The Calcineurin Inhibitor Tacrolimus Specifically Suppresses Human T Follicular Helper Cells

Abstract

BackgroundT follicular helper (Tfh) cells are key players in the production of antibody-producing B cells via the germinal center reaction. Therapeutic strategies targeting Tfh cells are important where antibody formation is implicated in disease, such as transplant rejection and autoimmune diseases. We investigated the impact of the immunosuppressive agent tacrolimus on human Tfh cell differentiation and function in transplant recipients.MethodsPaired blood and lymph node (LN) samples were obtained from 61 transplant recipients immediately prior to organ implantation. Living-donor recipients received a week of tacrolimus prior to kidney transplantation. Deceased-donor recipients served as controls, as tacrolimus was not administered until after the transplant operation. Flow cytometry was used to compare LN and circulating cell subsets.ResultsThe calcineurin inhibitor (CNIs) tacrolimus specifically suppresses both LN Tfh cells and circulating Tfh cells, but not their regulatory counterparts or other CD4 T cell subsets.ConclusionOur findings suggest that CNIs may have a more important role in the prevention of antibody formation than previously understood and, therefore, have potential for antibody-associated conditions in which aberrant Tfh function has been implicated in disease.

Successful preemptive therapy with single‐dose rituximab for Epstein‐Barr virus infection to prevent post‐transplant lymphoproliferative disease after pediatric hematopoietic stem cell transplantation

“…Among our study participants, there were 5 patients who had chronic GVHD and were receiving immunosuppressive drugs such as prednisolone, tacrolimus, cyclosporine, and mycophenolate mofetil; 4 patients did not recover their B cell count after rituximab infusion, and the remaining 1 patient recovered after the discontinuation of immunosuppressive drugs. These drugs are known to have side effects that inhibit B cell proliferation . Although the reason for B cell inhibition is unclear, we suggest that delayed B cell recovery was caused by the immunosuppressive drugs, and not by rituximab administration.…”

Predisposing factors for anti‐D immune response in D− patients with chronic liver disease transfused with D+ platelet concentrates

“…20 The reasons of the occurrence of early primary immunization in solid organ transplantation are unclear. In the context of therapy with calcineurin inhibitors (cyclosporine and tacrolimus) known to target T follicular helper cells, 21 we hypothesize that B cells activated by RBC epitopes do not enter germinal centers and instead are committed to the extrafollicular pathway of B cell growth which produce short-lived antibody response as early as 7-8 days after immunization but fail to generate long-lived memory B cells. 22 For these reasons, to avoid the underestimation of alloimmunization frequency, we included all anti-D responses detected at least 10 days after D + PC transfusion.…”

Tacrolimus treatment for infertility related to maternal‐fetal immune interactions

“…Although a few studies have reported a negative effect of tacrolimus on tDC maturation, others have demonstrated a positive role for tacrolimus in inducing the maturation of imDC to tDC cells, . B cells (activities, antibody production, and class switching) are suppressed via T follicular helper cells . These findings suggest that tacrolimus can inhibit rejection of and induce tolerance to the fetus by inhibiting activated NK/NKT cells and macrophages, and may also induce the differentiation of imDC to tDC.…”

“…Elucidation of the detailed mechanisms of signal transduction in cells has led to the successful use of tacrolimus in the fields of transplantation andautoimmune disease . Tacrolimus has been reported to act not only via the CN‐NFAT pathway in T cells, but also in other cell types, including NK/NKT cells, macrophages, B cells, and DC cells . Direct inhibition occurs in T cells, NK/NKT cells, and macrophages.…”

“…Galectin 1 is produced from these cells and induces Th1 apoptosis, tDC, and uterine NK in the matured endometrial epithelial cells . Second, tacrolimus inhibits the activities of type 1 cells, NK/NKT cells, and macrophages directly via the CN‐NFAT pathway, and third, it induces differentiation of imDC to tDC via the CN‐NFAT pathway, and consequently assists in the induction of Tregs . tDCs are also induced by other pharmacological mediators such as immunosuppressive drugs (cyclosporine, rapamycin, deoxyspergualin, mycophenolate mofetil, sanglifehrin A), anti‐inflammatory drugs (corticosteroids, aspirin), 1α25‐dihydroxyvitaminD 3 , N‐acetyl‐L‐cysteine, cAMP inducers (prostaglandin E 2, histamine, β 2 agonists, neuropeptides), glucosamine, and cobalt protoporphyrin …”