Prevention of bronchiolitis obliterans in rat lung allografts by type V collagen-induced oral tolerance.
BACKGROUND
We have reported that feeding type V collagen (col(V)) to lung allograft recipients induces immune tolerance that prevents acute lung allograft rejection. Repeated acute rejection is a risk factor for or associated with chronic rejection, known as bronchiolitis obliterans (BO), the leading cause of death in lung allograft recipients. The current study examines if col(V)-induced oral tolerance prevents BO.


METHODS
WKY rats (RT1l) were fed either col(V) or diluent before orthotopic transplantation of F344 (RT1lvl) lung allografts. No rats received any immunosuppression. At 10 weeks posttransplantation the time to onset of BO, delayed type hypersensitivity (DTH) responses to donor antigens, and col(V) were examined. In addition, proliferative responses of recipient T lymphocytes to donor antigens, and ability of recipient antigen presenting cells to present alloantigens in lung allografts were evaluated.


RESULTS
The data show that recipient rats have sustained DTH responses to donor antigens and col(V). T lymphocytes from col(V)-fed lung allograft recipients were unable to proliferate in response to donor antigens, but feeding col(V) had no effect on the presentation of donor alloantigens by recipient antigen presenting cells. All diluent fed rats developed BO, but only mild acute rejection (grade 2) was present in all rats fed col(V). Transforming growth factor (TGF)-beta production was up-regulated systemically in col(V)-fed, but not diluent fed, lung allograft recipients, and neutralizing TGF-beta [corrected] recovered the DTH response to donor antigens in col(V)-fed rats.


CONCLUSIONS
Collectively these data show that col(V)-induces oral tolerance that prevents BO, and that tolerance may be mediated by systemic production of TGF-beta [corrected].
Yasufuku
Kazuhiro
K
Department of Surgery, Institute of Pulmonary Cancer Research, Chiba University School of Medicine, Chiba, Japan.
Heidler
Kathleen M
KM
Woods
Kena A
KA
Smith
Gerald N
GN
Cummings
Oscar W
OW
Fujisawa
Takehiko
T
Wilkes
David S
DS
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000517:prevention & control*; D002455:Cell Division; D003094:Collagen / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D006968:Hypersensitivity, Delayed; D007519:Isoantigens / Q000276:immunology; D016040:Lung Transplantation / Q000473:pathology / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D013601:T-Lymphocytes / Q000473:pathology; D014184:Transplantation, Homologous
D007519:Isoantigens; D003094:Collagen