Allogeneic CD4+CD25high T Cells Regulate Obliterative Bronchiolitis of Heterotopic Bronchus Allografts in Both Porcinized and Humanized Mouse Models. Issue 3 (March 2015)

• Record Type: Journal Article
• Authors: Sommer, Wiebke; Knöfel, Ann-Kathrin; Madrahimov, Nodir; Avsar, Murat; Jonigk, Danny; Salman, Jawad; Dreckmann, Karla; Jansson, Katharina; Salguero, Gustavo; Maus, Ulrich A.; Welte, Tobias; Haverich, Axel; Warnecke, Gregor
• Is Part Of: Transplantation. Volume 99:Issue 3(2015)
• Publication Date: 2015-03
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000000632
• Languages: English
• ISSNs: 0041-1337

Abstract

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. Abstract : Using a humanized mouse model Sommer et al demonstrate that the development of bronchiolitis obliterans syndrome–a fibroproliferative process after lung transplantation–is controlled by CD4+ regulatory T cells.