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

Clin Exp Immunol. 2010 Feb;159(2):199-207. doi: 10.1111/j.1365-2249.2009.04051.x. Epub 2009 Nov 18.


In 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.

MeSH terms

  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Calcineurin Inhibitors*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Cyclosporine / pharmacology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Flow Cytometry
  • Humans
  • Immunoglobulins / metabolism
  • Immunosuppressive Agents / pharmacology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mycophenolic Acid / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Sirolimus / pharmacology
  • T-Lymphocytes, Helper-Inducer / drug effects*
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Tacrolimus / pharmacology


  • Calcineurin Inhibitors
  • Cytokines
  • Immunoglobulins
  • Immunosuppressive Agents
  • Cyclosporine
  • Mycophenolic Acid
  • Sirolimus
  • Tacrolimus