Gut microbiota–dependent modulation of innate immunity and lymph node remodeling affects cardiac allograft outcomes

Bromberg, Jonathan S.; Hittle, Lauren E.; Xiong, Yanbao; Saxena, Vikas; Smyth, Eoghan M.; Li, Lushen; Zhang, Tianshu; Wagner, Chelsea; Fricke, W. Florian; Thézenas, Simon; Brinkman, C. Colin; Mongodin, Emmanuel F.

doi:10.1172/jci.insight.121045

Cited by 55 publications

(82 citation statements)

References 94 publications

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“…Stools collected from untreated naive C57BL/6 mice were weighed and homogenized in PBS (200 mg/mL). For FMT experiments, recipient C57BL/6 mice fed amoxicillin (50 mg/mL in the drinking water) on days -11 to -1 were then conditioned with or without FMT (200 μl at 200 mg/mL) on days -1 and 0 by forced gavage prior to BALB/c liver transplantation surgery, as described previously (11).…”

Section: Discussionmentioning

confidence: 99%

“…Early exposure to germs was found to modify IR-triggered kidney damage and inflammation in mice (9). More recent studies have also identified the microbiota as an environmental factor influencing survival of mouse skin and cardiac allografts (10,11), whereas relatively little is known about its role in OLT (12,13). Although 2 weeks of antibiotic (Abx) pretreatment of the "donor" influenced Kupffer cell function and ameliorated hepatic IRI in mouse OLT (14), the clinical relevance of this strategy in cadaveric OLT is questionable.…”

Section: Introductionmentioning

confidence: 99%

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Antibiotic pretreatment alleviates liver transplant damage in mice and humans

Nakamura¹,

Kageyama²,

Itô³

et al. 2019

Journal of Clinical Investigation

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ResultsRecipient Abx pretreatment attenuates, but adjunctive fecal microbiota transfer recreates, hepatic IRI in mouse allogeneic OLT. We first aimed to determine the influence of Abx treatment on IRI severity in a clinically relevant allogeneic mouse OLT model (BALB/c> C57BL/6) with ex vivo cold storage (4°C for 18 hours), which mimics marginal human liver grafts. Mouse OLT recipients pretreated for 10 days (14, 15) with oral Abx (amoxicillin, 50 mg/mL) showed decreased serum aspartate aminotransferase (sAST) levels (OLT = 7047 ± 1332 vs. OLT + Abx = 3609 ± 447 IU/L, P = 0.0317; Figure 1A); attenuated sinusoidal congestion, edema/vacuolization and hepatocellular necrosis ( Figure 1B); decreased Suzuki's histological grading of IRI (OLT = 6.8 ± 0.6 vs. OLT + Abx = 3.6 ± 0.5, P

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antibiotic pretreatment alleviates liver transplant damage in mice and humans

Nakamura¹,

Kageyama²,

Itô³

et al. 2019

Journal of Clinical Investigation

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“…96,[113][114][115] Laminin 411 and 511 serve as coinhibitory and costimulatory li- Laminin α4 is associated with tolerance and laminin α5 is associated with immunity. Laminin α4 increases in response to tolerance induction, increasing the laminin α4:α5 ratio.…”

Section: Lymph Node Microenvironment: Stromal Fibers and Conduitsmentioning

confidence: 99%

“…Conversely, upregulation of laminin α5 occurs in response to immunity and inflammation, decreasing the laminin α4:α5 ratio. 96,[113][114][115] Laminin 411 and 511 serve as coinhibitory and costimulatory ligands for CD4 T cells, respectively. Laminin 411 suppresses CD4 T cell activation and Th1, Th2, and Th17 polarization, but favors iTreg polarization; laminin 511 displays the opposite effect on CD4 T cell differentiation.…”

Section: Immunity or Tolerance Induction Affect The Expression Of Lammentioning

confidence: 99%

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Role of lymph node stroma and microenvironment in T cell tolerance

Saxena

Paluskievicz

et al. 2019

Immunological Reviews

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Lymph nodes (LNs) are at the cross roads of immunity and tolerance. These tissues are compartmentalized into specialized niche areas by lymph node stromal cells (LN SCs). LN SCs shape the LN microenvironment and guide immunological cells into different zones through establishment of a CCL19 and CCL21 gradient. Following local immunological cues, LN SCs modulate activity to support immune cell priming, activation, and fate. This review will present our current understanding of LN SC subsets roles in regulating T cell tolerance. Three major types of LN SC subsets, namely fibroblastic reticular cells, lymphatic endothelial cells, and blood endothelial cells, are discussed. These subsets serve as scaffolds to support and regulate T cell homeostasis. They contribute to tolerance by presenting peripheral tissue antigens to both CD4 and CD8 T cells. The role of LN SCs in regulating T cell migration and tolerance induction is discussed. Looking forward, recent advances in bioengineered materials and approaches to leverage LN SCs to induce T cell tolerance are highlighted, as are current clinical practices that allow for manipulation of the LN microenvironment to induce tolerance. Increased understanding of LN architecture, how different LN SCs integrate immunological cues and shape immune responses, and approaches to induce T cell tolerance will help further combat autoimmune diseases and graft rejection.

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