Anti-inflammatory effects of alphav integrin antagonism in acute kidney allograft rejection.
Integrin-mediated cell adhesion and signaling is essential to vascular development and inflammatory processes. Elevated expression of integrin alpha(v)beta(3) has been detected in ischemia-reperfusion injury and rejecting heart allografts. We thus hypothesized that the inhibition of alpha(v)-associated integrins may have potent anti-inflammatory effects in acute kidney allograft rejection. We studied the effects of a peptidomimetic antagonist of alpha(v) integrins in two rat models of renal allotransplantation, differing in degree of major histocompatibility complex mismatch. Integrin alpha(v)beta(3) was up-regulated in rejecting renal allografts. Integrin antagonist reduced the histological signs of acute rejection, the intensity of the mononuclear cell infiltration, and cell proliferation in the grafted kidneys. This could be correlated to a reduced leukocyte-endothelial interaction and an improved peritubular microcirculation observed by intravital microscopy. In vitro under laminar flow conditions, the arrest of monocytes to interleukin-1beta-activated endothelium was decreased. Furthermore, in co-culture models the proliferation and transmigration of monocytes/macrophages, endothelium, and fibroblasts induced by renal tubular epithelia was efficiently inhibited by alpha(v) integrin antagonism. These data reveal an important role of this integrin subclass in leukocyte recruitment and development and maintenance of acute rejection; blockade of alpha(v) integrins may provide a new therapeutic strategy to attenuate acute allograft rejection.
Bedke
Jens
J
Department of Cellular and Molecular Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Kiss
Eva
E
Behnes
Carl-Ludwig
CL
Popovic
Zoran V
ZV
Heuser
Markus
M
Stojanovic
Tomislav
T
Sijmonsma
Tjeerd
T
Huber
Peter
P
Domhan
Sophie
S
Muschal
Stefan
S
Abdollahi
Amir
A
Gretz
Norbert
N
Gröne
Hermann-Josef
HJ
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D005347:Fibroblasts / Q000187:drug effects; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D039564:Integrin alphaV / Q000187:drug effects; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D016030:Kidney Transplantation; D036904:Leukocyte Rolling / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009930:Organic Chemicals / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D014184:Transplantation, Homologous
D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D009930:Organic Chemicals; C474314:S 247 compound
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