Blocking the CD28-B7 T-cell costimulatory pathway abrogates the development of obliterative bronchiolitis in a murine heterotopic airway model.
BACKGROUND
CTLA4IgG that binds to B7 effectively inhibits the signaling of CD28/B7 pathway and induces antigen-specific T-cell unresponsiveness in vitro and in vivo. We examined whether the development of obliterative bronchiolitis in a murine heterotopic airway transplantation model is T cell dependent and whether CTLA4IgG abrogates the development of obliterative bronchiolitis.


METHODS
Tracheae with main bronchi from C3H/He (H2k), BALB/C (H2d), or C57BL/6 (H2b) mice were transplanted heterotopically into subcutaneous pockets on the backs of BALB/C or BALB/C nu/nu mice on day 0. Recipient mice were untreated or intraperitoneally treated with either CTLA4IgG or human IgG with different time and dose schedules.


RESULTS
The development of obliterative bronchiolitis, which leads to luminal obliteration by fibrous tissue in a murine heterotopic airway transplantation model, was T cell dependent and the development of obliterative bronchiolitis was significantly abrogated by the CTLA4IgG treatment. However, the normal ciliated columnar respiratory epithelial cells in allografts were lost and replaced by flattened attenuated epithelial cells even after the CTLA4IgG treatment. We further demonstrated that CTLA4IgG treatment did not result in the induction of donor-specific unresponsiveness.


CONCLUSIONS
We demonstrated that the development of obliterative bronchiolitis in a murine heterotopic airway model involves both CD28/B7-dependent and -independent processes. The luminal obliteration by fibrous tissue is clearly CD28/B7 dependent and can be inhibited by CTLA4IgG. The luminal obliteration of allografted trachea by fibrous tissues and the loss of ciliated columnar respiratory epithelial cells represent distinct disease processes.
Yamada
A
A
Section of Immunopathogenesis, Institute of Immunological Science, Hokkaido University, Sapporo, Japan.
Konishi
K
K
Cruz
G L
GL
Takehara
M
M
Morikawa
M
M
Nakagawa
I
I
Murakami
M
M
Abe
T
T
Todo
S
S
Uede
T
T
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000097:blood / Q000276:immunology; D018122:B7-1 Antigen / Q000032:analysis*; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018106:CD28 Antigens / Q000032:analysis*; D060908:CTLA-4 Antigen; D006801:Humans; D007108:Immune Tolerance; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011183:Postoperative Complications / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D014132:Trachea / Q000473:pathology / Q000637:transplantation*; D016042:Transplantation, Heterotopic / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007074:Immunoglobulin G; D000069594:Abatacept