Treatment with IL-10 producing B cells in combination with E2 ameliorates EAE severity and decreases CNS inflammation in B cell-deficient mice

Abstract

Clinical improvement during pregnancy in multiple sclerosis (MS) patients suggests that sex hormones exert potent regulatory effects on immune function. Our previous studies demonstrated that estrogen-(17β-estradiol; E2) mediated protection against experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, hinges on the B cells, leading to elevated numbers of IL-10 secreting CD1d hi CD5 + B regulatory cells (B regs ) in wild type mice. Our data show that co-administration of E2 and IL-10 + B cells ameliorates EAE disease severity and limits CNS infiltrating leukocytes in B cell deficient mice. Additionally, treatment with E2 and B regs reduces demyelination and dramatically decreases the proportion of CD11b + CD45 hi activated microglia/macrophages found in the CNS of immunized animals compared to vehicle, E2 or B reg cells alone. Furthermore, mice given E2 and B regs exhibit increased numbers of peripheral programmed death-1 positive CD4 + Foxp3 + regulatory T cells (T regs ) and up-regulation of programmed death receptor-ligand-1 and CD80 expression on monocytes. Our study suggests IL-10 producing B regs have powerful therapeutic potential as an agent against EAE when augmented with E2 treatment.

IL-10 producing B cells partially restore E2-mediated protection against EAE in PD-L1 deficient mice

“…Our current study clearly demonstrates that transfer of IL-10 producing B cells, which also express PD-L1 on their cell surface, could partially resotre E2 mediated protection against EAE, mainly by inhibiting the infiltration of pro-inflammatory cells from the periphery, which in turn leads to a less inflammatory CNS. This finding is in concert with our previous report that IL-10 producing regulatory B cells in conjunction with E2 ameliorates EAE severity and decreases CNS inflammation in B cell-deficient mice (Zhang, Lapato, 2015)…”

“…In addition, we demonstrated that this protection is mediated by the interaction of programmed death receptor 1 (PD-1) with PD-L1 but not PD-L2 on B cells (Bodhankar et al, 2013b). Recently, we demonstrated that co-administration of E2 and IL-10 secreting CD1d hi CD5 + Bregs ameliorates EAE severity in B cell deficient mice (Zhang et al, 2015). However it was not yet established whether this protective effect of Bregs in combination with E2 is dependent on PD-L1 expression on Bregs or whether co-adminstration of E2 and Bregs would be sufficient to treat EAE in PD-L1 deficient mice.…”

Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis

“…Indeed, treatment with pregnancy levels as well as lower estrogen levels reduced disease severity and CNS lesions in EAE. Recently, we demonstrated that E2 mediated protection against EAE is dependent on the presence of PD-L1 expressing B cells (Bodhankar et al, 2013b, Zhang et al, 2015b). We further showed that E2 treatment could increase the frequency of CD5 + CD1d hi regulatory B cells and increase the cell surface expression of PD-L1 and IL-10 secretion from these cells (Bodhankar, Wang, 2011).…”

The regulatory role of B cells in autoimmunity, infections and cancer: Perspectives beyond IL10 production

“…This report provided insights about how important it would be to consider the timing of the autoimmune disease and the roles of the different B cell populations when establishing therapeutic treatments involving depletion or an autologous adoptive transference. Furthermore, PD-L1 + IL-10 + B cells were shown to be the key players in estrogen (E2)-mediated protection against EAE [57][58][59]. E2 has been proved to protect mice from EAE, while this protection was abrogated in B cell-deficient (muMT) mice [60].…”