During immune reconstitution post-transplantation we observed significant though transient increases in the proportion of CD4+FoxP3+ T cells (T regulatory cells that prevent autoimmunity) and natural killer cell subsets, which are cell subsets associated with immunoregulatory function. CD8+,CD57+cytotoxic T cells were persistently increased after therapy and were able to suppress CD4+ T cell proliferation with variable potency. In contrast, a proinflammatory CD8+, CD161 T cell subset was depleted at all time-points post-transplantation. Phenotypic characterization revealed that the CD161, CD8+ T cells were mucosal-associated invariant T cells, a novel cell population originating in the gut mucosa but expressing the central nervous system-homing receptor CCR6 (a chemokine receptor that controls cell migration..like a postcode/zip finder that tells the cell which address to go to).
Detection of mucosal-associated invariant T cells (Mucosal associated invariant T cells (MAITs) are a special type of T cell, which have a canonical T cell receptor (Vα19-Jα33 in mice and Vα7.2-Jα33 in humans), and which appear to play a regulatory role in immunity. They are dependant on gut microbiota, being absent in germ-free mice) in post-mortem multiple sclerosis brain white matter active lesions confirmed their involvement in the disease pathology (May be involved but may just be bystanders dragged into the CNS during blood brain barrier problems). Intracellular cytokine staining demonstrated interferon γ and interleukin 17 production and lack of interleukin 10 production, a pro-inflammatory profile. Mucosal-associated invariant T cell frequency did not change in patients treated with interferon β; and was more depleted after autologous haematopoietic stem cell transplantation than in patients who had received high-dose cyclophosphamide (n = 7) or alemtuzumab (n = 21) treatment alone, suggesting an additive (e.g. 1 + 2 = 3) or synergistic (more than just addition e.g. 1 + 2 = 5) effect of the conditioning regime components.
We propose that a favourably modified balance of regulatory and pro-inflammatory lymphocytes underlies the suppression of central nervous system inflammation in patients with multiple sclerosis following non-myeloablative autologous haematopoietic stem cell transplantation with a conditioning regimen consisting of cyclophosphamide and alemtuzumab.