Abstract
In multiple sclerosis (MS) and other autoimmune diseases, the autoreactive T cells overcome the resistance provided by the regulatory T cells (Tregs) due to a decrease in the number of Foxp3-expressing Tregs. Therefore, upregulation and/or maintenance of Tregs during an autoimmune insult may have therapeutic efficacy in autoimmune diseases. Although several immunomodulatory drugs and molecules are available, most present significant side effects over long-term use. Here we have undertaken an innovative approach to upregulate Tregs and achieve immunomodulation. RNS60 is a 0.9% saline solution generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. RNS60, but not NS (normal saline), RNS10.3 (TCP-modified saline without excess oxygen) and PNS60 (saline containing excess oxygen without TCP modification), was found to upregulate Foxp3 and enrich Tregs in MBP-primed T cells. Moreover, RNS60, but not NS, RNS10.3 and PNS60, inhibited the production of nitric oxide (NO) and the expression of iNOS in MBP-primed splenocytes. Incubation of the cells with an NO donor abrogated the RNS60-mediated upregulation of Foxp3. These results suggest that RNS60 boosts Tregs via suppression of NO production. Consistent to the suppressive activity of Tregs towards autoreactive T cells, RNS60, but not NS, RNS10.3, or PNS60, suppressed the differentiation of Th17 and Th1 cells and shifted the balance towards a Th2 response. Finally, RNS60 treatment exhibited immunomodulation and ameliorated adoptive transfer of experimental allergic encephalomyelitis, an animal model of MS, via Tregs. These results describe a novel immunomodulatory property of RNS60 and suggest its exploration for therapeutic intervention in MS and other autoimmune disorders.
Highlights
Regulatory T cells (Tregs), a special subset of T cells, serve as a primary regulator for the immune response that maintains homeostasis between immune activation and immune suppression [1,2]
Enrichment of the Treg population by RNS60 Because Tregs are most important immunomodulatory subtype of T lymphocytes, in order to understand immunomodulatory effect of RNS60, at first, we examined the effect of RNS60 on Tregs
myelin basic protein (MBP)-primed lymph node cells (LNC) were re-primed with MBP in the presence or absence of different doses of RNS60, normal saline (NS), RNS10.3, and PNS60 followed by monitoring the expression of the regulatory T cell marker forkhead box p3 (Foxp3)
Summary
Regulatory T cells (Tregs), a special subset of T cells, serve as a primary regulator for the immune response that maintains homeostasis between immune activation and immune suppression [1,2]. Tregs suppress activation and proliferation of selfreactive T cells and thereby inhibit immune response of selfreactive T cells against self-antigens [1,2]. There are several kinds of Tregs, including naturally occurring, inducible, and IL-10– producing Tregs, and several controversies lie in choosing proper parameters that characterize a particular kind of Treg [2,3] Irrespective of these discrepancies, recent advancements in research have established the transcription factor forkhead box p3 (Foxp3) as the most specific marker of Tregs [1]. During autoimmune pathogenesis, the immune system is dysregulated, resulting in a substantial decrease in the activity and the number of Tregs, and thereby leading to proliferation of self-reactive T cells and subsequent autoimmune attack
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