Clinical lung xenotransplantation - What donor genetic modifications may be necessary?

David K C Cooper, Burcin Ekser, Christopher Burlak, Mohamed Ezzelarab, Hidetaka Hara, Leela Paris, A. Joseph Tector, Carol Phelps, Agnes M. Azimzadeh, David Ayares, Simon C. Robson, Richard N. Pierson

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Barriers to successful lung xenotransplantation appear to be even greater than for other organs. This difficulty may be related to several macro anatomic factors, such as the uniquely fragile lung parenchyma and associated blood supply that results in heightened vulnerability of graft function to segmental or lobar airway flooding caused by loss of vascular integrity (also applicable to allotransplants). There are also micro-anatomic considerations, such as the presence of large numbers of resident inflammatory cells, such as pulmonary intravascular macrophages and natural killer (NK) T cells, and the high levels of von Willebrand factor (vWF) associated with the microvasculature. We have considered what developments would be necessary to allow successful clinical lung xenotransplantation. We suggest this will only be achieved by multiple genetic modifications of the organ-source pig, in particular to render the vasculature resistant to thrombosis. The major problems that require to be overcome are multiple and include (i) the innate immune response (antibody, complement, donor pulmonary and recipient macrophages, monocytes, neutrophils, and NK cells), (ii) the adaptive immune response (T and B cells), (iii) coagulation dysregulation, and (iv) an inflammatory response (e.g., TNF-α, IL-6, HMGB1, C-reactive protein). We propose that the genetic manipulation required to provide normal thromboregulation alone may include the introduction of genes for human thrombomodulin/endothelial protein C-receptor, and/or tissue factor pathway inhibitor, and/or CD39/CD73; the problem of pig vWF may also need to be addressed. It would appear that exploration of every available therapeutic path will be required if lung xenotransplantation is to be successful. To initiate a clinical trial of lung xenotransplantation, even as a bridge to allotransplantation (with a realistic possibility of survival long enough for a human lung allograft to be obtained), significant advances and much experimental work will be required. Nevertheless, with the steadily increasing developments in techniques of genetic engineering of pigs, we are optimistic that the goal of successful clinical lung xenotransplantation can be achieved within the foreseeable future. The optimistic view would be that if experimental pig lung xenotransplantation could be successfully managed, it is likely that clinical application of this and all other forms of xenotransplantation would become more feasible.

Original languageEnglish
Pages (from-to)144-158
Number of pages15
JournalXenotransplantation
Volume19
Issue number3
DOIs
StatePublished - May 2012

Fingerprint

Heterologous Transplantation
Lung
Swine
Alveolar Macrophages
von Willebrand Factor
HMGB1 Protein
Natural Killer T-Cells
Genetic Engineering
Adaptive Immunity
Microvessels
Protein C
Innate Immunity
Natural Killer Cells
C-Reactive Protein
Allografts
Blood Vessels
Monocytes
Interleukin-6
Neutrophils
Thrombosis

Keywords

  • Immune modulation
  • Immune response
  • Inflammation
  • Pig, genetically engineered
  • Thromboregulation
  • Xenotransplantation, lung

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Cooper, D. K. C., Ekser, B., Burlak, C., Ezzelarab, M., Hara, H., Paris, L., ... Pierson, R. N. (2012). Clinical lung xenotransplantation - What donor genetic modifications may be necessary? Xenotransplantation, 19(3), 144-158. https://doi.org/10.1111/j.1399-3089.2012.00708.x

Clinical lung xenotransplantation - What donor genetic modifications may be necessary? / Cooper, David K C; Ekser, Burcin; Burlak, Christopher; Ezzelarab, Mohamed; Hara, Hidetaka; Paris, Leela; Tector, A. Joseph; Phelps, Carol; Azimzadeh, Agnes M.; Ayares, David; Robson, Simon C.; Pierson, Richard N.

In: Xenotransplantation, Vol. 19, No. 3, 05.2012, p. 144-158.

Research output: Contribution to journalArticle

Cooper, DKC, Ekser, B, Burlak, C, Ezzelarab, M, Hara, H, Paris, L, Tector, AJ, Phelps, C, Azimzadeh, AM, Ayares, D, Robson, SC & Pierson, RN 2012, 'Clinical lung xenotransplantation - What donor genetic modifications may be necessary?', Xenotransplantation, vol. 19, no. 3, pp. 144-158. https://doi.org/10.1111/j.1399-3089.2012.00708.x
Cooper, David K C ; Ekser, Burcin ; Burlak, Christopher ; Ezzelarab, Mohamed ; Hara, Hidetaka ; Paris, Leela ; Tector, A. Joseph ; Phelps, Carol ; Azimzadeh, Agnes M. ; Ayares, David ; Robson, Simon C. ; Pierson, Richard N. / Clinical lung xenotransplantation - What donor genetic modifications may be necessary?. In: Xenotransplantation. 2012 ; Vol. 19, No. 3. pp. 144-158.
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