Rapamycin turns stops Th17 but promotes Treg

Frederick, Maryland -

Although mesenchymal stem cells are currently used in an allogeneic manner clinically, the question of whether they are truly tolerogenic is still debated. Other stem cell types such as CD34 or embryonic stem cells may possess different levels of immunogenicity and therefore may not be feasible clinically as "off the shelf" solutions. Due to this, there is a great interest in the field of stem cell therapeutics as to how one can transplant stem cells without needing to give long-term immune suppression as is given in organ transplants.

One possible method of avoiding long term immune suppression is through inducing immunological tolerance. This is the "Holy Grail" of the transplant immunologist. Essentially this means coaxing the recipient organism that the foreign transplanted cells are actually part of the recipient and thus the recipient immune system should not kill them.

Tolerance induction is associated with a specific type of T cell called the T regulatory cell. Many types of T regulatory cells exist, but their main function is to actively suppress other T cells in an antigen-specific manner.

In a recent paper (Kopf et al. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol. 2007 Dec 15;7(13):1819-24) it was demonstrated that the immune suppressant drug Rapamycin promoted Treg generation from naive CD4 T cells in vitro while the immune suppressant cyclosporine did not. However both cyclosporine and rapamycine inhibited generation of Th17 cells from naive CD4 T cells.

These data suggest that under specific conditions rapamycin may be more conducive to Treg generation and tolerance induction than cyclosporine.

These conclusions are supported by studies (Gao et al. Contrasting effects of cyclosporine and rapamycin in de novo generation of alloantigen-specific regulatory T cells. Am J Transplant. 2007 Jul;7(7):1722-32) that demonstrate administration of rapamycin but not cyclosporine induces generation of FoxP3 positive cells in vivo. The study of Gao was particularly interesting since they used FoxP3 promoter driven GFP mice as allotransplant recipients and showed many more green cells in the mice that recieved rapamycin as opposed to cyclosporine.