Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help

Abstract

SummaryIn general, humoral immune responses depend critically upon T cell help. In transplantation, prevention or treatment of humoral rejection therefore require drugs that ideally inhibit both B cell and T helper cell activity. Here, we studied the effects of commonly used immunosuppressive drugs [tacrolimus, cyclosporin, mycophenolic acid (MPA) and rapamycin] on T cell helper activity and on T cell-dependent B cell responses. T cells were activated polyclonally in the presence of immunosuppressive drugs in order to analyse the effect of these drugs on T cell proliferation, co-stimulatory ligand expression and cytokines. The impact of immunosuppressive drugs on T cell-dependent immunoglobulin production by B cells was addressed in T-B cell co-cultures. All drugs affected T cell proliferation and attenuated T cell co-stimulatory ligand (CD154 and CD278) expression when T cells were activated polyclonally. Tacrolimus, cyclosporin and rapamycin also attenuated B cell stimulatory cytokine mRNA levels in T cells. As a consequence, a decrease in immunoglobulin levels was observed in autologous T-B cell co-cultures, where T cell help is essential for immunoglobulin production. In contrast, when pre-activated T cells were used to stimulate autologous B cells, calcineurin inhibitors failed to inhibit B cell immunoglobulin production, whereas MPA and rapamycin did show inhibition. From these studies, it is evident that calcineurin inhibitors affect the humoral immune response by interfering with T helper signals, but not by targeting B cells directly. Furthermore, our studies support the necessity of intervening in T cell helper function to attenuate humoral responses.

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

“…These results indicate that CNIs affect the humoral immune response of patients with transplants by interfering with T helper signals and not by targeting B cells directly. 65 This hypothesis is supported by the study by Struijk et al, 66 which showed that patients with renal transplants who were stable on prednisolone plus CsA failed to develop antibodies against T cell-dependent model antigens but responded normally to T cell-independent antigens.…”

“…71 The fact that mTOR inhibitors are able to prevent the in vitro production of Ig with equal efficiency when human B cells are cultured with preactivated or not preactivated T cells further shows that mTOR inhibitors, in contrast with CNIs, have a direct effect on B cells. 65,72 This concept is also validated by the results of a recent study that compared the effects of CNI and mTOR inhibitors on B cells from healthy volunteers. Only sirolimus was able to inhibit the proliferation of B cells and their differentiation into plasma cells.…”

“…93 Similar findings have been reported in the T/B coculture model. 65,72 As expected, however, the drug has no effect on terminally differentiated plasma cells, 93 suggesting that it can only prevent (but not cure) AMR.…”

“…63 Although interesting, these experimental results cannot be directly translated into patients, because calcineurin inhibitors (CNIs), in contrast with genetic deletion, do not completely suppress calcineurin activity in lymphocytes. 64 In fact, when Heidt et al 65 tested the effect of CNIs in T and B cell cocultures, they observed that, whereas cyclosporin A (CsA) and tacrolimus were both capable of inhibiting Ig production when B cells were cultured with T cells that were not preactivated, they failed to do so when preactivated T cells were used to stimulate B cells. These results indicate that CNIs affect the humoral immune response of patients with transplants by interfering with T helper signals and not by targeting B cells directly.…”

Immunosuppressive Compounds Exhibit Particular Effects on Functional Properties of Human Anti-Aspergillus T H 1 Cells

“…Notably, CD154, also known as CD40L, plays an important role in T cell-dependent B cell proliferation, memory cell formation, and B cell antibody response (23,24). Our results suggest that CsA should be avoided, whenever possible, in patients receiving adoptive immunotherapy with anti-Aspergillus T H 1.…”