Immunologic, morphologic, and functional evaluation of long-term-surviving beagle lung allograft recipients treated with lethal total-body irradiation, autologous bone marrow, and methotrexate.

Immunologic, morphologic, and functional evaluations were performed in beagle dogs with single lung allografts surviving 3-13 years after transplantation. Immunosuppressive treatment included lethal total-body irradiation, autologous bone marrow reconstitution, and three doses of methotrexate. Three beagle recipients with full DLA-haplotype-matched grafts and five recipients with one-haplotype-mismatched grafts were studied. Evidence of rejection--i.e., infiltrates on chest roentgenograms, hypoperfusion on radionuclide lung scans, and histopathologic changes--were absent in the matched recipients and in three of the five mismatched recipients. Two of the mismatched recipients had decreased perfusion to their allografted lungs, and open-lung biopsy specimens revealed diffuse fibrotic blood vessels with narrowed lumina but no other abnormalities. Decreased fractional blood flow to the lung allograft of the five one-haplotype-mismatched recipients was correlated (r = -0.92) with the level of donor-specific cytolytic lymphocyte activity generated in mixed lymphocyte cultures (MLC). In contrast, the level of proliferative activity in donor-specific MLC did not correlate well with graft function. These findings suggest that the mechanism of tolerance to these lung allografts (with particular regard to vascular integrity) involves attenuation of the response against major histocompatibility complex (MHC) class I alloantigen since the induction of cytolytic T lymphocytes in MLC is directed primarily against these molecules. Though all of the mismatched recipients had the ability to react against MHC class II alloantigens in vitro (as demonstrated by proliferative responses in MLC), in vivo responses to class II gene products may not occur because of the lack of expression of these molecules on long-term surviving grafts.