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

Alexander Kroemer*, Leonid Belyayev, Khalid Khan, Katrina Loh, Jiman Kang, Anju Duttargi, Harmeet Dhani, Mohammed Sadat, Oswaldo Aguirre, Yuriy Gusev, Krithika Bhuvaneshwar, Bhaskar Kallakury, Christopher Cosentino, Brenna Houlihan, Jamie Diaz, Sangeetha Moturi, Nada Yazigi, Stuart Kaufman, Sukanya Subramanian, Jason HawksworthRaffaelle Girlanda, Simon C. Robson, Cal S. Matsumoto, Michael Zasloff, Thomas M. Fishbein

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Pages (from-to)1238-1254
Number of pages17
JournalAmerican Journal of Transplantation
Volume21
Issue number3
DOIs
StatePublished - Mar 2021
Externally publishedYes

Keywords

  • T cell biology
  • clinical research/practice
  • immunobiology
  • immunosuppression/immune modulation
  • immunosuppressive regimens
  • intestinal (allograft) function/dysfunction
  • intestine/multivisceral transplantation
  • mucosal immunity
  • rejection
  • translational research/science

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