In Vivo Development of Transplant Arteriosclerosis in Humanized Mice Reflects Alloantigen Recognition and Peripheral Treg Phenotype of Lung Transplant Recipients.
Experimentally, regulatory T cells inhibit rejection. In clinical transplantations, however, it is not known whether T cell regulation is the cause for, or an epiphenomenon of, long-term allograft survival. Here, we study naïve and alloantigen-primed T cell responses of clinical lung transplant recipients in humanized mice. The pericardiophrenic artery procured from human lung grafts was implanted into the aorta of NODrag-/-/IL-2rγc-/-mice reconstituted with peripheral blood mononuclear cells (PBMCs) from the respective lung recipient. Naïve or primed allogeneic PBMCs procured 21 days post-lung transplantation with or without enriching for CD4+CD25highT cells were used. Transplant arteriosclerosis was assessed 28 days later by histology. Mice reconstituted with alloantigen-primed PBMCs showed significantly more severe transplant arteriosclerosis than did mice with naïve PBMCs (p = 0.005). Transplant arteriosclerosis was equally suppressed by enriching for autologous naïve (p = 0.012) or alloantigen-primed regulatory T cells (Tregs) (p = 0.009). Alloantigen priming in clinical lung recipients can be adoptively transferred into a humanized mouse model. Transplant arteriosclerosis elicited by naïve or alloantigen-primed PBMCs can be similarly controlled by potent autologous Tregs. Cellular therapy with expanded autologous Tregs in lung transplantation might be a promising future strategy.
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
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Siemeni
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.|German Centre for Lung Research, BREATH Site, Hannover Medical School, Hannover, Germany.
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Knöfel
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
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Madrahimov
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.|German Centre for Lung Research, BREATH Site, Hannover Medical School, Hannover, Germany.
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Sommer
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
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Avsar
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
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Salman
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
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Ius
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
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Frank
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
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Büchler
Institute for Pathology, Hannover Medical School, Hannover, Germany.
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Jonigk
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
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Jansson
German Centre for Lung Research, BREATH Site, Hannover Medical School, Hannover, Germany.|Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
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Maus
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
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Tudorache
Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany.
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Falk
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.|German Centre for Lung Research, BREATH Site, Hannover Medical School, Hannover, Germany.
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Haverich
Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany. warnecke.gregor@mh-hannover.de.|German Centre for Lung Research, BREATH Site, Hannover Medical School, Hannover, Germany. warnecke.gregor@mh-hannover.de.
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Warnecke
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology*; D005260:Female; D006084:Graft Rejection / Q000209:etiology*; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008171:Lung Diseases / Q000276:immunology* / Q000601:surgery; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D066027:Transplant Recipients; D014184:Transplantation, Homologous
D007519:Isoantigens
alloantigen; animal models: murine; basic (laboratory) research/science; clinical research/practice; cytokines/cytokine receptors; immunosuppression/immune modulation; lung (allograft) function/dysfunction; lung transplantation/pulmonology; rejection: chronic