Expression of chemokines and chemokine receptors during human renal transplant rejection

Abstract

• Infiltration of renal allografts by leukocytes is a hallmark of acute transplant rejection. Chemokines attract leukocytes bearing specific chemokine receptors, and the specific leukocyte chemokine receptor phenotype is associated with types of immune responses, ie, T helper subtype 1 (Th1; CXC chemokine receptor 3 [CXCR3], CC chemokine receptor 5 [CCR5]) versus Th2 (CCR3, CCR4, CCR8). We studied the expression of the chemokine monocyte chemoattractant protein-1 and the chemokine receptors CCR2B and CXCR4 messenger RNA (mRNA) by in situ hybridization, as well as the chemokine receptors Duffy antigen receptor for chemokines (DARC) and CCR5 protein by immunohistochemistry in renal biopsy specimens with acute cellular rejection (n ‫؍‬ 12) and acute vascular rejection (n ‫؍‬ 8), transplant nephrectomy specimens (n ‫؍‬ 6), and normal areas of tumor nephrectomy specimens (n ‫؍‬ 5). CC chemokines and CC chemokine receptor mRNA expression were evaluated by ribonuclease protection assay in specimens from four transplant nephrectomies and one tumor nephrectomy. Upregulation of mRNAs for the chemokines, interferon-inducible protein-10 (IP-10); regulated on activation normal T-cell expressed and secreted; macrophage inflammatory protein-1␣ (MIP-1␣); MIP-1␤; and lymphotactin, as well as the chemokine receptors, CCR2 and CCR5, were documented during allograft rejection. CCR1 mRNA was detectable in both allografts and controls, but CCR3 and CCR8 were absent. The number of CXCR4, CCR5, and CCR2B mRNAs expressing leukocytes and DARC-positive vessels increased during rejection episodes. CXCR4 mRNA was the most widely expressed. Leukocytes in diffuse interstitial infiltrates were mainly CCR5 positive, but in areas in which leukocytes formed nodular aggregates of infiltrating cells, the number of CCR5-positive cells was low. Instead, leukocytes in these nodular aggregates mainly expressed CXCR4. DARC was expressed on peritubular capillaries, where it was upregulated in areas of interstitial infiltration. Induction of chemokines during renal allograft rejection is accompanied by infiltration of leukocytes bearing the respective chemokine receptors. The upregulation of the CXCR3 ligand IP-10, as well as CCR5 and its ligands, in the absence of CCR3 and CCR8 is indicative that renal allograft rejection is primarily the result of a Th1-type immune response.

Adenovirus Transduction Induces Expression of Multiple Chemokines and Chemokine Receptors in Murine β Cells and Pancreatic Islets

“…In situ hybridization was performed as described previously (21). Slides were deparaffinized in xylene and rehydrated in graded ethanol.…”

Prediction of Acute Renal Allograft Rejection by Urinary Monokine Induced by IFN-γ (MIG)

“…In rejecting murine heart allografts, a pattern of IFN-␥-dependent chemokine induction has been identified that includes induction of IFN-inducible protein 10 (IP-10) (CXCL10) and monokine induced by IFN-␥ (MIG) (CXCL9), which are both ligands of the chemokine receptor CXCR3. Immunohistochemical or cDNA array analysis of human cardiac and kidney transplantation biopsy specimens suggest that the appearance of CXCR3-positive cells, such as activated alloantigen-primed T cells and natural killer cells, strongly correlates to AR (11)(12)(13)(14).…”

Up-Regulation of Early Growth Response Gene-1 Via the CXCR3 Receptor Induces Reactive Oxygen Species and Inhibits Na+/K+-ATPase Activity in an Immortalized Human Proximal Tubule Cell Line

“…There, chemokines and their receptors play an important role in the pathogenesis of acute and chronic glomerular inflammation. Increased expression of the CXCR3 receptor has been demonstrated in patients with inflammatory kidney disease like IgA nephropathy, membranoproliferative glomerulonephritis, rapidly progressive glomerulonephritis, or nephrotoxic nephritis (10,11) and during acute allograft rejection (12).…”