Cd103+ CTL Accumulate Within the Graft Epithelium During Clinical Renal Allograft Rejection1

Ga, Hadley; Charandee, C; Mr, Weir; Wang, D; St, Bartlett; Cb, Drachenberg

doi:10.1097/00007890-200111150-00013

Cited by 38 publications

(35 citation statements)

References 24 publications

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“…As shown in Fig. 3A, left panel, CD103 expression by GIL was strongly biased toward the CD8 subset, a distribution highly similar to that previously described for rejecting clinical renal allografts (27). Thus, this model recapitulates the known clinical scenario in which subclinical tubulointerstitial inflammation in renal allografts is accompanied by accumulation of CD103 ϩ CD8 ϩ cells at the graft site concomitant with development of tubular atrophy and interstitial fibrosis.…”

Section: Progressive Accumulation Of Cd103supporting

confidence: 80%

“…Importantly, the intragraft localization and extended phenotype of CD103 ϩ CD8 ϩ cells (Fig. 3) that accumulate in rat renal allografts in our model are virtually identical to those associated with rejecting clinical renal allografts (13,27). The clinical relevance of the CsA-delayed rejection model is further supported by the observation that CD103 ϩ CD8 ϩ effectors are undetectable in clinical renal allografts undergoing early rejection episodes (33) but are abundant in grafts undergoing delayed rejection episodes (13,27).…”

Section: Discussionsupporting

confidence: 55%

“…ϩ CD8 ϩ effectors in renal allografts undergoing CsA-delayed rejection Clinical observational studies indicate that CD103 ϩ CD8 ϩ effectors are most abundant in renal allografts undergoing late rejection episodes (27). To model this rejection scenario, we administered a brief course of CsA (10 days at 5 mg/kg/day) to LEW recipients of BN allografts.…”

Section: Progressive Accumulation Of Cd103mentioning

confidence: 99%

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Critical Role for CD103+CD8+ Effectors in Promoting Tubular Injury following Allogeneic Renal Transplantation

Yuan¹,

El-Asady

Liu

et al. 2005

The Journal of Immunology

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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.

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Section: Progressive Accumulation Of Cd103supporting

confidence: 80%

Section: Discussionsupporting

confidence: 55%

Section: Progressive Accumulation Of Cd103mentioning

confidence: 99%

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Critical Role for CD103+CD8+ Effectors in Promoting Tubular Injury following Allogeneic Renal Transplantation

Yuan¹,

El-Asady

Liu

et al. 2005

The Journal of Immunology

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“…In vitro, CD103 + CD8 + T cells even surpass CD103 -cells in cytotoxic killing capacity. CD103 + T cells have been shown before to be very potent cytotoxic killers in a number of other settings (41)(42)(43)(44)(45)(46). Additionally, CD103 + CD8 + lung T cells are also strong Th1 cytokine producers.…”

Section: Discussionmentioning

confidence: 99%

CD8+ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung

Piet¹,

Bree²,

et al. 2011

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The human lung T cell compartment contains many CD8 + T cells specific for respiratory viruses, suggesting that the lung is protected from recurring respiratory infections by a resident T cell pool. The entry site for respiratory viruses is the epithelium, in which a subset of lung CD8 + T cells expressing CD103 (αE integrin) resides. Here, we determined the specificity and function of CD103 + CD8 + T cells in protecting human lung against viral infection. Mononuclear cells were isolated from human blood and lung resection samples. Variable numbers of CD103 + CD8 + T cells were retrieved from the lung tissue. Interestingly, expression of CD103 was seen only in lung CD8 + T cells specific for influenza but not in those specific for EBV or CMV. CD103 + and influenza-reactive cells preferentially expressed NKG2A, an inhibitor of CD8 + T cell cytotoxic function. In contrast to CD103 -CD8 + T cells, most CD103 + CD8 + cells did not contain perforin or granzyme B. However, they could quickly upregulate these cytotoxic mediators when exposed to a type I IFN milieu or via contact with their specific antigen. This mechanism may provide a rapid and efficient response to influenza infection, without inducing cytotoxic damage to the delicate epithelial barrier.

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“…Production of active TGF-␤ by renal tubular epithelial cells is markedly increased in the rejecting kidney, inducing CD103 expression on activated graft-infiltrating T cells (32). Indeed, this TGF-␤-mediated process appears to be required for development of tubulitis and CTL lysis of renal tubular epithelial cells (33). The benign interstitial infiltrates in renal transplants of graft recipients without maintenance immunosuppression (34) are therefore puzzling, because they may also be associated with elevated intragraft expression of TGF-␤1 (35,36).…”

Section: Discussionmentioning

confidence: 99%

Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates

Torrealba¹,

Katayama

Fechner

et al. 2004

The Journal of Immunology

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Approaches that prevent acute rejection of renal transplants in a rhesus monkey model were studied to determine a common mechanism of acceptance. After withdrawal of immunosuppression, all 14 monkeys retained normal allograft function for >6 mo. Of these, nine rejected their renal allograft during the study, and five maintained normal function throughout the study period. The appearance of TGF-β1+ interstitial mononuclear cells in the graft coincided with a nonrejection histology, whereas the absence/disappearance of these cells was observed with the onset of rejection. Analysis with a variety of TGF-β1-reactive Abs indicated that the tolerance-associated infiltrates expressed the large latent complex form of TGF-β1. Peripheral leukocytes from rejecting monkeys lacking TGF-β1+ allograft infiltrates responded strongly to donor Ags in delayed-type hypersensitivity trans-vivo assays. In contrast, allograft acceptors with TGF-β1+ infiltrates demonstrated a much weaker peripheral delayed-type hypersensitivity response to donor alloantigens (p < 0.01 vs rejectors), which could be restored by Abs that either neutralized active TGF-β1 or blocked its conversion from latent to active form. Anti-IL-10 Abs had no restorative effect. Accepted allografts had CD8+ and CD4+ interstitial T cell infiltrates, but only the CD4+ subset included cells costaining for TGF-β1. Our data support the hypothesis that the recruitment of CD4+ T regulatory cells to the allograft interstitium is a final common pathway for metastable renal transplant tolerance in a non-human primate model.

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Cd103+ CTL Accumulate Within the Graft Epithelium During Clinical Renal Allograft Rejection1

Cited by 38 publications

References 24 publications

Critical Role for CD103+CD8+ Effectors in Promoting Tubular Injury following Allogeneic Renal Transplantation

Critical Role for CD103+CD8+ Effectors in Promoting Tubular Injury following Allogeneic Renal Transplantation

CD8+ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung

Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates

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