Rejection of intestinal allotransplants is driven by memory T helper type 17 immunity and responds to infliximab

Abstract

Intestinal transplantation (ITx) can be life‐saving for patients with advanced intestinal failure experiencing complications of parenteral nutrition. New surgical techniques and conventional immunosuppression have enabled some success, but outcomes post‐ITx remain disappointing. Refractory cellular immune responses, immunosuppression‐linked infections, and posttransplant malignancies have precluded widespread ITx application. To shed light on the dynamics of ITx allograft rejection and treatment resistance, peripheral blood samples and intestinal allograft biopsies from 51 ITx patients with severe rejection, alongside 37 stable controls, were analyzed using immunohistochemistry, polychromatic flow cytometry, and reverse transcription‐PCR. Our findings inform both immunomonitoring and treatment. In terms of immunomonitoring, we found that while ITx rejection is associated with proinflammatory and activated effector memory T cells in the blood, evidence of treatment efficacy can only be found in the allograft itself, meaning that blood‐based monitoring may be insufficient. In terms of treatment, we found that the prominence of intra‐graft memory TNF‐α and IL‐17 double‐positive T helper type 17 (Th17) cells is a leading feature of refractory rejection. Anti–TNF‐α therapies appear to provide novel and safer treatment strategies for refractory ITx rejection; with responses in 14 of 14 patients. Clinical protocols targeting TNF‐α, IL‐17, and Th17 warrant further testing.

CD69+ resident memory T cells are associated with graft-versus-host disease in intestinal transplantation

“…Surgical technique, immunosuppression, and medical management were standardized. [22][23][24] Patients with GvHD received initial treatment with methylprednisolone (1 g x 2 then tapered) and thymoglobulin (1.5 mg/kg/day) for 10-14 doses if severe. If refractory, photopheresis (two patients) and ruxolitinib (one patient) were used.…”

The Microbiome and Metabolomic Profile of the Transplanted Intestine with Long-Term Function

“…Intestinal transplantations and post-operative surveillance and management were conducted per institutional protocol, as previously described [ 9 , 10 , 11 ]. Patients received one of four types of intestinal graft, as dictated by presenting diagnosis and gastrointestinal anatomy pre-transplant.…”

The Entangled World of Memory T Cells and Implications in Transplantation

“…Targeting this resistant population using anti-TNF-α (infliximab) was successful in resolving all patient cases of ATG refractory rejection in the study, suggesting that targeting proinflammatory cytokines could be extremely beneficial for resolving alloimmune responses. 78 Many of these new therapeutic targets show significant promise, particularly in their potential to function as secondary immunosuppression with costimulation blockade. This offers multiple avenues worth exploring that can specifically target costimulation blockade-resistant alloreactive memory T cells.…”