Published ahead of print on November 21, 2002, doi:10.1164/rccm.200209-1099OC Am. J. Respir. Crit. Care Med., Volume 167, Number 7, April 2003, 999-1007 A more recent version of this article appeared on April 1, 2003
Submitted on October 9, 2002 Hierarchical Contributions of Allorecognition Pathways in Chronic Lung RejectionWorakij Chalermskulrat1,1 Division of Pulmonary Disease and Critical Care Medicine and Lung Transplant Program, University of North Carolina, Chapel Hill, NC, USA, 2 Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA, 3 Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Pathology and Immunology, Washington University, St. Louis, MO, USA * To whom correspondence should be addressed. 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-DMA)-/- using MHC I-/- and wild-type allorecipients as controls. Similarly, MHC I-/-, MHC II-/-, or MHC I/II-/- allografts were transplanted into wild-type mice with appropriate controls. Grafts from non-immunosuppressed recipients were evaluated at weeks 2, 4, and 6. Grafts transplanted into MHC II-/- and H2-DMA-/- allorecipients showed a more intact epithelium and reduced lumen obliteration compared to 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 to allograft controls (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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