Post-Transplant Renal Tubulitis: The Recruitment, Differentiation and Persistence of Intra-Epithelial T Cells

Robertson, Helen Lee; Kirby, John A.

doi:10.1034/j.1600-6143.2003.30102.x

Cited by 46 publications

(34 citation statements)

References 91 publications

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“…It is known that during acute renal allograft rejection, leukocytes leave the blood, migrate toward the tubular basement membranes, and invade the tubular epithelium, resulting in renal tubulitis (44). In this setting, leukocytes expressing L-selectin may encounter the L-selectin binding HSPGs in tubular basement membranes, which may possibly lead to adhesion, retention, and/or activation of the cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of L-selectin Binding Heparan Sulfates Attached to Collagen Type XVIII

Celie¹,

Keuning²,

Beelen³

et al. 2005

Journal of Biological Chemistry

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L-selectin is a C-type lectin expressed on leukocytes that is involved in both lymphocyte homing to the lymph node and leukocyte extravasation during inflammation. Known L-selectin ligands include sulfated Lewis-type carbohydrates, glycolipids, and proteoglycans. Previously, we have shown that in situ detection of different types of L-selectin ligands is highly dependent on the tissue fixation protocol used. Here we use this knowledge to specifically examine the expression of L-selectin binding proteoglycans in normal mouse tissues. We show that L-selectin binding chondroitin/dermatan sulfate proteoglycans are present in cartilage, whereas Lselectin binding heparan sulfate proteoglycans are present in spleen and kidney. Furthermore, we show that L-selectin only binds a subset of renal heparan sulfates, attached to a collagen type XVIII protein backbone and predominantly present in medullary tubular and vascular basement membranes. As L-selectin does not bind other renal heparan sulfate proteoglycans such as perlecan, agrin, and syndecan-4, and not all collagen type XVIII expressed in the kidney binds L-selectin, this indicates that there is a specific L-selectin binding domain on heparan sulfate glycosaminoglycan chains. Using an in vitro L-selectin binding assay, we studied the contribution of N-sulfation, O-sulfation, C5-epimerization, unsubstituted glucosamine residues, and chain length in L-selectin binding to heparan sulfate/heparin glycosaminoglycan chains. Based on our results and the accepted model of heparan sulfate domain organization, we propose a model for the interaction of L-selectin with heparan sulfate glycosaminoglycan chains. Interestingly, this opens the possibility of active regulation of L-selectin binding to heparan sulfate proteoglycans, e.g. under inflammatory conditions.A well known function for L-selectin, a C-type lectin expressed on leukocytes, is its key role in the homing of lymphocytes to lymph nodes. This process involves the binding of L-selectin to its ligands expressed on high endothelial venules (HEVs), 1 which induces rolling of the lymphocytes and results in extravasation. L-selectin ligands on HEVs are well characterized and known to be mucin-like glycoproteins containing sulfated, sialylated, and fucosylated Lewis-related carbohydrate structures, which are expressed by the high endothelial cells (1, 2). In addition to the lymph node, L-selectin ligands have been described to be expressed on endothelium under inflammatory conditions, including Crohn disease, asthma, heart and kidney acute allograft rejection, and a number of skin diseases (1, 2). In vitro studies show that, in addition to the well known Lewis-related glycoproteins, L-selectin can also bind to other types of molecules, including glycolipids and proteoglycans (3-5).Proteoglycans are glycoconjugates that consist of a core protein to which linear carbohydrate chains (glycosaminoglycans, GAGs) are linked. The composition of these GAGs is specific for the different types of proteoglycans, which are chondroitin su...

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Section: Discussionmentioning

confidence: 99%

Identification of L-selectin Binding Heparan Sulfates Attached to Collagen Type XVIII

Celie¹,

Keuning²,

Beelen³

et al. 2005

Journal of Biological Chemistry

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“…Thus CD103 on effector T cells may mediate interaction with epithelial cells (12,13), promoting cytotoxicity (14) and potentially affecting other processes through the role of E-cadherin in adherens junction signaling (15,16) and induction of cell polarity (17). Renal tubules also express other cadherins including kidney specific (Ksp)-cadherin (18), which is not known to engage CD103 (19)…”

Section: Many Infiltrating Cells In Tubulitis Lesions Display Cytotmentioning

confidence: 99%

Tubulitis and Epithelial Cell Alterations in Mouse Kidney Transplant Rejection Are Independent of CD103, Perforin or Granzymes A/B

Einecke¹,

Fairhead²,

Hidalgo³

et al. 2006

American Journal of Transplantation

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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.

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“…A model has been proposed (6) in which activated allospecific T cells traffic from the blood to graft renal tubules under the influence of chemokines such as RANTES. After penetration of the tubular basement membrane, the cells encounter immobilized TGF-␤ and differentiate to the CD103 phenotype characteristic of intraepithelial T cells.…”

mentioning

confidence: 99%

Chronic Renal Allograft Dysfunction

Robertson¹,

Ali²,

McDonnell³

et al. 2004

Journal of the American Society of Nephrology

115

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Post-Transplant Renal Tubulitis: The Recruitment, Differentiation and Persistence of Intra-Epithelial T Cells

Abstract: Tubulitis is used by the

Cited by 46 publications

References 91 publications

Identification of L-selectin Binding Heparan Sulfates Attached to Collagen Type XVIII

Identification of L-selectin Binding Heparan Sulfates Attached to Collagen Type XVIII

Tubulitis and Epithelial Cell Alterations in Mouse Kidney Transplant Rejection Are Independent of CD103, Perforin or Granzymes A/B

Chronic Renal Allograft Dysfunction

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