Abstract
The role of minor histocompatibility Ag (mHAg)-specific CD8 super(+) CTLs in the pathogenesis of chronic lung allograft rejection (bronchiolitis obliterans syndrome) remains to be elucidated. Thus, the goal of this study was to define the role of a single mHAg mismatch at the polymorphic H13 allele in the development of obliterative airway disease (OAD) after murine heterotopic tracheal transplantation. The H13 super(a) and H13 super(b) alleles encode for the SSVVGVWYL (SVL9) and SSVIGVWYL (SIL9) mHAgs, respectively, presented in the context of the H2D super(b) MHC class I molecule. Toward this, C56BL/10SnJ (H13 super(a)) tracheal allografts were transplanted into congenic B10.CE-H13 super(b) A super(w)(30NX)/Sn (H13 super(b)) recipients. The allografts were harvested at 30, 60, and 90 days after transplantation, and OAD lesions (epithelial damage, cellular infiltration, and luminal fibrosis) were confirmed histologically. Selected groups of mice were immunized (s.c.) or tolerized (i.v.) with the SVL9 peptide before transplantation. This single mHAg mismatch induced the development of OAD within 90 days. SVL9 immunization significantly accelerated the kinetics of the OAD lesions. In contrast, SVL9 tolerization completely abrogated the development of OAD. This was correlated with a complete abrogation of H13 super(a)-specific CD8 super(+) CTL responses with a significant reduction in the frequency of IFN- gamma - producing CTLs and the activation of TGF- beta -producing CD8 super(+) T cells. In conclusion, a single mHAg mismatch can induce the development of OAD. These data also suggest that mHAg-reactive CD8 super(+) CTLs may play an important role in the pathogenesis of chronic lung allograft rejection in humans.