Donor Lymphoid Organs Are a Major Site of Alloreactive T-Cell Priming Following Intestinal Transplantation

Wang, J.; Dong, Ying; Sun, Jiaren; Taylor, Roger R.; Guo, Chunguang; Alegre, Maria‐Luisa; Williams, Ifor R.; Newell, Kenneth A.

doi:10.1111/j.1600-6143.2006.01516.x

Cited by 34 publications

(24 citation statements)

References 21 publications

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“…Both clinical and experimental data have demonstrated that intestinal allografts elicit a strong immune response (24). The severity of this immune response contributes to the lowered graft and patient survival rates in patients undergoing SBTx, especially when compared with other organs such as the heart or kidney (23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of C4d Deposition and Circulating Antibody in Small Bowel Transplantation

Serre

Canioni

Lacaille

et al. 2008

American Journal of Transplantation

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Antibody-mediated rejection (AMR) consensus criteria are defined in kidney and heart transplantation by histological changes, circulating donor-specific antibody (DSA), and C4d deposition in affected tissue. AMR consensus criteria are not yet identified in small bowel transplantation (SBTx). We investigated those three criteria in 12 children undergoing SBTx, including one retransplantation and four combined liver-SBTx (SBTx), with a follow-up of 12 days to 2 years. All biopsies (91) were evaluated with a standardized grading scheme for acute rejection (AR), vascular lesions and C4d expression. Sera were obtained at day 0 and during the follow-up. C4d was expressed in 37% of biopsies with or without AR, but in 50% of biopsies with severe vascular lesions. In addition, vascular lesions were always associated with AR and a poor outcome. All children with AR (grade 2 or 3) observed before the third month died or lost the graft. DSA were never found in any studied sera. We found no evidence that C4d deposition was of any clinical relevance to the outcome of SBTx. However, the grading of vascular lesions may constitute a useful marker to identify AR that is potentially resistant to standard treatment, and for which an alternative therapy should be considered.

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Section: Discussionmentioning

confidence: 99%

Evaluation of C4d Deposition and Circulating Antibody in Small Bowel Transplantation

Serre

Canioni

Lacaille

et al. 2008

American Journal of Transplantation

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“…Mandy Ford and Kenneth Newell, Emory University). Mice were genotyped for the wild-type and aly mutant alleles of Map3k14 (mitogen-activated protein kinase kinase kinase 14) gene by running two separate PCRs with allele-specific forward primers [5′-CACATCCCGAGCTACTTCAACA-3′ for aly and 5′-CACATCCCGAGCTACTTCAACG-3′ for wild-type NF-κB-inducing kinase (NIK)] and a common reverse primer (5′-CCTTCGGGGACTCTACAGGC-3′ for NIK) (50). The mutant and wild-type NIK alleles both yielded 266-bp PCR products.…”

Section: Methodsmentioning

confidence: 99%

TNF-α augments RANKL-dependent intestinal M cell differentiation in enteroid cultures

Wood

Ríos

Williams

2016

American Journal of Physiology-Cell Physiology

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Microfold (M) cells are phagocytic intestinal epithelial cells in the follicle-associated epithelium of Peyer's patches that transport particulate antigens from the gut lumen into the subepithelial dome. Differentiation of M cells from epithelial stem cells in intestinal crypts requires the cytokine receptor activator of NF-κB ligand (RANKL) and the transcription factor Spi-B. We used three-dimensional enteroid cultures established with small intestinal crypts from mice as a model system to investigate signaling pathways involved in M cell differentiation and the influence of other cytokines on RANKL-induced M cell differentiation. Addition of RANKL to enteroids induced expression of multiple M cell-associated genes, including Spib, Ccl9 [chemokine (C-C motif) ligand 9], Tnfaip2 (TNF-α-induced protein 2), Anxa5 (annexin A5), and Marcksl1 (myristoylated alanine-rich protein kinase C substrate) in 1 day. The mature M cell marker glycoprotein 2 (Gp2) was strongly induced by 3 days and expressed by 11% of cells in enteroids. The noncanonical NF-κB pathway was required for RANKL-induced M cell differentiation in enteroids, as addition of RANKL to enteroids from mice with a null mutation in the mitogen-activated protein kinase kinase kinase 14 (Map3k14) gene encoding NF-κB-inducing kinase failed to induce M cell-associated genes. While the cytokine TNF-α alone had little, if any, effect on expression of M cell-associated genes, addition of TNF-α to RANKL consistently resulted in three- to sixfold higher levels of multiple M cell-associated genes than RANKL alone. One contributing mechanism is the rapid induction by TNF-α of Relb and Nfkb2 (NF-κB subunit 2), genes encoding the two subunits of the noncanonical NF-κB heterodimer. We conclude that endogenous activators of canonical NF-κB signaling present in the gut-associated lymphoid tissue microenvironment, including TNF-α, can play a supportive role in the RANKL-dependent differentiation of M cells in the follicle-associated epithelium.

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“…However, little is known about how HvG and GvH responses influence the turnover, phenotype and repertoire of tissue-resident T-cell populations following transplantation. Studies in mice( 10 ) and humans( 11 ) have indicated that recipient-derived T cells repopulate the GALT (Gut-Associated Lymphoid Tissues) of intestinal allografts early after transplantation. However, the turnover rate of mucosal T cells after intestinal transplantation has been investigated in only a few patients( 12 ) in cross-sectional studies( 11 ), without phenotype or repertoire analysis( 11, 12 ).…”

Section: Introductionmentioning

confidence: 99%

Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome

et al. 2016

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A paradigm in transplantation states that graft-infiltrating T cells are largely non-alloreactive “bystander” cells. However, the origin and specificity of allograft T cells over time has not been investigated in detail in animals or humans. Here, we use polychromatic flow cytometry and high throughput TCR sequencing of serial biopsies to show that gut-resident T cell turnover kinetics in human intestinal allografts are correlated with the balance between intra-graft host-vs-graft (HvG) and graft-vs-host (GvH) reactivities and with clinical outcomes. In the absence of rejection, donor T cells were enriched for GvH-reactive clones that persisted long-term in the graft. Early expansion of GvH clones in the graft correlated with rapid replacement of donor APCs by the recipient. Rejection was associated with transient infiltration by blood-like recipient CD28+ NKG2DHi CD8+ alpha beta T cells, marked predominance of HvG clones, and accelerated T cell turnover in the graft. Ultimately, these recipient T cells acquired a steady state tissue-resident phenotype, but regained CD28 expression during rejections. Increased ratios of GvH to HvG clones were seen in non-rejectors, potentially mitigating the constant threat of rejection posed by HvG clones persisting within the tissue-resident graft T cell population.

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Donor Lymphoid Organs Are a Major Site of Alloreactive T-Cell Priming Following Intestinal Transplantation

Cited by 34 publications

References 21 publications

Evaluation of C4d Deposition and Circulating Antibody in Small Bowel Transplantation

Evaluation of C4d Deposition and Circulating Antibody in Small Bowel Transplantation

TNF-α augments RANKL-dependent intestinal M cell differentiation in enteroid cultures

Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome

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