had two aims, first to describe the frequency of memory T cells, Tregs, T helper type 1 (Th1) and T helper type 17 (Th17) cells after HSCT. Second, to explore if activation of T cells from MS patients by myelin oligodendrocyte glycoprotein (MOG) could be demonstrated and that this reactivity could be reversed by HSCT.
Methods: Patients that had undergone HSCT with the BEAM protocol for very aggressive relapsing remitting MS (RRMS) (n=12), or RRMS patients treated with NTZ (n=15) as well as healthy controls (n=9) were included in this study. HSCT-treated patients had a pre-treatment annualised relapse rate (AAR) of 1.9, with an increase in the number of relapses in the year prior to HSCT, reaching ARR >10 in some cases. White blood cells from patients were analysed with flow cytometry and supernatants from T cell cultures were analysed with Luminex.
Results: HSCT treated patients had similar levels of natural Tregs (defined as CD3+CD4+Foxp3+Helios+); Th1 and Th17 cells as controls, whereas NTZ treated patients had lower frequencies of natural Tregs; and higher frequencies of Th1 and Th17 cells.
There was no impact of myelin oligodendrocyte glycoprotein (MOG) antigen on T cell proliferation in either group but central memory T cells from NTZ-treated patients were activated by MOG. No such activation could be seen in the HSCT-treated group and controls.
Compared to T cells from NTZ treated patients, cells from HSCT treated patients cultured with MOG produced more TGF-beta suggestive of a Treg response. Conversely, T cells from NTZ patients more IL-17, IL-1 and IL-10 indicating a Th17 response.
Conclusion: We found evidence for the removal of auto-reactive clones as well as development of tolerance after HSCT.