Antibody-mediated rejection (AMR) is a significant complication after solid organ transplantation which can occur during the immediate and chronic stages of transplantation. Long-term survival rates of patients undergoing solid organ transplantation have remained relatively unchanged over the past few decades despite development of better immune targeted therapeutics. It is clear that more specific and effective strategies are needed to successfully prevent AMR.1 Most current strategies involve treating AMR therapeutically and involve attenuating existing donor specific antibody levels or inhibiting their function (eg, through plasmaphoresis, immunoabsorption, complement inhibition or antibody cleavage). Although these therapeutic treatments have had some success, a more effective strategy may be to prevent antibodies from being generated during engraftment. One tantalizing strategy to accomplish this may be to promote the immune system's own regulatory mechanisms to prevent donor-specific antibody responses. However, the lack of sufficient understanding of how antibody responses are regulated has limited the development of specific strategies to accomplish long-term tolerance in transplantation. Studies over the past few years have helped elucidate more precise mechanisms by which the immune system controls antibody responses. These studies have demonstrated that a specific cell type, called a T follicular regulatory (Tfr) cell, has potent and specific roles in regulating antibody responses. In this issue of Transplantation, Wallin reviews the current understanding of the role(s) of Tfr cells in transplant rejection and highlights how current therapeutics may be modulating this cell type.2
Tfr cells are a subset of effector T regulatory cell that gain access to B-cell follicles of lymphoid organs and suppresses T follicular helper–mediated activation of B cells and antibody responses, ensuring these responses are both targeted and proportional to the stimulus.3,4 Even though Tfr cells were only discovered in 2011, a number of studies have suggested that Tfr cells may have key roles in diseases, such as lupus/nephritis, myasthenia gravis, arthritis, multiple sclerosis, immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX), ankylosing spondylitis, chronic viral infection (human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV)/hepatitis), aging, gut homeostasis, and transplantation.5 Although only a few studies have assessed Tfr cells in transplantation, data are promising. For instance, Tfr cells are present in lymph nodes of kidney transplant recipients.6 Moreover, Tfr cells have been shown to inhibit pathology in mouse models of chronic graft-versus-host disease, suggesting that Tfr cells can control pathogenic antibodies during transplantation.7 Although more studies are necessary to elucidate the putative role(s) of Tfr cells in mitigating AMR in solid organ transplant, these cells have high prophylactic and therapeutic potential. Augmenting Tfr cells before organ engraftment may eliminate donor-specific antibody responses while avoiding side effects of broad immunosuppression. Moreover, because some Tfr cells have immunological memory properties, augmenting Tfr cells may induce long-term tolerance during transplantation.8 Promoting Tfr memory in this way may limit chronic rejection and the need for long-term immunosuppression. More studies need to be performed to assess these possibilities.
In addition to the therapeutic potential of Tfr cells, analysis of Tfr cell frequency and/or phenotype may be useful for diagnostic purposes in the context of transplantation. Analysis of Tfr cells may have diagnostic potential because altered Tfr ratios can correlate with pathogenic antibody levels. Moreover, a recent study has demonstrated that careful analysis of Tfr cells may be a more sensitive way of staging disease in Sjogren's syndrome than current methodologies.9 In a similar manner, careful analysis of Tfr cells in the circulation of transplant patients may better predict donor-specific antibody responses, facilitating earlier intervention to prevent AMR.
Solid-organ transplantation may also be a perfect setting for advancing our knowledge of basic Tfr biology, because (1) the antigens mediating transplant rejection (eg, HLA, blood group, vasculature, etc.) are well defined because of advanced screening tools; (2) the timing of antigenic challenge in transplantation is well known (because the time of graft surgery is well known), allowing longitudinal studies; (3) the lymphoid organs where B cell responses occur can be predicted with high accuracy because the graft is transplanted in a specific location; and (4) lymphoid tissue can be harvested during follow-up procedures in some types of transplantation, allowing more in-depth analysis of B-cell responses where they originate. These features are in contrast to other diseases where Tfr cells are thought to have key roles, such as lupus, where the antigen is not well defined, the timing of antigenic challenge to elicit pathogenic antibody formation is unknown, and the systemic nature of the disease precludes identification of the primary location of B cell responses.
In summary, Tfr cells have a bright future in the context of transplantation either therapeutically, diagnostically or as a research tool. The study of Tfr cells in transplant rejection will synergistically benefit both the antibody regulation and transplantation fields, thereby enhancing both basic science and clinical care.
1. Montgomery RA, Loupy A, Segev DL. Antibody-mediated rejection: New approaches in prevention and management. Am J Transplant
. 2018;18(Suppl 3):3–17.
2. Wallin EF. T follicular regulatory cells and antibody responses in transplantation. Transplantation
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5. Sage PT, Sharpe AH. T follicular regulatory cells. Immunol Rev
6. Wallin EF, Jolly EC, Suchánek O, et al. Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers. Blood
7. McDonald-Hyman C, Flynn R, Panoskaltsis-Mortari A, et al. Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner. Blood
8. Sage PT, Alvarez D, Godec J, et al. Circulating T follicular regulatory and helper cells have memory-like properties. J Clin Invest
9. Fonseca VR, Romão VC, Aqua-Doce A, et al. Blood T follicular regulatory cells/T follicular helper cells ratio marks ectopic lymphoid structure formation and PD-1(+) ICOS(+) T follicular helper cells indicate disease activity in primary Sjogren's syndrome. Arthritis & rheumatology
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