Persistent rejection of peritubular capillaries and tubules is associated with progressive interstitial fibrosis.
BACKGROUND
We have reported that a 12-day course of high dose cyclosporine A treatment in thymectomized miniature swine with major histocompatibility complex (MHC) class I-mismatched renal allografts results in transient acute rejection followed by either in chronic rejection (progression group) or graft acceptance (recovery group). Here, we examined the differential features between both groups in the peritubular capillaries (PTCs) and tubules to clarify the pathogenesis of the progressive interstitial fibrosis in chronic rejection.


METHODS
Morphometric and immunohistochemical studies were performed on serial renal biopsies (days 0 to 100) obtained from both groups, focusing on the cellular infiltrate, rejection of PTCs and tubules, myofibroblast accumulation, and progressive interstitial fibrosis.


RESULTS
In the progression group, acute rejection occurred by day 8 and progressed to chronic rejection by day 100, with the development of interstitial fibrosis. PTC endothelial cell and tubular epithelial cell death associated with CD3+ cell infiltration was evident, confirmed by nick end-labeling (TUNEL), commencing by day 8 and continuing thereafter. In acute rejection, destruction of PTCs and tubules accompanied by disruption of basement membrane (BM) occurred with capillaritis or tubulitis in areas with a severe cellular infiltrate. During the development of chronic rejection, capillaritis of PTCs and tubulitis continued by day 100, accompanied by persistent T cell infiltration, and the remaining PTCs and tubules exhibited progressive atrophy with thickening and/or lamination of BM. On day 100, identifiable PTCs and tubules were lost in areas of interstitial fibrosis. Proliferating (PCNA+) alpha-actin+ myofibroblasts accumulated around PTCs, tubules and in interstitium, and widespread interstitial fibrosis developed by day 100. In contrast, in the recovery group, injured PTCs and tubules recovered by day 100 based on the resolution of acute rejection, and minimal loss of PTCs and tubules was evident by day 100 with minimal interstitial fibrosis.


CONCLUSIONS
Persistent rejection directed at PTCs and tubules, and proliferation of myofibroblasts are prominent features in the progressive interstitial fibrosis in chronic rejection, and are probably key events in its pathogenesis.
Shimizu
Akira
A
Department of Pathology and Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
Yamada
Kazuhiko
K
Sachs
David H
DH
Colvin
Robert B
RB
D000818:Animals; D001284:Atrophy; D017252:CD3 Complex / Q000032:analysis; D002196:Capillaries / Q000276:immunology / Q000473:pathology; D002908:Chronic Disease; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D016030:Kidney Transplantation / Q000276:immunology*; D007684:Kidney Tubules / Q000098:blood supply* / Q000276:immunology / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D013556:Swine, Miniature
D017252:CD3 Complex; D018809:Proliferating Cell Nuclear Antigen