Cecil Staples

Introduction. Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease responsible for attacking myelinated sheaths of axons in the CNS.¹ This T cell mediated inflammatory disease currently does not have a known causative agent, but is thought to be a combination of genetic and environmental factors.^1,2 While T Helper Type 1 cells (Th1) were thought to be the culprit of this autoimmune response, newer research has indicated increased T Helper Type 17 cells (Th17) and decreased Regulatory T cells (Tregs) play a key role in MS.³ Due to this imbalance, researches are trying to ascertain the possibility of treating MS by increasing Tregs. Methods. In the first of these studies, 52 patients with MS who had not had prior treatment 8 weeks prior to having their blood drawn were enrolled in the study along with 22 healthy donors. They compared levels of CD4+ CD25+ FoxP3+ CD127low Treg cells using flow cytometry measuring those cellular markers.⁴ Once T cells were expanded ex vivo, levels were measured again using Flow Cytometry and PCR.⁴ Suppression capability was then measured by using T cells capable of expansion and exposing them to both healthy donor T reg cells and patient Treg cells created in ex vivo expansion.⁴ Numbers of proliferating cells were then measured.⁴ In the second study, 12 patients with MS who did not respond to other treatments for MS were recruited for non-myeloablative immunosuppressive conditioning with cyclophosphamide and alemtuzumab.⁵ The patients were followed for 2 years and compared against 40 other patients with MS, some receiving standard therapy and 7 healthy individuals. Results. Expanded ex vivo Tregs had almost 3-5 times expression of FoxP3 and doubled Helios expression.⁴ These ex vivo Tregs also showed demethylation levels of MS patients and donors that had no significant difference.⁴ Additionally these ex vivo Tregs showed a greater suppressive ability than those of peripheral Tregs.⁴ In the other study, there were significant increases in the level of CD4⁺ FoxP3⁺ T cells that are associated with immunoregulatory function.⁵ By returning balance of Treg and T cells, CNS inflammation was suppressed in MS patients.⁵ Conclusion. While the methods of achieving an increased Treg level were different, both of these studies exhibited the effect that normal Treg levels had on MS. The ability to grow Tregs with suppressive capability equal to that of healthy donors and restore Treg numbers is a treatment option that would help to suppress MS. Returning levels of regulatory T cells, Th17, and other effector T cells to normal levels effectively suppressed the autoimmune reaction in relapse-remitting Multiple Sclerosis for those patients undergoing the non-myeloablative immunosuppressive conditioning.

1. Goldberg M. Multiple Sclerosis Review. Pharmacy and Therapeutics. 2012;37(3):175-184.
2. Mcfarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nature Immunology. 2007;8(9):913-919. doi:10.1038/ni1507.
3. Noack MCA, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmunity Reviews. 2014;13(6):668-677. doi:10.1016/j.autrev.2013.12.004.
4. Lifshitz GV, Zhdanov DD, Lokhonina AV, et al. Ex vivo expanded regulatory T cells CD4 CD25 FoxP3 CD127Low develop strong immunosuppressive activity in patients with remitting-relapsing multiple sclerosis. Autoimmunity. 2016;49(6):388-396. doi:10.1080/08916934.2016.1199020.
5. Abrahamsson SV, Angelini DF, Dubinsky AN, et al. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain. 2013;136(9):2888-2903. doi:10.1093/brain/awt182