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Induction of Obliterative Airway Disease in Murine Tracheal Allografts by CD8⁺ CTLs Recognizing a Single Minor Histocompatibility Antigen¹

Toru Higuchi^2,*, Takahiro Maruyama^2,*, Andrés Jaramillo^* and Thalachallour Mohanakumar^3,*,

Departments of ^* Surgery and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

The role of minor histocompatibility Ag (mHAg)-specific CD8⁺ 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^a and H13^b alleles encode for the SSVVGVWYL (SVL9) and SSVIGVWYL (SIL9) mHAgs, respectively, presented in the context of the H2D^b MHC class I molecule. Toward this, C56BL/10SnJ (H13^a) tracheal allografts were transplanted into congenic B10.CE-H13^b A^w(30NX)/Sn (H13^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^a-specific CD8⁺ CTL responses with a significant reduction in the frequency of IFN--producing CTLs and the activation of TGF--producing CD8⁺ T cells. In conclusion, a single mHAg mismatch can induce the development of OAD. These data also suggest that mHAg-reactive CD8⁺ CTLs may play an important role in the pathogenesis of chronic lung allograft rejection in humans.

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