CXCR3 and CCR5 positive T-cell recruitment in acute human renal allograft rejection.
BACKGROUND
Experimental studies suggest that the infiltration of activated T cells into the allograft, the key event in the development of acute renal allograft rejection, depends on the expression of chemokines and their interaction with chemokine receptors expressed on T cells.


METHODS
For a more detailed comprehension of the pathogenesis of T-cell recruitment in human acute rejection, the in situ expression of chemokines and chemokine receptors in allografts of 26 patients between day 3 and 9 after renal transplantation was examined in the present prospective study.


RESULTS
Immunohistochemical staining showed a significantly increased number of CXCR3 (P<0.01) and CCR5 positive T cells (P<0.01) in the tubulointerstitium of patients with acute allograft rejection according to Banff grade Ia-IIb. Likewise the intrarenal RNA expression of the CXCR3 ligands IP-10 (5.2-fold) and I-TAC (7.2-fold) and the CCR5 ligand RANTES (5.7-fold), was significantly up-regulated in rejecting organs. In situ hybridization revealed that IP-10 but not I-TAC was predominantly expressed by infiltrating leukocytes in the tubulointerstitial area, co-localizing with CXCR3 positive T cells. To a lesser degree expression by tubular cells could be detected, providing a possible explanation for the increased urinary IP-10 excretion we found in patients with rejecting organs.


CONCLUSIONS
These data from a prospective, biopsy-controlled study indicate that the local expression of IP-10 and RANTES leads to the directional movement of activated CXCR3 and CCR5 bearing T cells into the renal allograft and mediates acute rejection. Our data provide a rationale that blocking CXCR3 and CCR5 may offer a unique therapeutic approach to prevent episodes of acute rejection in the early phase after renal transplantation.
Panzer
Ulf
U
Medizinische Klinik IV, Universitätsklinikum Hamburg Eppendorf, Germany.
Reinking
Rüdiger R
RR
Steinmetz
Oliver M
OM
Zahner
Gunther
G
Sudbeck
Ulrike
U
Fehr
Susanne
S
Pfalzer
Benjamin
B
Schneider
André
A
Thaiss
Friedrich
F
Mack
Matthias
M
Conrad
Stefan
S
Huland
Hartwig
H
Helmchen
Udo
U
Stahl
Rolf A K
RA
D000208:Acute Disease; D000328:Adult; D000368:Aged; D001706:Biopsy; D054371:Chemokine CXCL11; D018925:Chemokines / Q000652:urine; D019743:Chemokines, CXC / Q000235:genetics; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D019713:Receptors, CCR5 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054371:Chemokine CXCL11; D018925:Chemokines; D019743:Chemokines, CXC; D012333:RNA, Messenger; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine