Indirect recognition and antibody production against a single mismatched HLA-A2-transgenic molecule precede the development of obliterative airway disease in murine heterotopic tracheal allografts.
BACKGROUND
Previous studies have implicated the allogeneic immune response in the development of obliterative bronchiolitis after lung transplantation. However, the progression of specific pathogenic events leading to this form of chronic allograft dysfunction have not been well characterized. We used a murine tracheal transplantation model in which a single mismatched HLA-A2-transgenic molecule is indirectly recognized by the recipient CD4(+) T cells to show that obliterative airway disease (OAD) that developed in these allografts was preceded by indirect recognition of the HLA-A2 molecule and subsequent development of anti-HLA-A2 antibodies.


METHODS
Tracheas from HLA-A2(+) C57BL/6 mice were heterotopically transplanted into C57BL/6 mice. Allograft histopathology as well as anti-HLA-A2 T-cell proliferative responses and anti-HLA-A2 antibody development were determined at days 5, 10, 20, and 28 after transplantation.


RESULTS
All of the HLA-A2(+) tracheal allografts transplanted into C57BL/6 recipients demonstrated complete development of OAD by day 20. Spleen cells from the mice that underwent transplantation demonstrated significant proliferation against HLA-A2(+) cells by day 5. Indirect recognition of HLA-A2-derived peptides by spleen cells from allograft recipients was also higher on days 5 and 10 as compared with irrelevant peptides derived from HLA-A1, HLA-A3, and HLA-B44. Allograft recipients showed detectable levels of anti-HLA-A2 antibodies by day 5 and full development of anti-HLA-A2 antibodies by day 20.


CONCLUSIONS
These results show that sensitization of CD4+ T cells against the mismatched HLA-A2 alloantigen precedes the development of anti-HLA antibodies as well as OAD, suggesting an important role for alloreactive CD4(+) T-cell activation and alloantibody development in the immunopathogenesis of OAD.
Smith
Michael A
MA
Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, USA.
Jaramillo
Andrés
A
SivaSai
Krovvidi S R
KS
Naziruddin
Bashoo
B
Kaleem
Zahid
Z
Patterson
G Alexander
GA
Mohanakumar
T
T
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006084:Graft Rejection; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006650:Histocompatibility Testing; D007518:Isoantibodies / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014132:Trachea / Q000637:transplantation*; D014184:Transplantation, Homologous
D015789:HLA-A2 Antigen; D007518:Isoantibodies