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Multiple Sclerosis (MS) is a chronic neuro-inflammatory demyelinating disorder of the central nervous system (CNS) that predominantly affects young adults. There are approximately 1.1 million cases worldwide.  Empirical evidence points toward an autoimmune pathogenesis, where myelin-specific CD4+ and CD8+ T cells are thought to play a central role by reacting against and destroying the myelin sheath.  Autoimmune destruction of myelin leads to a long-term breakdown of saltatory conduction in myelinated fibers with subsequent impairment of neuronal function and axonal loss.  The disease results in multiple neuralgic symptoms and signs, which are often disabling and show exacerbations and remissions that, can lead to a chronic progressive course in later years.  

In this research, we show that PARACTIN^® is able to down modulate both humeral and cellular adaptive immune responses. In vitro, PARACTIN^® was able to interfere with T cell proliferation and cytokine release in response to allergenic stimulation. These results were consistent with the observation that T cell activation by dendritic cells (DCs) was completely abolished by exposing DCs to PARACTIN^® during antigen pulse. This extract was able to interfere with maturation of DCs and with their ability to present antigens to T cells. Furthermore, in vivo immune responses such as antibody response to a thymus-dependent antigen and delayed type hypersensitivity were drastically diminished in mice by PARACTIN^® treatment.

Result

In vitro T cell activation is inhibited by PARACTIN^®.
The ability of PARACTIN^® to interfere with T cell activation was evaluated.  T cell proliferation and IL-2 release were inhibited by PARACTIN^® in a dose dependent fashion.  The experiment shows that treating DCs with PARACTIN^® prevented them from activating both CD4+ and CD8+ OVA-specific T cell hybridomas.  (Multiple Sclerosis is an autoimmune pathogenesis, where myelin-specific CD4+ and CD8+ T cells are thought to play a central role by reacting against and destroying the myelin sheath).  In addition, DCs remains unaffected after treatment with PARACTIN^® which suggest T cell deactivation. 

In addition to impair generation of peptide-MHC complexes, PARACTIN^® reduced the efficiency of DC maturation in response to LPS. Thus up-regulation of co-stimulating molecules CD40 and CD86 on DCs treated with LPS was impaired by PARACTIN^®. The interference with DC maturation suggests an explanation for the interference of PARACTIN^® on T cell activation in vivo. 

In vivo T cell function is suppressed by PARACTIN^® treatment.
The experiment suggested that PARACTIN^® is able to interfere with the initiation of an immune response, by inhibiting T cell activation.  6 mice were treated with PARACTIN^® and immunized with NP17- BSA (a thymus-dependent antigen). Seven days post-immunization, Antibody (IgG) secretion against the T cell dependent antigen NP17-BSA was significantly reduced by PARACTIN^® treatment compared to untreated control.    Similarly, the delayed type hypersensitivity (DTH) response against the antigen OVA was diminished to background levels by PARACTIN^® treatment compared to control.  These results support the notion that T cell-mediated immune responses can be effectively impaired by PARACTIN^®

PARACTIN® treatment significantly reduces severity of Experimental Autoimmune Encephalomyelitis in the mouse.
The ability of PARACTIN^® to inhibit T cell activation was applied to interfere with the onset of Experimental Autoimmune Encephalomyelitis (EAE), an inflammatory demyelinating disease of the central nervous system that is primarily mediated by CD4+ T cells and serves as an animal model for human Multiple Sclerosis.  6 mice were induced with EAE by injection of a MOG35-55 peptide, which leads to chronic spinal cord demyelination and paralysis. Half the mice were treated with PARACTIN^® started one week before MOG sensitization and continued through all the experiment. Treated and control mice were clinically evaluated on a daily basis. The experiment showed that treatment with PARACTIN^® not only delayed the onset of EAE, but also significantly reduced the severity and incidence of disease. 

Reduced anti-myelin T cell and antibody response in PARACTIN^® treated mice.
3 weeks after EAE induction, lymph nodes (LN) were obtained from control and PARACTIN^® -treated mice to evaluate cytokine release in response to MOG peptide.  IFN-g and IL-2 secretion (two important proinflammatory cytokines that participate in EAE pathogenesis) was observed only in LN suspensions obtained from untreated mice suffering from EAE and were not detected in PARACTIN^® -treated mice. 

In addition, anti-MOG IgG could only be measured from controls animals suffering from EAE and not seen in mice treated with PARACTIN^®.  Thus, it seems likely that PARACTIN^® treatment significantly reduced EAE severity by impairing T cell activation as well as antibody production against myelin antigens.

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