Chronic rejection of major histocompatibility complex class II-disparate skin grafts after anti-CD3 therapy: a model of antibody-independent transplant vasculopathy.
BACKGROUND
Chronic rejection remains a leading cause of allograft loss. Histologically, it is characterized by arterial intimal thickening and parenchymal fibrosis. The immune mechanisms triggering chronic rejection are still uncompletely understood.


METHODS
We performed major histocompatibility complex (MHC) class H-incompatible skin grafts from C-H2bm12 (bm12, H2bm12) into C57BL/6 (C57BL/6, H2b) recipients immunosuppressed with a short course of anti-CD3 monoclonal antibodies to prevent acute rejection.


RESULTS
More than 80% of grafts survived for prolonged periods, but eventually all displayed macroscopic and microscopic evidence of chronic rejection. At histology, there was a progressive arterial intimal thickening as well as intense dermal fibrosis. This was accompanied by an inflammatory infiltrate consisting of lymphocytes and macrophages, but also of a considerable number of eosinophils. Mice with chronic rejection were unable to generate anti-donor MHC class II cytotoxic T lymphocyte activity at either 20 or 60 days after transplant. Furthermore, transplantation of bm12 skins on C57BL/6-congenic, Ig knock-out mice was associated with the development of a chronic rejection that was identical to that occurring in wild-type C57BL/6 animals, indicating that alloantibodies are not necessary in this model.


CONCLUSIONS
(1) Skin grafts may undergo chronic rejection with the characteristic lesions of vasculopathy and fibrosis; (2) chronic rejection of MHC class II-disparate skins may occur in the absence of direct cytotoxic T lymphocyte activity or alloantibodies.
Le Moine
A
A
Department of Nephrology, Hopital Erasme, Brussels, Belgium.
Flamand
V
V
Noël
J C
JC
Fayt
I
I
Goldman
M
M
Abramowicz
D
D
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D017252:CD3 Complex / Q000276:immunology*; D002908:Chronic Disease; D005260:Female; D006084:Graft Rejection / Q000628:therapy; D000949:Histocompatibility Antigens Class II / Q000032:analysis*; D007136:Immunoglobulins / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000009:adverse effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D014652:Vascular Diseases / Q000209:etiology
D000906:Antibodies; D017252:CD3 Complex; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins