A. The role of recently discovered innate lymphoid cells (ILCs) in intestinal transplant (ITx) patients is poorly understood. Here, we postulate that intestinal ILC subsets are dysregulated in the lamina propria after ITx thus controlling intestinal homeostasis and intestinal stem cell (ISC) regeneration.

B. Intestinal biopsies (Bx) were obtained immediately after ITx at day 0 and followed longitudinally. Phenotypic analysis of lamina propria cells was conducted by flow cytometry and immunohistochemistry (IHC). Gating was performed on viable linage negative isolated lamina propria cells with group 1 and 3 ILCs identified by expression of CD56, NKp44, CD117, and CD127. Isolated graft infiltrating lymphocytes were flow sorted and rtPCR was performed to investigate effector cytokine and transcription factor profiles.

C.To test our hypothesis we studied ITx lamina propria Bx at day 0 via flow cytometry, IHC and rtPCR and compared stable patients greater than 6 months post ITx. Critically, we found that the proinflammatory IFN-gamma-producing CD127+ ILC1 subset (p=0.4918) was preserved in fresh ITx at a level comparable to stable patients. To our surprise we found IL-22-producing NCR+ ILC3 population (p=0.0029) were absent in fresh allografts compared to NCR+ ILC3 populations in stable recipients 6 months out. We hypothesized that ILC1-ILC3 dysbalance resolves in ITx over time and tested this by examining Bx of recent ITx patients with flow cytometry, IHC, and rtPCR longitudinally starting from day 0 to 6 months post ITx. Intriguingly, we found that the IFN-gamma ILC1 population remained stable while there was recovery of IL-22-producing NCR+ ILC3 population in complication free ITx patients after 4-8 weeks post ITx (p=0.0245), corroborating that ILC dysbalance resolves post ITx due to recovery of protective ILC3. This had a profound impact on allograft homeostasis post ITx as we further found that recovery of ILC3 correlated with a significantly enhanced expression level of IL-22-dependent Lgr5+ ISC by postoperative week 4 (p=0.0033).

D. This study suggests an important dysbalance between proinflammatory and protective ILC populations immediately following ITx that resolves over time with ILC3 recovery playing a role in targeting ISC recovery thus allograft homeostasis early after ITx.

CITATION INFORMATION: Cha P, Houlihan B, Kaiser J, Cosentino C, Monahan B, Shukla A, Hawksworth J, Matsumoto C, Fishbein T, Kroemer A. Innate Lymphoid Cells Play a Critical Role in Regulating Allograft Homeostasis in Human Intestinal Transplantation. Am J Transplant. 2017;17 (suppl 3).

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