trattamento emofilia 370x280 - A promising approach for treatment of severe hemophilia A patients with inhibitor.

A promising approach for treatment of severe hemophilia A patients with inhibitor.

Current standard therapy for severe hemophilia A is regular infusions of either plasma-derived or recombinant factor VIII (FVIII) for prophylaxis and for treating bleeding episodes when they occur (“on demand” therapy). Nowadays the most important complication of replacement therapy is that a significant number of patients develop neutralizing alloantibodies (inhibitors) against exogenous FVIII. Inhibitors are generated in about 25-30% of the patients with severe hemophilia A and in about 5% of patients with mild hemophilia A. The treatment to eliminate inhibitors is a high-dose administration of FVIII, termed Immune Tolerance Induction (ITI). However ITI is expensive and fails in approximately 30% of patients after maximum 33 months of treatment. Human T regulatory cells (Tregs) have been proposed as a new strategy to treat antibody response, as well as other diseases. Polyclonal Tregs are nonspecific and might cause general immunosuppression, so that an antigen-specific Tregs are needed to be generated. Novel tolerenogenic approaches to FVIII include the use of engineered human and mouse antigen-specific Tregs, or alternatively antigen-specific cytotoxic cells, to delete, anergize or kill FVIII-specific lymphocytes.

This immune response also occurs following gene therapy in hemophilic mouse models. Miao CH et al. (Blood 2009 Nov 5;114(19):4034-44) showed that in plasmid-mediated gene therapy-treated hemophilia mice, receiving adoptively transferred Tregs from FVIII-exposed HemA/Foxp3-Tg mice, produced significantly low antibody titers compared with controls after initial challenge with FVIII plasmid and second challenge 16 weeks after first plasmid treatment.

Authors concluded that “antigen-specific Tregs can provide long-lasting protection against immune responses in vivo and limit recall responses induced by a second challenge via infectious tolerance”. In addition Miao CH (Expert Rev Hematol. 2010 Aug;3(4):469-83) reports that, beyond other successful protocols, a dominant tolerance can be induced by suppression of activated T cells by Treg cells. Recent advances on mode of action of Treg cells for suppressing various immune responses may be useful to develop a novel strategy in order to prevent and/or eradicate inhibitory antibodies, and possibly induce long-term immune tolerance against specific antigens. The regulation and suppression of autoimmune and alloimmune responses by CD4+CD25+ Treg cells has been shown (Immunity 2000;12(4):431–440; Blood 2002;99(10):3493– 3499). Treg cell is able to exert immunomodulation of inhibitors in hemophilia A. Activated CD4+Foxp3+Treg cells induce suppression of FVIII-specific responses and mantain a long-term antigen-specific tolerance to FVIII.

Previously Kim YC et al. (Blood. 2015 Feb 12;125(7):1107-15) reported that the expansion of Tregs for clinical setting is a great promise for the treatment of immune responses in autoimmunity, transplantation, allergy, and antidrug antibody developement, including inhibitor responses in patients with severe hemophilia. However, polyclonal Tregs are nonspecific, so that might cause a global immunosuppression. The generation of an antigen-specific Tregs would have avoided this drawback. Authors reported on the production and properties of engineered antigen-specific Tregs transducing a recombinant T-cell receptor isolated from a hemophilia A subject’s T-cell clone, into expanded human FoxP3(+) Tregs. Such engineered FVIII-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitor in hemophilia A patients.

Yoon J et al. (Blood 2017 Jan 12;129(2):238-245) have engineered an FVIII-specific chimeric antigen receptor (ANS8 CAR) using a FVIII-specific scFv derived from a synthetic phage display library. Transduced ANS8 CAR T cells specific for the A2 domain proliferated in response to FVIII and ANS8 CAR Tregs suppressed the proliferation of FVIII-specific T-effector cells with specificity for a different FVIII domain in vitro.

These interesting results confirm that other tolerenogenic treatments than ITI could be in the next future a promising approach to treat severe hemophiliacs A with inhibitor.

Suggested reading:

  • Miao CH, Harmeling BR, Ziegler SF, Yen BC, Torgerson T, Chen L, Yau RJ, Peng B, Thompson AR, Ochs HD, Rawlings DJ. CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII-specific immune responses in plasmid-mediated gene therapy-treated hemophilia mice. Blood. 2009 Nov 5;114(19):4034-44.
  • Kim YC, Zhang AH, Su Y, Rieder SA, Rossi RJ, Ettinger RA, Pratt KP, Shevach EM, Scott DW. Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses. Blood. 2015 Feb 12;125(7):1107-15.
  • Yoon J, Schmidt A, Zhang AH, Königs C, Kim YC, Scott DW. FVIII-specific human chimeric antigen receptor T-regulatory cells suppress T- and B-cell responses to FVIII. Blood. 2017 Jan 12;129(2):238-245.


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