Critical role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation.
Immune destruction of the graft renal tubules is an important barrier to the long-term function of clinical renal allografts, but the underlying mechanisms remain obscure. CD103-an integrin conferring specificity for the epithelial cell-restricted ligand, E-cadherin-defines a subset of CD8 effectors that infiltrate the graft tubular epithelium during clinical rejection episodes, predicting a causal role for CD103+CD8+ effectors in tubular injury. In the present study, we used rodent transplant models to directly test this hypothesis. Surprisingly, CD8 cells infiltrating renal allografts undergoing unmodified acute rejection did not express significant levels of CD103. However, we demonstrate that a brief course of cyclosporine A to rat renal allograft recipients promotes progressive accumulation of CD103+CD8+ cells within the graft, concomitant with the development of tubular atrophy and interstitial fibrosis. As in the known clinical scenario, graft-associated CD103+CD8+ cells exhibited a T effector phenotype and were intimately associated with the renal tubular epithelium. Treatment with anti-CD103 mAb dramatically attenuated CD8 infiltration into the renal tubules and tubular injury. Mouse studies documented that CD103 expression is required for efficient destruction of the graft renal tubules by CD8 effectors directed to donor MHC I alloantigens. Taken together, these data document a causal role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation and identify novel targets for therapeutic intervention in this important clinical problem.
Yuan
Rongwen
R
Department of Surgery, University of Maryland Medical School, Baltimore 21201, USA.
El-Asady
Riham
R
Liu
Kechang
K
Wang
Donghua
D
Drachenberg
Cinthia B
CB
Hadley
Gregg A
GA
D000818:Animals; D015703:Antigens, CD / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000209:etiology*; D039001:Integrin alpha Chains / Q000032:analysis*; D016030:Kidney Transplantation / Q000276:immunology*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D015703:Antigens, CD; D039001:Integrin alpha Chains; C091367:alpha E integrins; D016572:Cyclosporine