Plasmapheresis Improves the Suppressive Function of Regulatory T Cells in Patients with Fast-Progressing Amyotrophic Lateral Sclerosis (P3.183)

Objective: To determine whether plasmapheresis restores regulatory T cell (Treg) suppressive function and lowers the levels of pro-inflammatory factors in patients with fast-progressing amyotrophic lateral sclerosis (ALS). Background: Tregs become dysfunctional with respect to their suppressive capabilities in ALS. Their degree of dysfunction correlates with the extent and rapidity of the disease. Tregs isolated from fast-progressing ALS patients regain their suppressive ability when expanded ex vivo (unpublished observation). This suggests that soluble factors in the blood may trigger Treg dysfunction, and raises the question as to whether such factors can be effectively removed by plasmapheresis. Experiments performed decades ago indicated that plasmapheresis did not alter the long-term clinical course in ALS. Here, we test the hypothesis that removing soluble factors enhances Treg suppressive function and mediates short-term clinical benefit. Methods: This study has been approved by the Institutional Review Board and is currently ongoing in patients with fast-progressing ALS. Patients undergo 3 sessions of plasmapheresis in one week, followed by a 3-week off period, and then 3 more sessions of plasmapheresis. Before and after each week of plasmapheresis, clinical assessments are performed and blood samples are obtained. The suppressive capabilities of isolated Tregs are assessed on the proliferation of T effector cells. T-lymphocytes and their FoxP3 protein expression are assessed by flow cytometry. Pro-inflammatory factors are measured by ELISA. Results: In preliminary studies, plasmapheresis improved the suppressive function and increased the percentage of Tregs. Levels of TNFα, IFNγ, IL-8, soluble TNF receptor 2, soluble CD14, and lipopolysaccharide-binding protein clearly changed following plasmapheresis, possibly contributing to a brief plateauing of clinical status in patients on a rapid decline. Conclusions: Plasmapheresis appears to transiently improve Treg suppressive function and increase the percentage of Tregs. These data suggest that soluble factors in the blood contribute to impaired Treg suppressive capability. Disclosure: Dr. Thonhoff has nothing to disclose. Dr. Beers has received research support from Glaxo Smith Kline. Dr. Zhao has received research support from GlaxoSmithKline. Dr. Wen has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Lay has nothing to disclose. Dr. Thompson has nothing to disclose. Dr. Leveque has nothing to disclose. Dr. Appel has received research support from Neuraltus, Inc., and GlaxoSmithKline.