Adjuvant facilitates tolerance induction to factor VIII in hemophilic mice through a Foxp3-independent mechanism that relies on IL-10

Abstract

Key Points An adjuvant (alum), known to boost immune responses, can be used to facilitate a tolerogenic protocol. Nondepleting anti-CD4 can lead to Foxp3+ regulatory T-cell–independent tolerance that relies on IL-10.

Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals

“…By the use of constitutive Treg-deficient sf mice which develop autoimmunity without exogenous manipulation, we were able to examine Foxp3 þ Treg-independent anti-CD4-induced tolerance in isolation. Our results are in line with a recent study showing that anti-CD4 induces tolerance to factor VIII in a Foxp3-independent fashion [40]. However, whereas tolerance to factor VIII was dependent on IL-10 [40], we found no increased IL-10 expression by tolerized CD4 þ T cells and actually reduced IL-10 levels in the serum of tolerized sf mice.…”

“…Our results are in line with a recent study showing that anti-CD4 induces tolerance to factor VIII in a Foxp3-independent fashion [40]. However, whereas tolerance to factor VIII was dependent on IL-10 [40], we found no increased IL-10 expression by tolerized CD4 þ T cells and actually reduced IL-10 levels in the serum of tolerized sf mice. Supporting our findings, we report that Treg-indpendent tolerance is recessive and noninfectious.…”

Non-depleting anti-CD4 monoclonal antibody induces immune tolerance to ERT in a murine model of Pompe disease

“…Data from a Phase 1 clinical trial showed that TRX1 was well tolerated and did not deplete T cells [24]. Proposed mechanisms of action of non-depleting anti-CD4 include down-modulation of the CD4 receptor on T cells, and induction of regulatory T-cells [25], [26], [27]. In this study we showed that a short-course treatment with an anti-CD4 mAb successfully induced long-term ERT-specific immune tolerance in Pompe disease mice, implying that this may prove a favorable prophylactic ITI protocol for infants.…”

Suppression of inhibitor formation against FVIII in a murine model of hemophilia A by oral delivery of antigens bioencapsulated in plant cells

“…4 Although there are currently no prophylactic protocols against inhibitor formation in patients, preclinical experiments in murine models of hemophilia A have provided proof of principle that preventive immune tolerance to FVIII can be established. [6][7][8][9][10][11] However, such protocols use genetic manipulation or immune suppressive drugs, raising safety concerns for translation to human treatment. In contrast, oral tolerance could be a more readily acceptable form of prophylactic tolerance induction and may be more readily tested in clinical trials.…”