Contributions
Abstract: P628
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: Total lymphocyte counts (TLC) usually reach 80% of pre-treatment values three months after fingolimod cessation. Here we examine the profile of T cell subsets in patients whose TLC return to baseline months after fingolimod cessation.
Methods: Five patients were followed for 2-3 months, and three of these patients were followed further up to 8-9 months post fingolimod cessation. TLC, CD4+ and CD8+ T cell counts were examined pre-treatment, on-treatment and at early and late time points following drug cessation. More detailed T-cell subset analysis was performed using flow cytometry of cryopreserved peripheral blood mononuclear cells; subsets included naïve (TN), central memory (TCM), effector memory (TEM), terminally differentiated effector memory (TEMRA), regulatory (Treg) and recent thymic emigrant (RTE) cells.
Results: At 2-3 months after fingolimod cessation, the CD4:CD8 ratio, which was reduced on treatment, was greater than 75% of baseline in four patients with pre-treatment comparators. The fingolimod-induced increase in TEM/TEMRA and reduction in TN frequencies had begun to reverse by this time point. However, a lower proportion of circulating cells were TN and a greater proportion were TEM compared to pre-treatment. At 8-9 months, TLC had returned to normal (1.22 - 2.13 × 109 cells/L) and were at least 90% of baseline. TLC reconstitution was predominantly due to an increase in CD4+ T cells (mean increase 621 ± 87 cells/µL, p=0.0064), the subset most depleted by fingolimod. Despite normalized CD4:CD8 ratios at month 8-9, the altered TN/TEM proportions had still failed to fully revert to baseline. Low RTE counts also tended to persist at month 8-9 (130 ± 9 cells/µL, n=3) compared with untreated patients (309 ± 41 cells/µL, n=16; p=0.0815).
Conclusions: Relative frequencies of circulating naïve and memory T cell subsets are altered during fingolimod treatment and may not return to pre-treatment levels for many months after cessation, even when clinical laboratory tests (TLC and CD4:CD8 ratios) return to normal. Whether this relates to prolonged sequestration in lymph nodes or altered turnover of the peripheral naïve T cells is unclear. Inhibition of thymic release of new T cells may underlie persistent low RTE counts. Prolonged alterations in the peripheral immune repertoire after fingolimod cessation may have implications for the timing and safety of commencing alternative MS therapies and warrant further study.
Disclosure: This study was supported in part by a grant from Novartis Pharmaceuticals Canada.
Dr Mahtab Ghadiri is a recipient of the BMRI/McGill University Multiple Sclerosis scholarship, funded by Novartis.
Leslie Fitz-Gerald: nothing to disclose.
Ayman Rezk: nothing to disclose.
Dr Rui Li: nothing to disclose.
Mukanthu Nyrirenda was supported by postdoctoral fellowships from the Multiple Sclerosis Society of Canada (EGID: 1655 and EGID: 2470).
Dr David Haegert: nothing to disclose.
Dr Paul Giacomini has received personal compensation for speaking, consulting, and advisory board participation from Allergan, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Novartis, Roche and Teva Neuroscience, has received research support from Biogen Idec and Teva Neuroscience, has been a consultant for NeuroRx Research, an imaging Contract Research Organization, and has acted as a principal investigator or sub-investigator for clinical trials for Alexion, Bayer HealthCare, Biogen Idec, Elan, EMD Serono, GlaxoSmithKline, Novartis, Ono, Roche-Genentech, Sanofi-Aventis and Teva Neuroscience.
Dr Jack Antel serves on advisory/safety monitoring boards for Novartis, Sanofi-Genzyme, Biogen Idec, EMD Serono and Medday Pharmaceuticals, and as editor of the Americas, Multiple Sclerosis Journal.
Dr Amit Bar-Or has participated as a speaker at meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, Guthy-Jackson/GGF, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, Sanofi-Genzyme, Teva Neuroscience, Wyeth.
Abstract: P628
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: Total lymphocyte counts (TLC) usually reach 80% of pre-treatment values three months after fingolimod cessation. Here we examine the profile of T cell subsets in patients whose TLC return to baseline months after fingolimod cessation.
Methods: Five patients were followed for 2-3 months, and three of these patients were followed further up to 8-9 months post fingolimod cessation. TLC, CD4+ and CD8+ T cell counts were examined pre-treatment, on-treatment and at early and late time points following drug cessation. More detailed T-cell subset analysis was performed using flow cytometry of cryopreserved peripheral blood mononuclear cells; subsets included naïve (TN), central memory (TCM), effector memory (TEM), terminally differentiated effector memory (TEMRA), regulatory (Treg) and recent thymic emigrant (RTE) cells.
Results: At 2-3 months after fingolimod cessation, the CD4:CD8 ratio, which was reduced on treatment, was greater than 75% of baseline in four patients with pre-treatment comparators. The fingolimod-induced increase in TEM/TEMRA and reduction in TN frequencies had begun to reverse by this time point. However, a lower proportion of circulating cells were TN and a greater proportion were TEM compared to pre-treatment. At 8-9 months, TLC had returned to normal (1.22 - 2.13 × 109 cells/L) and were at least 90% of baseline. TLC reconstitution was predominantly due to an increase in CD4+ T cells (mean increase 621 ± 87 cells/µL, p=0.0064), the subset most depleted by fingolimod. Despite normalized CD4:CD8 ratios at month 8-9, the altered TN/TEM proportions had still failed to fully revert to baseline. Low RTE counts also tended to persist at month 8-9 (130 ± 9 cells/µL, n=3) compared with untreated patients (309 ± 41 cells/µL, n=16; p=0.0815).
Conclusions: Relative frequencies of circulating naïve and memory T cell subsets are altered during fingolimod treatment and may not return to pre-treatment levels for many months after cessation, even when clinical laboratory tests (TLC and CD4:CD8 ratios) return to normal. Whether this relates to prolonged sequestration in lymph nodes or altered turnover of the peripheral naïve T cells is unclear. Inhibition of thymic release of new T cells may underlie persistent low RTE counts. Prolonged alterations in the peripheral immune repertoire after fingolimod cessation may have implications for the timing and safety of commencing alternative MS therapies and warrant further study.
Disclosure: This study was supported in part by a grant from Novartis Pharmaceuticals Canada.
Dr Mahtab Ghadiri is a recipient of the BMRI/McGill University Multiple Sclerosis scholarship, funded by Novartis.
Leslie Fitz-Gerald: nothing to disclose.
Ayman Rezk: nothing to disclose.
Dr Rui Li: nothing to disclose.
Mukanthu Nyrirenda was supported by postdoctoral fellowships from the Multiple Sclerosis Society of Canada (EGID: 1655 and EGID: 2470).
Dr David Haegert: nothing to disclose.
Dr Paul Giacomini has received personal compensation for speaking, consulting, and advisory board participation from Allergan, Bayer HealthCare, Biogen Idec, EMD Serono, Genzyme, Novartis, Roche and Teva Neuroscience, has received research support from Biogen Idec and Teva Neuroscience, has been a consultant for NeuroRx Research, an imaging Contract Research Organization, and has acted as a principal investigator or sub-investigator for clinical trials for Alexion, Bayer HealthCare, Biogen Idec, Elan, EMD Serono, GlaxoSmithKline, Novartis, Ono, Roche-Genentech, Sanofi-Aventis and Teva Neuroscience.
Dr Jack Antel serves on advisory/safety monitoring boards for Novartis, Sanofi-Genzyme, Biogen Idec, EMD Serono and Medday Pharmaceuticals, and as editor of the Americas, Multiple Sclerosis Journal.
Dr Amit Bar-Or has participated as a speaker at meetings sponsored by, received consulting fees and/or received grant support from: Amplimmune, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, Diogenix, Eli-Lilly, Genentech, GlaxoSmithKline, Guthy-Jackson/GGF, Merck/EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, Sanofi-Genzyme, Teva Neuroscience, Wyeth.