Update on immunosuppressive strategies in intestinal transplantation

Abstract

Purpose of reviewThe intestine is the most immunologically complex solid organ allograft with the greatest risk of both rejection and graft-versus-host disease (GVHD). High levels of immunosuppression are required, further increasing morbidity. Due to low volume of transplants and few centers with experience, there is paucity of evidence-based, standardized, and effective therapeutic regimens. We herein review the most recent data about immunosuppression, focusing on novel and emerging therapies.Recent findingsRecent data are moving the field toward increasing use of basilixumab and consideration of alemtuzumab for induction and inclusion of mammalian target of rapamycin inhibitors and antimetabolites for maintenance. For rejection, we highlight novel roles for tumor necrosis factor-α inhibition, α4β7 integrin inhibition, microbiome modulation, desensitization protocols, and tolerance induction strategies. We also highlight emerging novel therapies for GVHD, especially the promising role of Janus kinase inhibition.SummaryNew insights into immune pathways associated with rejection and GVHD in intestinal allografts have led to an evolution of therapies from broad-based immunosuppression to more targeted strategies that hold promise for reducing morbidity from infection, rejection, and GVHD. These should be the focus of further study to facilitate their widespread use.

Current Advances in Graft-versus-host Disease After Intestinal Transplantation

“…Although this practice has been shown in animal models of ITx to prevent GvHD, there is little information to support the efficacy of this practice in clinical transplantation. 2,[77][78][79][80]…”

“…Several mechanisms are likely to contribute to the therapeutic efficacy of extracorporeal photopheresis (ECP). 77,85,86 One of the direct effects of ECP is the induction of lymphocyte and monocyte apoptosis mediated via photosensitizing agents generating free oxygen radicals upon exposure to UV light, leading to oxidative stress and cell death. 87 Additionally, ECP has been known to play a role in the transition from Th1 to Th2 immune response, as well as increasing the number of Treg.…”

“…rabbit-specific antigens, thereby minimizing response to treatment. 77 Although addition of ATG to corticosteroid therapy in GvHD management after ITx is well established, its impact on survival is not well elucidated. 12,77 Kaufman et al 2 reported that of the 13 patients in their study who received ATG (10 rabbit ATG and 3 equine ATG), 4 survived and 9 died (P = 0.2761).…”

“…Second-line therapies vary by center and generally include the use of ATG, TNF-α inhibitors, rituximab, or JAK inhibitors. 2,4,9,12,77 An algorithmic approach to the management of ITx patients with GvHD would require further data than are currently available. However, based on our center's experience, given the promising data surrounding ruxolitinib in HSCT and case reports in ITx, earlier intervention in SR-GvHD with JAK inhibitors in patients could be considered.…”

“…88 Multiple studies have demonstrated the efficacy of ECP in refractory GvHD after HSCT; however, limited studies have shown the effectiveness of ECP in GvHD after ITx. 77,85,86,89 Merola et al 77 described 2 case reports demonstrating the potential benefits from ECP. Decreased chimerism in both patients, in addition to full recovery in one patient, was described.…”