Treatment with the Retinoid X Receptor Agonist IRX4204 Ameliorates Active and Passive Experimental Autoimmune Encephalomyelitis in Mice (P5.315)

Objective: To determine if treatment with the retinoid X receptor (RXR) agonist IRX4204 decreases disease severity and modulates the activity of CD4 T cells in active and passively transferred T helper (Th) 17-mediated experimental autoimmune encephalomyelitis (EAE) in mice. Background: RXRs are key nuclear receptors which form homodimers with each other and heterodimers with many other nuclear receptor family members, including RARs, PPARs, Nurr1, and Nur77, to regulate cell growth, differentiation, and survival. We studied the effects of the highly selective RXR agonist IRX4204, which transactivates RXR-Nurr1 and RXR-Nur77 but not RXR-RAR and RXR-PPARγ heterodimers. Methods: Naive murine CD4 T cells were differentiated in vitro under inducible regulatory T cell (Treg) and Th17 conditions, to determine if IRX4204 could promote or inhibit their differentiation. In addition, we studied the effects of IRX4204 treatment in vivo during active and Th17-mediated passive Results: We found that IRX4204 increases FoxP3 expression by CD4 T cells under both conditions, and inhibits IL-17A and TNFα production under Th17 differentiation conditions in vitro. In addition, IRX4204 treatment profoundly attenuates clinical scores in both active and Th17-mediated passive EAE. In the periphery this is associated with decreased numbers of CD4 T cells producing pro-inflammatory cytokines. Further, CD4 T cells from IRX4204 treated mice express less Ki-67 and more CTLA-4. Additional studies suggest that IRX4204 may also be acting on other cell types to ameliorate CNS pathology. Conclusions: Our findings demonstrate that treatment with the RXR agonist IRX4204 results in immune modulation and inhibition of clinical scores in active and passive EAE.Supported by SBIR Phase 1 Grant 1R43AI112512-01A1 awarded to Io Therapeutics, Inc. Disclosure: Dr. Nowak has received royalty payments from Io Therapeutics, Inc. Dr. Rosh Chandraratna has received personal compensation for activities with Io Therapeutics, Inc. as the President and Chief Scientific Officer. Dr. Noelle has received personal compensation for activities with therapeutics, Inc. as an advisory board member.