Diverse Regulatory Cell Populations in Antibody Mediated Rejection

Antibody-mediated rejection (ABMR) is a leading cause of late graft loss, and current therapies act almost exclusively on the effector arm of the alloimmune response. This review examines three classes of regulatory cell from innate and adaptive lineages and the stages of the ABMR response at which each acts, in order to assess their potential as therapeutic targets.

CD4⁺ Tregs constrain alloimmune priming through CTLA4 dependent costimulatory blockade, cytokine-mediated suppression, and competition for IL-2. CXCR5⁺CD8⁺ antibody-suppressor cells directly eliminate donor-reactive IgG⁺ B cells in murine models. T follicular regulatory (Tfr) cells restrain germinal center reactions and alloantibody generation, and their loss produces enhanced, more pathogenic donor-specific antibody (DSA). Notably, Tfr regulation is initiated early in T-B interactions, Tfr expansion physiologically lags that of Tfh cells, and Tfr numbers are reduced in chronic ABMR. Regulatory B cells and myeloid-derived suppressor cells remain comparatively unexplored in ABMR, and the latter carry a risk of profibrotic differentiation under chronic inflammatory conditions.

Regulatory cell populations act predominantly during the early phases of the alloimmune response. Their therapeutic utility in ABMR is therefore likely to be constrained by timing, and to lie in the prevention of de novo DSA rather than the reversal of established rejection.