title: Allogeneic CD4+CD25high T cells regulate obliterative bronchiolitis of heterotopic bronchus allografts in both porcinized and humanized mouse models.
abstract: BACKGROUND
  Bronchiolitis obliterans syndrome is caused by a fibroproliferative process in lung allografts resulting in irreversible damage. In this study, we induced obliterative bronchiolitis and studied the contribution of regulatory T cells to its development in immune-deficient mice receiving heterotopic porcine bronchus transplants, and major histocompatibility complex-mismatched porcine peripheral blood mononuclear cell. Furthermore, we aimed to corroborate our findings in a humanized mouse model.
  
  
  METHODS
  Heterotopic bronchus transplantation was performed in 33 NOD.rag(−/−)γc(−/−) mice, using miniature pigs as tissue donors.The recipient mice then either received saline (negative control), unsorted MHC-mismatched PBMC (positive control), PBMC enriched with CD4(+)CD25(high) cells or PBMC depleted of CD4(+)CD25(high) cells for reconstitution. The results were validated in 28 NOD.rag(−/−)γc(−/−) mice undergoing heterotopic human bronchus transplantation and reconstitution with allogeneic human PBMC.
  
  
  RESULTS
  Histological lesions similar to those typical for obliterative bronchiolitis developed in vivo after reconstitution with allogeneic PBMC and were more severe in animals engrafted with PBMC depleted of CD4(+)CD25(high) cells. In contrast, the group reconstituted with PBMC enriched with CD4(+)CD25(high) cells showed well-preserved histology. The results of the humanized model confirmed those obtained in the porcinized model.
  
  
  CONCLUSIONS
  In conclusion, both porcinized and humanized mouse models of heterotopic subcutaneous bronchus transplantation imitate the in vivo development of bronchiolitis obliterans syndrome-like lesions and reveal its sensitivity to T-cell regulation.
authors.affiliation: 1 Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany. 2 German Center for Lung Research, Germany. 3 Institute of Pathology, Hannover Medical School, Hannover, Germany. 4 Department of Hematology, Hannover Medical School, Hannover, Germany. 5 Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Sommer
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Knöfel
authors.forename: Nodir
authors.initials: N
authors.lastname: Madrahimov
authors.forename: Murat
authors.initials: M
authors.lastname: Avsar
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.forename: Jawad
authors.initials: J
authors.lastname: Salman
authors.forename: Karla
authors.initials: K
authors.lastname: Dreckmann
authors.forename: Katharina
authors.initials: K
authors.lastname: Jansson
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salguero
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Maus
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.forename: Gregor
authors.initials: G
authors.lastname: Warnecke
mesh_terms: D064591:Allografts; D000818:Animals; D001980:Bronchi / Q000473:pathology / Q000637:transplantation; D001989:Bronchiolitis Obliterans / Q000276:immunology* / Q000503:physiopathology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002469:Cell Separation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008285:Major Histocompatibility Complex; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010641:Phenotype; D013552:Swine; D013556:Swine, Miniature; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D014019:Tissue Donors
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit