The Transcription Factor, T-bet, Primes Intestine Transplantation Rejection and Is Associated With Disrupted Mucosal Homeostasis

Ranganathan, Sarangarajan; Ashokkumar, Chethan; Ningappa, Mylarappa; Schmitt, Lori; Higgs, Brandon W.; Sindhi, Rakesh

doi:10.1097/tp.0000000000000445

Cited by 8 publications

(3 citation statements)

References 16 publications

(22 reference statements)

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“…In contrast with the long‐term cohort, in patient P9 we identified an ILC1 expansion coincident with the appearance of acute rejection and CMV infection. The role of ILC1 in controlling CMV at sites of initial infection in response to local pro‐inflammatory cytokines has been already described [45‐48]. Since rejection and CMV infection affect the whole intestinal mucosa, changes in hILC subsets are observed not only in IEp but also in LP.…”

Section: Discussionmentioning

confidence: 99%

Donor helper innate lymphoid cells are replaced earlier than lineage positive cells and persist long‐term in human intestinal grafts – a descriptive study

et al. 2020

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Summary Intestinal grafts carry large donor lymphoid load that is replaced by recipient cells. The dynamics of this process may influence the tolerance, rejection or graft‐versus‐host disease. We analysed distribution and turnover of T and B (Lin+) lymphocytes, natural killer (NK) and helper innate lymphoid cells (hILC) in intestinal epithelium (IEp) and lamina propia (LP) from a long‐term cohort of eight intestinal recipients and from a single patient monitored deeply during the first 8 months post‐transplant (posTx). Long‐term intestinal grafts showed significantly higher %hILC than native bowels in IEp and LP until 10 years posTx and recovery to normal levels was observed afterwards. We also observed an imbalance between hILC subsets in IEp [increase of type 1 (ILC1) and decrease in type 3 (ILC3) innate lymphoid cells] that persisted along posTx time even when %hILC was similar to native bowels. Regarding hILC origin, we still detected the presence of donor cells at 13 years posTx. However, this chimerism was significantly lower than in Lin+ and NK populations. According to these findings, observation from the patient monitored in early posTx period showed that recipient hILC repopulate earlier and faster than Lin+ cells, with increase in ILC1 related to rejection and infection episodes.

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Section: Discussionmentioning

confidence: 99%

Donor helper innate lymphoid cells are replaced earlier than lineage positive cells and persist long‐term in human intestinal grafts – a descriptive study

et al. 2020

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“…Specifically, the dysregulation of Th17 cytokines, which are expressed by ILC3s, is thought to contribute to the development of IBD and other inflammatory and autoimmune conditions (26). Similarly, dysregulation of the Th1 response, driven by the transcription factor T-bet and characterized by IFN-γ secretion, has been associated with rejection after ITx (25, 27). More detailed analyses in additional patients might reveal associations between these phenomena and the turnover and function of various ILC populations.…”

Section: Discussionmentioning

confidence: 99%

Long-term Persistence of Innate Lymphoid Cells in the Gut After Intestinal Transplantation

et al. 2017

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Background Little is known about innate lymphoid cell (ILC) populations in the human gut, and the turnover of these cells and their subsets after transplantation has not been described. Methods Intestinal samples were taken from 4 isolated intestine (ITx) and 3 multivisceral (MvTx) transplant recipients at the time of any operative resection, such as stoma closure or revision. ILCs were isolated and analyzed by flow cytometry. The target population was defined as being negative for lineage markers and double-positive for CD45/CD127. Cells were further stained to define ILC subsets and a donor- or recipient-specific HLA marker to analyze chimerism. Results Donor-derived ILCs were found to persist greater than 8 years after transplantation. Additionally, the percentage of cells thought to be Lymphoid tissue inducer (LTi) cells among donor ILCs was far higher than that among recipient ILCs. Conclusions Our findings demonstrate that donor-derived ILCs persist long-term after transplantation and support the notion that human LTi cells may form in the fetus and persist throughout life, as hypothesized in rodents. Correlation between chimerism and rejection, graft failure, and patient survival requires further study.

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“…Severe rejection episodes involve immune mechanisms that eventually damage the intestinal absorptive capacity and favor the translocation of luminal bacteria, which are closely associated with graft loss and patient death. Other posttransplant (post-Tx) events such as lymphoproliferative disease, graft versus host disease, ulcers, enteritis, eosinophilic syndromes or de novo autoimmunity, derive from a complex interplay of both non-immune and immune factors as yet barely understood (Fishbein, 2009;Kroemer et al, 2016;Loo et al, 2017;Ranganathan et al, 2015;Selvaggi et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

5-gene differential expression predicts stability of human intestinal allografts

Talayero

Alonso

Padilla

et al. 2017

Experimental and Molecular Pathology

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In intestinal allografts, endoscopy and histology detect the injury once changes in the bowel wall architecture have occurred. We aimed to identify a molecular signature that could predict early deterioration, within histologically indistinguishable biopsies with "minimal changes" (MC) pathology. Sixty biopsies from 12 adult recipients were longitudinally taken during 8years post-transplant. They were classified as either stable (STA) or non-stable (NSTA) according to the prospectively recorded number, frequency and severity of rejection events of the allograft. In a discovery set of MC samples analyzed by RNA-Seq, 816 genes were differentially expressed in STA vs NSTA biopsies. A group of 5 genes (ADH1C, SLC39A4, CYP4F2, OPTN and PDZK1) correctly classified all NSTA biopsies in the discovery set and all STA biopsies from an independent set. These results were validated by qPCR in a new group of MC biopsies. Based on a logistic regression model, a cutoff of 0.28 predicted the probability of being a NSTA biopsy with 85% sensitivity and 69% specificity. In conclusion, by analyzing MC samples early after transplantation, the expression of a 5-gene set may predict the evolution of the bowel allograft. This prognostic biomarker may be of help to personalize care of the intestinal transplant recipient.

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The Transcription Factor, T-bet, Primes Intestine Transplantation Rejection and Is Associated With Disrupted Mucosal Homeostasis

Abstract: The transcription factor, t-bet, primes ITx rejection, and associates with disrupted homeostatic relationships between innate and adaptive immune cells in the allograft mucosa during rejection.

Cited by 8 publications

References 16 publications

Donor helper innate lymphoid cells are replaced earlier than lineage positive cells and persist long‐term in human intestinal grafts – a descriptive study

Donor helper innate lymphoid cells are replaced earlier than lineage positive cells and persist long‐term in human intestinal grafts – a descriptive study

Long-term Persistence of Innate Lymphoid Cells in the Gut After Intestinal Transplantation

5-gene differential expression predicts stability of human intestinal allografts

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