Targeting Antigen-Specific B Cells Using Antigen-Expressing Transduced Regulatory T Cells.

Area of Science:

• Immunology
• Cell Therapy
• Hematology

Background:

• Uncontrolled immune responses are a significant challenge in treating autoimmune diseases and adverse reactions to biotherapeutics.
• In hemophilia A, a substantial portion of patients develop neutralizing antibodies (inhibitors) against therapeutic Factor VIII (FVIII), hindering treatment efficacy.

Purpose of the Study:

• To develop a novel strategy for controlling immune responses, specifically targeting B cells involved in antibody production.
• To evaluate the efficacy of antigen-specific regulatory T cells (Tregs) engineered to target B cells in a mouse model of hemophilia A.

Main Methods:

• Engineered human CD4+CD25hiCD127low Tregs with a chimeric receptor (BAR) linking FVIII antigen domains with CD28-CD3ζ signaling domains.
• Transduced Tregs (C2- and A2-BAR) were tested for their ability to suppress anti-FVIII antibody responses in vitro and in vivo.
• Mechanistic studies analyzed the impact of BAR-Tregs on B cells and T cells in tolerized and control mouse models.

Main Results:

• BAR-Tregs specifically suppressed recall antibody responses in spleen cultures from FVIII-immunized mice.
• BAR-Treg treatment completely prevented the development of anti-FVIII antibodies following FVIII immunization in vivo.
• Mechanistic studies revealed direct suppression or anergy induction of FVIII-specific B cells, while T cell responses remained unaffected.

Conclusions:

• Antigen-expressing Tregs engineered with B cell-targeting chimeric receptors (BAR-Tregs) represent a successful proof-of-principle strategy.
• This approach offers a method for directly targeting and suppressing specific B cell populations.
• The BAR-Treg strategy holds potential for adaptation to manage other adverse immune responses beyond hemophilia.