TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

Abstract

ObjectiveNatalizumab blocks α4‐integrin‐mediated leukocyte migration into the central nervous system (CNS). It diminishes disease activity in multiple sclerosis (MS), but carries a high risk of progressive multifocal encephalopathy (PML), an opportunistic infection with JV virus that may be prompted by diminished CNS immune surveillance. The initial host response to viral infections entails the synthesis of type I interferons (IFN) upon engagement of TLR3 receptors. We hypothesized that TLR3 agonism reestablishes CNS immune competence in the setting of α4‐integrin deficiency.MethodWe generated the conditional knock out mouse strain Mx1.Cre+ α4‐integrinfl/fl, in which the α4‐integrin gene is ablated upon treatment with the TLR3 agonist poly I:C. Adoptive transfer of purified lymphocytes from poly I:C‐treated Mx1.Cre+ α4‐integrinfl/fl donors into naive recipients recapitulates immunosuppression under natalizumab. Active experimental autoimmune encephalomyelitis (EAE) in Mx1.Cre+ α4‐integrinfl/fl mice treated with poly I:C represents immune‐reconstitution.ResultsAdoptive transfer of T cells from poly I:C treated Mx1.Cre+ α4‐integrinfl/fl mice causes minimal EAE. The in vitro migratory capability of CD45+ splenocytes from these mice is reduced. In contrast, actively‐induced EAE after poly I:C treatment results in full disease susceptibility of Mx1.Cre+ α4‐integrinfl/fl mice, and the number and composition of CNS leukocytes is similar to controls. Extravasation of Evans Blue indicates a compromised blood‐brain barrier. Poly I:C treatment results in a 2‐fold increase in IFN β transcription in the spinal cord.InterpretationOur data suggest that TLR3 agonism in the setting of relative α4‐integrin deficiency can reestablish CNS immune surveillance in an experimental model. This pathway may present a feasible treatment strategy to treat and prevent PML under natalizumab therapy and should be considered for further experimental evaluation in a controlled setting.

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“…Cells from lymph nodes and spleen were isolated by pressing through a 70-µm nylon mesh cell retainer as described previously ( 8 – 10 ). Cells were treated with red blood cell (RBC) lysis buffer (Sigma-Aldrich), washed twice with cold PBS, and resuspended in PBS for counting by hemocytometer.…”

Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

“…Natalizumab prevents the infiltration of leukocytes into the CNS by inhibiting α4 integrin, thereby alleviating the autoimmune response of MS ( 162 ). However, the strong immunosuppression declined the ability of the immune system to monitor, potentially increasing the risk of progressive multifocal encephalopathy (PML) ( 163 ). Surprisingly, TLR3 agonists could re-establish CNS immune surveillance in EAE when α4 integrin was inhibited and reduced the risk of PML, suggesting that natalizumab therapy in combination with TLR3 agonists may restore a more appropriate immune balance in MS ( 163 ).…”

“…However, the strong immunosuppression declined the ability of the immune system to monitor, potentially increasing the risk of progressive multifocal encephalopathy (PML) ( 163 ). Surprisingly, TLR3 agonists could re-establish CNS immune surveillance in EAE when α4 integrin was inhibited and reduced the risk of PML, suggesting that natalizumab therapy in combination with TLR3 agonists may restore a more appropriate immune balance in MS ( 163 ). Fingolimod (FTY720) is the first modulator of sphingosine 1-phosphate receptors (S1PR) to receive regulatory approval for relapsing-remitting MS. S1P1 is critical for the regulation of lymphocyte transport.…”