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: Wiebke Sommer, Ann-Kathrin Knöfel, Nodir Madrahimov, Murat Avsar, Danny Jonigk, Jawad Salman, Karla Dreckmann, Katharina Jansson, Gustavo Salguero, Ulrich A Maus, Tobias Welte, Axel Haverich, Gregor Warnecke
• Journal: Transplantation (Transplantation) Vol. 99 Issue 3 Pg. 482-91 (Mar 2015) ISSN: 1534-6080 [Electronic] United States
• PMID: 25695787 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-2 Receptor alpha Subunit

Topics

• Allografts
• Animals
• Bronchi (pathology, transplantation)
• Bronchiolitis Obliterans (immunology, physiopathology)
• CD4-Positive T-Lymphocytes (cytology)
• Cell Separation
• Disease Models, Animal
• Female
• Humans
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Leukocytes, Mononuclear (cytology)
• Major Histocompatibility Complex
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Phenotype
• Swine
• Swine, Miniature
• T-Lymphocytes, Regulatory (cytology)
• Tissue Donors