Contributions
Abstract: P1148
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: Fingolimod (FTY), one of the treatments used in multiple sclerosis (MS), is active through the retention of B and T cells in peripheral lymph nodes, reducing access of activated T cells to the central nervous system (CNS). Strikingly, FTY has been associated with the reactivation of herpes viruses and five cases of progressive multifocal leukoencephalopathy (PML). One hypothesis is that the reactivation of these viruses in the CNS would be related to a suboptimal immune surveillance induced by FTY.
Objective: To assess the role of FTY on the tissue trafficking profile and function of T cells ex vivo in a four-year observation period.
Methods: We enrolled 29 MS patients under FTY, 14 under natalizumab (NTZ), and 11 under other treatments. Blood draws were done before treatment onset (T0) and after 6, 12, 24 and 48 months
(T6, T12, T24, T48, respectively). The ex vivo expression of homing molecules to: 1. the CNS (CD49d, CD29, CD11a); 2. the skin (CCR4, CCR10); and 3. the gut (CD49d, β7) was assessed using flow cytometry, gating on CD4+ and CD8+T cells. Adhesion profiles of CD3+ T cells were measured in vitro with integrin ligands (VCAM-1, ICAM-1, MAdCAM-1; specific ligands of VLA-4, LFA-1 and α4β7, respectively) in a selected number of patients before and after 12 and 48 months (n=6-10 patients per group).
Results: We demonstrate first that FTY sustains a reshuffling of the T cell migration profile over the whole treatment duration. Indeed, FTY doubles the frequency of VLA-4 (CD49d+CD29+) and LFA-1 (CD11ahigh)-expressing CD4+ and CD8+ T cells, and almost triples the frequency of skin-related CCR4+CCR10+CD4+ T cells. However, under FTY, there is a decrease of T cells able to migrate to the gut (α4β7). These phenomena are directly related to the retention of TN and TCM in secondary lymphoid organ. However, and of high interest, we observed, already at T12, a drop in CD3+ T cell adhesion to VCAM-1 (p=0.027) and to MAdCAM-1 (p=0.008) but not to ICAM-1 (p=0.57), after FTY onset. This profile strikingly resembles what was detected in NTZ-treated MS patients.
Conclusions: Despite the elevated relative frequency of CNS-related T cells expressing VLA-4, the function of this integrin is impaired under FTY. Thus, the dysfunction of VLA-4 integrin, a major player for T cells entrance into the CNS to perform immune surveillance, could contribute to explain the occurrence of CNS viral infections such as PML.
Disclosure:
Mathias A.: nothing to disclose
Perriot S.: nothing to disclose
Canales M.: nothing to disclose
Gaubicher C.: nothing to disclose
Engelhardt B.: nothing to disclose
Schluep M. has served as a consultant for Merck-Serono, has received honoraria, payment for development of educational presentations and travel support from Biogen-Idec, Genzyme, Merck-Serono, Novartis, and Sanofi-Aventis.
Du Pasquier R. has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva, and has received funding for travel or speaker honoraria from Biogen Idec, Teva, Merck Serono, and Genzyme.
Source of funding: Investigator-initiated trial (Novartis), Swiss National Foundation 320030_159997.
Abstract: P1148
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: Fingolimod (FTY), one of the treatments used in multiple sclerosis (MS), is active through the retention of B and T cells in peripheral lymph nodes, reducing access of activated T cells to the central nervous system (CNS). Strikingly, FTY has been associated with the reactivation of herpes viruses and five cases of progressive multifocal leukoencephalopathy (PML). One hypothesis is that the reactivation of these viruses in the CNS would be related to a suboptimal immune surveillance induced by FTY.
Objective: To assess the role of FTY on the tissue trafficking profile and function of T cells ex vivo in a four-year observation period.
Methods: We enrolled 29 MS patients under FTY, 14 under natalizumab (NTZ), and 11 under other treatments. Blood draws were done before treatment onset (T0) and after 6, 12, 24 and 48 months
(T6, T12, T24, T48, respectively). The ex vivo expression of homing molecules to: 1. the CNS (CD49d, CD29, CD11a); 2. the skin (CCR4, CCR10); and 3. the gut (CD49d, β7) was assessed using flow cytometry, gating on CD4+ and CD8+T cells. Adhesion profiles of CD3+ T cells were measured in vitro with integrin ligands (VCAM-1, ICAM-1, MAdCAM-1; specific ligands of VLA-4, LFA-1 and α4β7, respectively) in a selected number of patients before and after 12 and 48 months (n=6-10 patients per group).
Results: We demonstrate first that FTY sustains a reshuffling of the T cell migration profile over the whole treatment duration. Indeed, FTY doubles the frequency of VLA-4 (CD49d+CD29+) and LFA-1 (CD11ahigh)-expressing CD4+ and CD8+ T cells, and almost triples the frequency of skin-related CCR4+CCR10+CD4+ T cells. However, under FTY, there is a decrease of T cells able to migrate to the gut (α4β7). These phenomena are directly related to the retention of TN and TCM in secondary lymphoid organ. However, and of high interest, we observed, already at T12, a drop in CD3+ T cell adhesion to VCAM-1 (p=0.027) and to MAdCAM-1 (p=0.008) but not to ICAM-1 (p=0.57), after FTY onset. This profile strikingly resembles what was detected in NTZ-treated MS patients.
Conclusions: Despite the elevated relative frequency of CNS-related T cells expressing VLA-4, the function of this integrin is impaired under FTY. Thus, the dysfunction of VLA-4 integrin, a major player for T cells entrance into the CNS to perform immune surveillance, could contribute to explain the occurrence of CNS viral infections such as PML.
Disclosure:
Mathias A.: nothing to disclose
Perriot S.: nothing to disclose
Canales M.: nothing to disclose
Gaubicher C.: nothing to disclose
Engelhardt B.: nothing to disclose
Schluep M. has served as a consultant for Merck-Serono, has received honoraria, payment for development of educational presentations and travel support from Biogen-Idec, Genzyme, Merck-Serono, Novartis, and Sanofi-Aventis.
Du Pasquier R. has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva, and has received funding for travel or speaker honoraria from Biogen Idec, Teva, Merck Serono, and Genzyme.
Source of funding: Investigator-initiated trial (Novartis), Swiss National Foundation 320030_159997.