p38 MAPK pathway inhibitors as female-specific therapeutics

Example 1

p38 MAPK as a Female-Specific Druggable Target in Autoimmune Disease of the CNS

[0241]The data presented herein further investigates the role of p38 MAPK in mediating the inflammatory responses during EAE, the principle autoimmune model of multiple sclerosis. Previous studies have shown that p38 MAPK activation is required for the development and progression of both chronic and relapsing-remitting forms EAE. Furthermore, it was shown that regulation of p38 MAPK activity specifically in T cells is sufficient to modulate EAE severity (Noubade et al., 2011, Blood; 118(12): 3290-3300, which is incorporated herein by reference). The present data demonstrates a gender-specific role of p38 MAPK.

[0242]The materials and methods used in the following experiments are now described.

[0243]Mice

[0244]C57BL / 6J (B6) and B10.BR-H2k H2-T18 / SgSnJ (B10.BR) mice were purchased from The Jackson Laboratory. MKK6 transgenic (Rincon et al., 1998, EMBO J., 17(10):2817-2829) and do-p38 transgenic (Die

Example 2

Myeloid Specific Conditional Knock Out of p38alpha Induces Female-Specific Reduction of EAE Severity and Reduced Cytokine Production

[0269]It is shown that pharmacological inhibition of p38 MAPK by SB203580 (SB) in female, but not male C57BL / 6 (B6) mice ameliorated EAE (FIG. 6A). Further, as described elsewhere herein, it is indicated that genetic manipulation of p38 MAPK activity in T cells in B10.BR mice was sufficient to alter EAE progression.

[0270]Further experiments were performed where WT and Tg mice expressing constitutively active MKK6 (MKK6 Tg) were immunized using 1×CFA / MOG79-96+PTX protocol and scored daily. These studies have now revealed that augmentation of p38 activity in T cells, in the form of MKK6 Tg B10.BR mice, enhanced disease in both males and females (FIG. 6B). Furthermore, inhibition of p38 activity by the expression of a dominant negative p38 MAPK allele inhibited disease in male and female mice. These results suggest that the sexual dimorphism in S

Example 3

Sex-Specific Control of CNS Autoimmunity by p38 MAPK Signaling in Myeloid Cells

[0280]Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored.

[0281]The experiments presented herein used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. As presented herein, pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38α signaling in macrophages / myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflamm