Tubulitis and epithelial cell alterations in mouse kidney transplant rejection are independent of CD103, perforin or granzymes A/B.
One of the defining lesions of kidney allograft rejection is epithelial deterioration and invasion by inflammatory cells (tubulitis). We examined epithelial changes and their relationship to effector T cells and to CD103/E-cadherin interactions in mouse kidney allografts. Rejecting allografts showed interstitial mononuclear infiltration from day 5. Loss of epithelial mass, estimated by tubular surface area, and tubulitis were minimal through day 7 and severe by day 21. Tubules in day 21 allografts manifested severe reduction of E-cadherin and Ksp-cadherin by immunostaining with redistribution to the apical membrane, indicating loss of polarity. By flow cytometry T cells isolated from allografts were 25% CD103+. Laser capture microdissection and RT-PCR showed increased CD103 mRNA in the interstitium and tubules. However, allografts in hosts lacking CD103 developed tubulitis, cadherin loss, and epithelial deterioration similar to wild-type hosts. The loss of cadherins and epithelial mass was also independent of perforin and granzymes A and B. Thus rejection is characterized by severe tubular deterioration associated with CD103+ T cells but not mediated by CD103/cadherin interactions or granzyme-perforin cytotoxic mechanisms. We suggest that alloimmune effector T cells mediate epithelial injury by contact-independent mechanisms related to delayed type hypersensitivity, followed by invasion of the altered epithelium to produce tubulitis.
Einecke
G
G
Department of Medicine, Division of Nephrology and Transplantation Immunology, University of Alberta, Edmonton, Canada.
Fairhead
T
T
Hidalgo
L G
LG
Sis
B
B
Turner
P
P
Zhu
L-F
LF
Bleackley
R C
RC
Hadley
G A
GA
Famulski
K S
KS
Halloran
P F
PF
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology*; D053804:Granzymes; D007124:Immunoenzyme Techniques; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism*; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009393:Nephritis / Q000378:metabolism / Q000473:pathology*; D052899:Pore Forming Cytotoxic Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D015703:Antigens, CD; D039001:Integrin alpha Chains; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; C091367:alpha E integrins; C483886:perforin, mouse; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases