Combined Lung and Liver Transplantation: the United States Experience

Kotru, Anil; Sheperd, Ross; Nadler, Michelle; Chapman, William; Huddleston, Charles B.; Lowell, Jeffrey A.

doi:10.1097/01.tp.0000227923.85536.2f

Cited by 19 publications

(9 citation statements)

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“…Moreover, liver transplants were described to induce donor‐specific tolerance 36. In humans, the tolerogenic effects mediated by liver transplants are controversially discussed 37, 38. The underlying mechanisms responsible for these tolerogenic effects are not completely understood, and many factors may be involved.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial and immunoregulatory properties of human tryptophan 2,3‐dioxygenase

et al. 2009

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In mammals, the regulation of local tryptophan concentrations by the IFN-c-i inducible enzyme IDO is a prominent antimicrobial and immunoregulatory effector mechanism. Here, we show for the first time that another tryptophan-degrading enzyme, the liverspecific tryptophan 2,3-dioxygenase (TDO), is also capable of mediating antimicrobial and immunoregulatory effects. Using a tetracycline inducible eukaryotic system, we were able to express recombinant TDO protein, which exhibits functional properties of native TDO. We found that HeLa cells expressing recombinant TDO were capable of inhibiting the growth of bacteria (Staphylococcus aureus), parasites (Toxoplasma gondii) and viruses (herpes simplex virus). These TDO-mediated antimicrobial effects could be blocked by the addition of tryptophan. In addition, we observed that, similar to IDO-positive cells, TDOpositive cells were capable of inhibiting anti CD3-driven T-cell proliferation and IFN-c production. Furthermore, TDO-positive cells also restricted alloantigen-induced T-cell activation. Here, we describe for the first time that TDO mediates antimicrobial and immunoregulatory effects and suggest that TDO-dependent inhibition of T-cell growth might be involved in the immunotolerance observed in vivo during allogeneic liver transplantation.Key words: Kynurenine . T cells . Tolerance . Tryptophan . Tryptophan 2,3-dioxygenase Introduction L-tryptophan (L-trp) is an essential amino acid that is not only required for the synthesis of proteins, but also for the biosynthesis of neurotransmitters such as serotonin and melatonin. Nevertheless, most of the dietary L-trp is catabolised via the kynurenine pathway to kynurenines and these are eliminated in the urine (hence their names). A small amount of the dietary tryptophan is used to produce the physiological relevant NAD [1,2].In mammals, the first and rate-limiting step of the kynurenine pathway, namely the oxidation of tryptophan to N-formyl kynurenine, is catalysed by the hepatic tryptophan 2,3-dioxygenase (TDO, EC 1.13.11.11) and the extra-hepatic IDO (EC 1.13.11.52). Recently, a third tryptophan-degrading enzyme, IDO2, was described, however, the in vivo function of this enzyme remains speculative [3,4].The function of IDO has been most intensively analysed and shown to be involved in several essential processes. Being an immunoregulated enzyme with antimicrobial and immunoregulatory function, IDO regulates T-cell responses and induces maternal tolerance towards the allogeneic foetus [5]. Interestingly, IDO also seems to play a role in cancer progression as the magnitude of its expression, for example, correlates with the overall survival of serous-type ovarian cancer patients, specifying IDO as a marker for a poor prognosis [6].IDO mediates its activity locally, in inflamed tissue or lymph nodes. In contrast, TDO activity is mainly expressed in the liver and is not regulated by the immune system but does have Ã These authors contributed equally to this work. systemic effects by controlling the tryptophan levels in ...

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Section: Discussionmentioning

confidence: 99%

Antimicrobial and immunoregulatory properties of human tryptophan 2,3‐dioxygenase

et al. 2009

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“…Thus, the liver appears to play an important role in oral (50) and portal venous tolerance (51), whereas hepatic allografts are accepted more readily than others types of organ transplant (52–53), and can protect other grafts from the same donor from rejection (54–55). Furthermore, hepatitis B and C virus infection is more likely to induce chronic infection of the liver than other organs (56–57).…”

Section: Discussionmentioning

confidence: 99%

NOD2 Ligation Subverts IFN-α Production by Liver Plasmacytoid Dendritic Cells and Inhibits Their T Cell Allostimulatory Activity via B7-H1 Up-Regulation

Castellaneta

Sumpter

Chen³

et al. 2009

The Journal of Immunology

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The nucleotide-binding oligomerization domain (NOD)2/CARD15 protein, which senses muramyl dipeptide (MDP), a product of bacterial peptidoglycan, appears to play an important role in regulating intestinal immunity. Although the liver is exposed to gut-derived MDP, the influence of NOD2 ligation on hepatic APC, in particular dendritic cells (DC), is unknown. Freshly isolated mouse liver and spleen plasmacytoid (p)DC expressed higher levels of NOD2 message than conventional myeloid (m)DC. Following MDP stimulation in vivo, liver pDC, but not mDC, up-regulated expression of IFN regulatory factor 4 (IRF-4), a negative regulator of TLR signaling, and induced less allogeneic T cell proliferation and IFN-γ production. The adoptive transfer of liver pDC from MDP-treated mice failed to prime allogeneic T cells in vivo. By contrast, splenic DC IRF-4 levels and T cell stimulatory activity remained unchanged. Liver pDC from MDP-stimulated mice also displayed greater IκBα, cell surface B7-H1, and B7-H1 relative to CD86 than control liver pDC. No similar effects were observed for liver mDC or spleen DC. Absence of B7-H1 on liver pDC reversed the inhibitory effect of MDP. After ex vivo stimulation with LPS or CpG, liver pDC but not mDC from MDP-treated animals secreted less IL-12p70, IL-6, and TNF-α and induced weaker allogeneic T cell proliferation than those from controls. Moreover, CpG-stimulated liver pDC from MDP-treated mice secreted less IFN-α than their splenic counterparts, and systemic levels of IFN-α were reduced in MDP-treated animals after CpG administration. These findings suggest that differential effects of NOD2 ligation on liver pDC may play a role in regulating hepatic innate and adaptive immunity.

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“…For example, LTx performed simultaneously with other transplanted organs can provide protection against their rejection (eg, kidney and lung)1 2 and, furthermore, can reverse the rejection of another allograft transplanted a few days before the liver 3. Interestingly, in normal practice, human leukocyte antigen (HLA) typing is not generally used even to select a matched donor–recipient combination because it is argued that matching has no significant impact on LTx survival 4 5.…”

Section: Immunological Considerations With Liver Transplantationmentioning

confidence: 99%

Immunosuppression for liver transplantation

Geissler

Schlitt

2008

Gut

122

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In the last few decades liver transplantation (LTx) has become a reliable life-saving procedure for patients with chronic end-stage liver diseases. LTx has an outstanding success rate in the first few years after allografting, especially considering that many patients are on the brink of survival at the time of transplantation. The success of LTx is owed to the pioneers who developed the surgical procedures and to researchers who discovered the medications to help prevent immunological rejection of allografts. However, several problems continue to impose serious limits on LTx today, including a shortage of donor livers, recurrence of disease (eg, hepatitis, hepatocellular cancer), preservation of long-term allograft function and the side effects of anti-rejection drugs. While the dilemma of organ shortage is not a focus of this review, we will address the latter issues as they relate to the "oldest" and "newest" approaches to immunosuppression, and discuss the prospect that recipients could potentially be made immunologically tolerant to liver transplants. Due to the critical shortage of organs, new strategies to preserve transplanted liver allografts for the longest possible time are of paramount importance.

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Combined Lung and Liver Transplantation: the United States Experience

Cited by 19 publications

References 1 publication

Antimicrobial and immunoregulatory properties of human tryptophan 2,3‐dioxygenase

Antimicrobial and immunoregulatory properties of human tryptophan 2,3‐dioxygenase

NOD2 Ligation Subverts IFN-α Production by Liver Plasmacytoid Dendritic Cells and Inhibits Their T Cell Allostimulatory Activity via B7-H1 Up-Regulation

Immunosuppression for liver transplantation

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