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Hierarchical Contributions of Allorecognition Pathways in Chronic Lung Rejection

Division of Pulmonary Disease and Critical Care Medicine and the Lung Transplantation Program; and Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Robert M. Aris, M.D., 420 Burnett-Womack Building, CB# 7020, Chapel Hill, NC 27599. E-mail: aris{at}med.unc.edu

The role of allorecognition in initiating lung graft rejection is not clearly defined. Using the heterotopic tracheal transplantation model, we examined the contributions of the indirect and direct allorecognition pathways in chronic airway rejection. Fully mismatched, wild-type grafts were transplanted into major histocompatibility complex (MHC) II^-/-, class II-like accessory molecule (H2-DM)^-/- using MHC I^-/- and wild-type allorecipients as control subjects. Similarly, MHC I^-/-, MHC II^-/-, or MHC I/II^-/- allografts were transplanted into wild-type mice with appropriate control subjects. Grafts from nonimmunosuppressed recipients were evaluated at Weeks 2, 4, and 6. Grafts transplanted into MHC II^-/- and H2-DM^-/- allorecipients showed a more intact epithelium and reduced lumen obliteration compared with grafts transplanted into wild-type or MHC I^-/- allorecipients (p < 0.05 for each). These grafts exhibited abundant CD4+ and CD8+ cell infiltrates similar to control allografts. MHC I^-/- and MHC I/II^-/- but not MHC II^-/- allografts placed in wild-type animals demonstrated less severe rejection compared with allograft control subjects (p < 0.05 for each). Although the indirect allorecognition pathway has the strongest influence on rejection, the direct pathway is sufficient to ultimately cause chronic airway rejection. In addition, these results suggest that MHC class I molecules are the principal alloantigens in the mouse heterotopic tracheal model of obliterative bronchiolitis.

Key Words: allorecognition • alloantigen • lung transplant • trachea transplant model • obliterative bronchiolitis

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