Immunosuppressive and metabolic agents that influence allo‐ and xenograft survival by in vivo expansion of T regulatory cells

Abstract

The transplanted organs or cells survive if the recipient receives adequate long-term immunosuppressive therapy. Immunosuppressive therapy combined with cell-based strategies (eg, regulatory T cell [Treg]-based therapy) promotes graft survival. A combination of Treg-based therapy and minimal or no immunosuppressive drug therapy would have the potential to minimize the risks of the complications and side effects of these drugs. Fortunately, some immunosuppressive and other agents not only impede the effector T cell response, but also help generate new CD4 + Tregs from conventional effector T cells. These agents include IL-2, TGF-β, agents that block the CD40/ CD40L costimulation pathway, mTOR inhibitors, and histone deacetylase inhibitors. Consequently, a state of relative unresponsiveness to the transplanted organ may be induced through the expansion of Tregs. We here review the effect of these various agents on expansion of CD4 + Tregs in allo-and xenotransplantation. The expansion of Tregs might allow a dose reduction of the standard immunosuppressive drugs.

The case for the therapeutic use of mechanistic/mammalian target of rapamycin (mTOR) inhibitors in xenotransplantation

“…54 The mechanism by which anti-CD154 mAb induces tolerance is by inducing Tregs. [55][56][57] In contrast, another report suggested that monotherapy with an anti-CD154mAb cannot induce tolerance and is not sufficient to prevent chronic graft vasculopathy. 58 Thus, the combination of an mTOR-I and an anti-CD154 mAb may have additive or synergistic effects.…”

“…Anti‐CD154 (anti‐CD40 ligand) monoclonal antibody (mAb) is attractive as an immunosuppressant, and may lead to tolerance 54 . The mechanism by which anti‐CD154 mAb induces tolerance is by inducing Tregs 55–57 . In contrast, another report suggested that monotherapy with an anti‐CD154mAb cannot induce tolerance and is not sufficient to prevent chronic graft vasculopathy 58 .…”

Xenotransplantation literature update, November/December 2020

“…Zhao et al chose to review the many available methods that have been used to isolate, purify, and expand Tregs. They provide a thorough list of the many methods used to isolate and expand them along with the advantages and disadvantages of each 15 …”

“…Emerging data also indicate that manipulation of other cellular signaling pathways and metabolic agents which regulate the expansion of Tregs. These agents include acetic acid, vitamin D3, vitamin C, tocilizumab, and IL‐17‐neutralizing antibody 15 …”