In vivo induction of regulatory T cells for immune tolerance in hemophilia

Abstract

Current therapy for the X-linked coagulation disorder hemophilia is based on intravenous infusion of the specifically deficient coagulation factor. However, 20–30% of hemophilia A patients (factor VIII, FVIII, deficiency) generate inhibitory antibodies against FVIII. Whilst formation of inhibitors directed against factor IX, FIX, resulting from hemophilia B treatment is comparatively rare, a serious complication that is often associated with additional immunotoxicities, e.g. anaphylaxis, occurs. Current immune tolerance protocols to eradiate inhibitors are lengthy, expensive, not effective in all patients, and there are no prophylactic tolerance regimens to prevent inhibitor formation. The outcomes of recent experiments in animal models of hemophilia demonstrate that regulatory CD4+ T cells (Treg) are of paramount importance in controlling B cell responses to FVIII and FIX. This article reviews several novel strategies designed to in vivo induce coagulation factor-specific Treg cells and discusses the subsets of Treg that may promote immune tolerance in hemophilia. Among others, drug- and gene transfer-based protocols, lymphocyte transplant, and oral tolerance are reviewed.

Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce

“…Antigen presentation to MHC-II-restricted CD4 + T cells results in induction of several subsets of T-reg cells. CD4 + CD25 + FoxP3 + T-reg cells and interleukin-10 (IL)-10-expressing LAP + CD4 + CD25 − FoxP3 − T-reg cells systemically enforce suppression of antibody formation, which we found to be antigen specific 20, 36. Immunological reagents in the canine model are limited (for example, an antibody to canine LAP is lacking).…”

Advances in knowledge of inhibitor formation in severe haemophilia A

“…The induction of regulatory T cells is highly dependent on the APCs that naïve T cells interact with and is critical for the prevention of FVIII inhibitor formation (Wang et al , ). As mentioned previously, after intravenous infusion of FVIII in HA mice the majority of the FVIII protein localises in the spleen where the cellular architecture is ideally suited for developing FVIII inhibitors (Navarrete et al , ).…”

“…In the majority of severe HA patients, naïve T cells differentiate into immunosuppressive regulatory T cells through peripheral tolerance mechanisms that can eliminate inhibitor responses to FVIII through the production of anti‐inflammatory cytokines and negative co‐stimulatory molecule expression (Wang et al , ). In the context of inhibitor formation, however, this suppressive response is inadequate.…”

Vaccination via Chloroplast Genetics: Affordable Protein Drugs for the Prevention and Treatment of Inherited or Infectious Human Diseases

“…Detailed mechanisms of oral tolerance have been reviewed elsewhere (15, 144), but we provide a brief conceptual overview here. Induction of antigen-specific regulatory T cells (Tregs) is a key component of the tolerance mechanism (142, 144). Secretion of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) by Tregs induces apoptosis or cell cycle arrest in effector T cells and blocks co-stimulation and maturation of DCs, which shifts DCs into tolerogenic function; when immature DCs present antigens to T cells in the absence of inflammation, tolerance is induced (75, 86).…”

“…Thus, the interaction between Tregs and DCs plays a major role in oral tolerance (15). The frequency of oral antigen administration is critical; multiple antigen feedings are more effective than a single feeding in inducing oral tolerance in inflammatory immune responses and autoimmune disease models (50, 91, 142). Moreover, continuous feeding correlates with enhanced production of IL-10 and TGF-β (140).…”