In Vivo Development of Transplant Arteriosclerosis in Humanized Mice Reflects Alloantigen Recognition and Peripheral Treg Phenotype of Lung Transplant Recipients |
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| Authors: | T. Siemeni A.‐K. Knöfel N. Madrahimov W. Sommer M. Avsar J. Salman F. Ius N. Frank G. Büchler D. Jonigk K. Jansson U. Maus I. Tudorache C. S. Falk A. Haverich G. Warnecke |
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| Affiliation: | 1. Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany;2. German Centre for Lung Research, BREATH Site, Hannover Medical School, Hannover, Germany;3. Institute for Pathology, Hannover Medical School, Hannover, Germany;4. Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany;5. Institute of Transplant Immunology, IFB‐Tx, Hannover Medical School, Hannover, Germany |
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| Abstract: | 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+CD25high T 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. |
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| Keywords: | basic (laboratory) research/science clinical research/practice lung transplantation/pulmonology immunosuppression/immune modulation lung (allograft) function/dysfunction rejection: chronic alloantigen animal models: murine cytokines/cytokine receptors |
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