Chronic rejection of mouse kidney allografts.
BACKGROUND
Chronic renal allograft rejection is the leading cause of late graft failure. However, its pathogenesis has not been defined.


METHODS
To explore the pathogenesis of chronic rejection, we studied a mouse model of kidney transplantation and examined the effects of altering the expression of donor major histocompatibility complex (MHC) antigens on the development of chronic rejection.


RESULTS
We found that long-surviving mouse kidney allografts develop pathological abnormalities that resemble chronic rejection in humans. Furthermore, the absence of MHC class I or class II antigens did not prevent the loss of graft function nor alter the pathological characteristics of chronic rejection. Expression of transforming growth factor-beta (TGF-beta), a pleiotropic cytokine suggested to play a role in chronic rejection, was markedly enhanced in control allografts compared with isografts. However, TGF-beta up-regulation was significantly blunted in MHC-deficient grafts. Nonetheless, these differences in TGF-beta expression did not affect the character of chronic rejection, including intrarenal accumulation of collagens.


CONCLUSIONS
Reduced expression of either class I or II direct allorecognition pathways is insufficient to prevent the development of chronic rejection, despite a reduction in the levels of TGF-beta expressed in the allograft. This suggests that the severity of chronic rejection is independent of the level of MHC disparity between donor and recipient and the level of TGF-beta expression within the allograft.
Mannon
R B
RB
Department of Medicine, Duke Medical Center, Durham, North Carolina, USA. roslyn.mannon@acpub.duke.edu
Kopp
J B
JB
Ruiz
P
P
Griffiths
R
R
Bustos
M
M
Platt
J L
JL
Klotman
P E
PE
Coffman
T M
TM
D000818:Animals; D015152:Blotting, Northern; D002908:Chronic Disease; D003094:Collagen / Q000032:analysis / Q000276:immunology; D015870:Gene Expression; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000032:analysis / Q000276:immunology; D007124:Immunoenzyme Techniques; D007519:Isoantigens / Q000032:analysis / Q000276:immunology; D007668:Kidney / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D016030:Kidney Transplantation; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000276:immunology; D014181:Transplantation Immunology / Q000276:immunology*; D014184:Transplantation, Homologous
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007519:Isoantigens; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen