Abstract
Over the past decade, antibody-mediated (humoral) rejection has been recognized as a common cause of graft dysfunction after organ transplantation and an important determinant for graft loss. In humoral alloimmunity, T follicular helper (Tfh) cells play a crucial role, because they help naïve B cells to differentiate into memory B cells and alloantibody-producing plasma cells within germinal centers. In this way, they contribute to the induction of donor-specific antibodies, which are responsible for the humoral immune response to the allograft. In this article, we provide an overview of the current knowledge on the effects of immunosuppressive therapies on Tfh cell development and function, and discuss possible new approaches to influence the activity of Tfh cells. In addition, we discuss the potential use of Tfh cells as a pharmacodynamic biomarker to improve alloimmune-risk stratification and tailoring of immunosuppression to individualize therapy after transplantation.
Highlights
Organ transplantation is the treatment of choice for end-stage organ failure
T follicular helper (Tfh) cells express the coinhibitory protein programmed death 1 (PD-1) and inducible T-cell costimulatory molecule (ICOS) [7, 9]. It has been demonstrated in a conditional knock out mouse model that Tfh cells express the transcription factors lymphoid enhancer binding factor 1 and T cell factor 1, both of which are involved in regulation of the Tfh transcriptional repressor B cell lymphoma 6 (Bcl-6) [13]
Chen et al showed that the ratio of T follicular regulatory (Tfr) cells in peripheral blood and renal graft biopsies from patients with antibody-mediated rejection (AMR) was significantly lower than in non-AMR patients, whereas Tfh2 and Tfh17 ratios increased, suggesting that increased Tfh activation levels contribute to AMR [34]
Summary
Current immunosuppressive regimens are effective in the short-term, long-term allograft survival rates are still suboptimal with rejection being the leading cause of graft loss [1]. Allograft rejection can develop from either cellular or humoral immune responses against the allograft, or from “mixed rejection” involving both types of responses [2]. Humoral anti-donor reactivity via the formation of donor-specific antibodies (DSA) is associated with poor allograft outcomes [3,4,5]. Formation of DSA relies on antigen-activated T follicular helper (Tfh) cells, which are located in the germinal centers (GC) where they provide help to antigen-activated B cells, which in turn respond by differentiating into immunoglobulin-producing plasma cells and high-affinity memory B cells [6, 7]
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