Short-Term TNF-Alpha Inhibition Reduces Short-Term and Long-Term Inflammatory Changes Post-Ischemia/Reperfusion in Rat Intestinal Transplantation

Gerlach, Undine; Atanasov, Georgi; Wallenta, Leah; Polenz, Dietrich; Reutzel‐Selke, Anja; Kloepfel, Maren; Jurisch, Anke; Marksteiner, Marion; Loddenkemper, Christoph; Neuhaus, P.; Sawitzki, Birgit; Pascher, Andreas

doi:10.1097/tp.0000000000000032

Cited by 29 publications

(13 citation statements)

References 30 publications

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“…In recent studies, the inflammatory gene expression profiling of injured mouse kidney revealed a significant severity-and time-dependent association of the inflammatory pathway with AKI [13]. TNF-α inhibitors decreased inflammatory changed after IRI [14]. In a HgCl 2 -induced AKI mice model, IL-19 expression was high in the kidney [15].…”

Section: Discussionmentioning

confidence: 97%

Augmenter of liver regeneration attenuates inflammation of renal ischemia/reperfusion injury through the NF-kappa B pathway in rats

et al. 2015

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Section: Discussionmentioning

confidence: 97%

Augmenter of liver regeneration attenuates inflammation of renal ischemia/reperfusion injury through the NF-kappa B pathway in rats

et al. 2015

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“…Grafts were gently manipulated since organ manipulation per se induces substantial inflammatory changes . In the last six patients, anti‐TNFα was administered given its protective effect against intestinal ischemia–reperfusion injury . Interestingly, TNFα inhibition has been demonstrated to restore Tregs levels and function in rheumatoid arthritis patients .…”

Section: Discussionmentioning

confidence: 99%

The Leuven Immunomodulatory Protocol Promotes T-Regulatory Cells and Substantially Prolongs Survival After First Intestinal Transplantation

Ceulemans

Braza

Monbaliu

et al. 2016

American Journal of Transplantation

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Intestinal transplantation (ITx) remains challenged by frequent/severe rejections and immunosuppression-related complications (infections/malignancies/drug toxicity). We developed the Leuven Immunomodulatory Protocol (LIP) in the lab and translated it to the clinics. LIP consists of experimentally proven maneuvers, destined to promote T-regulatory (Tregs)-dependent graft-protective mechanisms: donor-specific blood transfusion (DSBT); avoiding high-dose steroids/calcineurin-inhibitors; and minimizing reperfusion injury and endotoxin translocation. LIP was tested in 13 consecutive ITx from deceased donors (2000-2014) (observational cohort study). Recipient age was 37 years (2.8-57 years). Five-year graft/patient survival was 92%. One patient died at 9 months due to aspergillosis, another at 12 years due to nonsteroidal anti-inflammatory drug-induced enteropathy. Early acute rejection (AR) developed in two (15%); late AR in three (23%); all were reversible. No chronic rejection (CR) occurred. No malignancies developed and estimated glomerular filtration rate remained stable post-Tx. At last follow-up (3.5 years [0.5-12.5 years]), no donor-specific antibodies were detected and 11 survivors were total parenteral nutrition free with a Karnofsky score >90% in 8 recipients (follow-up >1 years). A high frequency of circulating CD4 CD45RA Foxp3 memory Tregs was found (1.8% [1.39-2.21]), comparable to tolerant kidney transplant (KTx) recipients and superior to stable immunosuppression (IS)-KTx, KTx with CR, and healthy volunteers. In this ITx cohort we show that DSBT in a low-inflammatory/pro-regulatory environment activates Tregs at levels similar to tolerant-KTx, without causing sensitization. LIP limits rejection under reduced IS and thereby prolongs long-term survival to an extent not previously attained after ITx.

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“…A variety of cytokines and chemokines are detected in gut tissue, lymph draining the intestine, and plasma following intestinal I/R, including TNF-a, IL-1b, Il-6, IL-8, IL-10, MIP-1, and KC (183,348,423,467,538). With the exception of IL-10, these cytokines promote the recruitment of leukocytes in postischemic tissue, and experimental interventions directed toward immunoneutralization or genetic deletion of specific cytokines have been shown to blunt the inflammatory response to gut I/R (124,156,348,536). The appearance of the cytokines in postischemic tissue parallels the increased expression of endothelial cell adhesion molecules like E-selectin (124,416).…”

Section: Consequences and Mechanisms Of Ischemic Injurymentioning

confidence: 98%

The Gastrointestinal Circulation: Physiology and Pathophysiology

Granger

Holm

Kvietys

2015

Comprehensive Physiology

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The gastrointestinal (GI) circulation receives a large fraction of cardiac output and this increases following ingestion of a meal. While blood flow regulation is not the intense phenomenon noted in other vascular beds, the combined responses of blood flow, and capillary oxygen exchange help ensure a level of tissue oxygenation that is commensurate with organ metabolism and function. This is evidenced in the vascular responses of the stomach to increased acid production and in intestine during periods of enhanced nutrient absorption. Complimenting the metabolic vasoregulation is a strong myogenic response that contributes to basal vascular tone and to the responses elicited by changes in intravascular pressure. The GI circulation also contributes to a mucosal defense mechanism that protects against excessive damage to the epithelial lining following ingestion of toxins and/or noxious agents. Profound reductions in GI blood flow are evidenced in certain physiological (strenuous exercise) and pathological (hemorrhage) conditions, while some disease states (e.g., chronic portal hypertension) are associated with a hyperdynamic circulation. The sacrificial nature of GI blood flow is essential for ensuring adequate perfusion of vital organs during periods of whole body stress. The restoration of blood flow (reperfusion) to GI organs following ischemia elicits an exaggerated tissue injury response that reflects the potential of this organ system to generate reactive oxygen species and to mount an inflammatory response. Human and animal studies of inflammatory bowel disease have also revealed a contribution of the vasculature to the initiation and perpetuation of the tissue inflammation and associated injury response.

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Short-Term TNF-Alpha Inhibition Reduces Short-Term and Long-Term Inflammatory Changes Post-Ischemia/Reperfusion in Rat Intestinal Transplantation

Abstract: Infliximab significantly reduced both acute IRI and, as with other TNFα inhibitors, long-term inflammatory responses after rat ITX. TNFα inhibition may help diminish chronic inflammatory long-term effects and avoid chronic allograft enteropathy.

Cited by 29 publications

References 30 publications

Augmenter of liver regeneration attenuates inflammation of renal ischemia/reperfusion injury through the NF-kappa B pathway in rats

Augmenter of liver regeneration attenuates inflammation of renal ischemia/reperfusion injury through the NF-kappa B pathway in rats

The Leuven Immunomodulatory Protocol Promotes T-Regulatory Cells and Substantially Prolongs Survival After First Intestinal Transplantation

The Gastrointestinal Circulation: Physiology and Pathophysiology

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