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

Abstract

The mechanistic/mammalian target of rapamycin (mTOR) is one of the systems that are necessary to maintain cell homeostasis, such as survival, proliferation, and differentiation. mTOR inhibitors (mTOR‐Is) are utilized as immunosuppressants and anti‐cancer drugs. In organ allotransplantation, current regimens infrequently include an mTOR‐I, which are positioned more commonly as alternative immunosuppressants. In clinical allotransplantation, long‐term efficacy has been established, but there is a significant incidence of adverse events, for example, inhibition of wound healing, buccal ulceration, anemia, hyperglycemia, dyslipidemia, and thrombocytopenia, some of which are dose‐dependent. mTOR‐Is have properties that may be especially beneficial in xenotransplantation. These include suppression of T cell proliferation, increases in the number of T regulatory cells, inhibition of pig graft growth, and anti‐inflammatory, anti‐viral, and anti‐cancer effects. We here review the potential benefits and risks of mTOR‐Is in xenotransplantation and suggest that the benefits exceed the adverse effects.

Current challenges in xenotransplantation

“…In addition, an induction treatment aimed at depleting T cells, preferably CD4 + T cells [ 12 ], and a maintenance immunosuppression based on the use of blockers of the CD40/CD154 co-stimulation pathway appear fundamental. Likewise, the use of rapamycin, included by some in the preclinical immunosuppressive regimen, has been shown to block CD4 + T helper cells and cytotoxic T cells and increase the number of Tregs [ 26 ]. In addition, rapamycin reduces pro-inflammatory cytokines.…”

“…Preclinical studies, however, show that pig kidneys are able to maintain almost all electrolytes in a physiologically normal range and maintain functionality for a long time. Hypercalcemia and hypophosphatemia have been reported following TKO kidney xenotransplantation in NHP [ 26 ]. The mechanisms underlying this dysregulation are still unclear and necessitate further investigations in preclinical and clinical studies [ 29 , 31 ].…”

Antibody‐mediated rejection in xenotransplantation: Can it be prevented or reversed?

“…In view of rapamycin's many properties that suggest it will be effective in xenotransplantation 302 (Table 4), we have selected it as the second agent. In addition, in NHPs it can be administered by the intramuscular route, whereas mycophenolate mofetil [MMF] is usually administered orally, making it difficult to know whether it has been ingested and/or absorbed sufficiently (unless given by continuous i.v.…”

“…have considered it beneficial to inhibit systemic complement activation during the first few post-transplant days, though we have no definitive evidence for this.A maintenance regimen based on CD40/CD154 pathway blockade, first introduced by Buhler et al in 2000,21 combined with rapamycin, for which there are several theoretical advantages302 (Table4), with or without steroids, has proved moderately successful in preventing AMR, Suggested immunosuppressive regimen to (A) prevent AMR or (B) reverse AMR. (A) Prevention of AMR InductionAnti-thymocyte globulin (ATG) -to reduce the CD3 + T cell count to <500 cells/mm 3 Rituximab (10 mg/kg i.v.…”

Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection

“…RAPA is a macrolide immunosuppressant that inhibits the cell cycle in the G1 phase and can inhibit cell- and antibody-mediated rejection through immunosuppressive effects [ 33 ]. mTOR inhibitors (mTOR-Is), such as RAPA, impair DC endocytic functions and reduce MHC-II expression.…”