Technique for xenogeneic cross-circulation to support human donor lungs ex vivo

Wu, Wei; Guenthart, Brandon A.; O’Neill, John D.; Hozain, Ahmed E.; Tipograf, Yuliya; Ukita, Rei; Stokes, John W.; Patel, Yatrik J; Pinezich, Meghan R.; Talackine, Jennifer; Cardwell, Nancy L.; Fung, Kenmond; Vunjak‐Novakovic, Gordana; Bacchetta, Matthew

doi:10.1016/j.healun.2022.11.002

Cited by 10 publications

(8 citation statements)

References 30 publications

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“…1 h before cross-circulation initiation in the perfusing pig, at a “bolus” dose classically used in pig lung transplantation (i.e. 20 mg/kg ( 22 – 24 ),), which is in the same order of magnitude as the dose used in humans. We followed the clinical parameters hourly and performed tissue sampling at 0 h (before cross-circulation initiation), 6 h and 10 h.…”

Section: Resultsmentioning

confidence: 99%

Differential early response of monocyte/macrophage subsets to intra-operative corticosteroid administration in lung transplantation

Glorion,

Pascale,

Huriet

et al. 2023

Front. Immunol.

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IntroductionLung transplantation often results in primary and/or chronic dysfunctions that are related to early perioperative innate allo-responses where myeloid subsets play a major role. Corticosteroids are administered upon surgery as a standard-of-care but their action on the different myeloid cell subsets in that context is not known.MethodsTo address this issue, we used a cross-circulatory platform perfusing an extracorporeal lung coupled to cell mapping in the pig model, that enabled us to study the recruited cells in the allogeneic lung over 10 hours.ResultsMyeloid cells, i.e. granulocytes and monocytic cells including classical CD14pos and non-classical/intermediate CD16pos cells, were the dominantly recruited subsets, with the latter upregulating the membrane expression of MHC class II and CD80/86 molecules. Whereas corticosteroids did not reduce the different cell subset recruitment, they potently dampened the MHC class II and CD80/86 expression on monocytic cells and not on alveolar macrophages. Besides, corticosteroids induced a temporary and partial anti-inflammatory gene profile depending on cytokines and monocyte/macrophage subsets.DiscussionThis work documents the baseline effects of the standard-of-care corticosteroid treatment for early innate allo-responses. These insights will enable further optimization and improvement of lung transplantation outcomes.

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Section: Resultsmentioning

confidence: 99%

Differential early response of monocyte/macrophage subsets to intra-operative corticosteroid administration in lung transplantation

Glorion,

Pascale,

Huriet

et al. 2023

Front. Immunol.

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“…[10] This technique enabled functional organ preservation with improved histopathologic injury over 12 hours. In studies in the lung, our group also demonstrated that cross-circulation supported the functional recovery and multiday maintenance of ex vivo swine lungs, [11][12][13][14] as well as the viability and functional recovery of unallocated human lungs using xenogeneic cross-circulation (XC). [15] We hypothesize that, likewise, XC of ex vivo human livers could enable multisystem physiological regulation, preservation of tissue integrity, and functional organ rehabilitation.…”

Section: Introductionmentioning

confidence: 89%

“…This technique enabled functional organ preservation with improved histopathologic injury over 12 hours. In studies in the lung, our group also demonstrated that cross-circulation supported the functional recovery and multiday maintenance of ex vivo swine lungs, 11–14 as well as the viability and functional recovery of unallocated human lungs using xenogeneic cross-circulation (XC) 15 …”

Section: Introductionmentioning

confidence: 90%

Xenogeneic cross-circulation for physiological support and recovery of ex vivo human livers

Ukita

Patel

et al. 2023

Hepatology

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Background and Aims: The scarcity of suitable donor livers highlights a continuing need for innovation to recover organs with reversible injuries in liver transplantation. Approach and Results: Explanted human donor livers (n = 5) declined for transplantation were supported using xenogeneic cross-circulation of whole blood between livers and xeno-support swine. Livers and swine were assessed over 24 hours of xeno-support. Livers maintained normal global appearance, uniform perfusion, and preservation of histologic and subcellular architecture. Oxygen consumption increased by 75% (p = 0.16). Lactate clearance increased from −0.4 ± 15.5% to 31.4 ± 19.0% (p = 0.02). Blinded histopathologic assessment demonstrated improved injury scores at 24 hours compared with 12 hours. Vascular integrity and vasoconstrictive function were preserved. Bile volume and cholangiocellular viability markers improved for all livers. Biliary structural integrity was maintained. Conclusions: Xenogeneic cross-circulation provided multisystem physiological regulation of ex vivo human livers that enabled functional rehabilitation, histopathologic recovery, and improvement of viability markers. We envision xenogeneic cross-circulation as a complementary technique to other organ-preservation technologies in the recovery of marginal donor livers or as a research tool in the development of advanced bioengineering and pharmacologic strategies for organ recovery and rehabilitation.

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“…The xenogeneic XC technique has been previously described in detail ( 68 ). All swine participants ( n = 4) underwent intramuscular anesthetic induction with ketamine (2.2 mg/kg; Zoetis), tiletamine (4.4 mg/kg; Zoetis), and xylazine (2.2 mg/kg; Bimeda).…”

Section: Methodsmentioning

confidence: 99%

Immune characterization of a xenogeneic human lung cross-circulation support system

Stier

Stokes

et al. 2023

Sci. Adv.

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Improved approaches to expanding the pool of donor lungs suitable for transplantation are critically needed for the growing population with end-stage lung disease. Cross-circulation (XC) of whole blood between swine and explanted human lungs has previously been reported to enable the extracorporeal recovery of donor lungs that declined for transplantation due to acute, reversible injuries. However, immunologic interactions of this xenogeneic platform have not been characterized, thus limiting potential translational applications. Using flow cytometry and immunohistochemistry, we demonstrate that porcine immune cell and immunoglobulin infiltration occurs in this xenogeneic XC system, in the context of calcineurin-based immunosuppression and complement depletion. Despite this, xenogeneic XC supported the viability, tissue integrity, and physiologic improvement of human donor lungs over 24 hours of xeno-support. These findings provide targets for future immunomodulatory strategies to minimize immunologic interactions on this organ support biotechnology.

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Technique for xenogeneic cross-circulation to support human donor lungs ex vivo

Cited by 10 publications

References 30 publications

Differential early response of monocyte/macrophage subsets to intra-operative corticosteroid administration in lung transplantation

Differential early response of monocyte/macrophage subsets to intra-operative corticosteroid administration in lung transplantation

Xenogeneic cross-circulation for physiological support and recovery of ex vivo human livers

Immune characterization of a xenogeneic human lung cross-circulation support system

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