Relationship between TGFβ1, intratubular CD103 positive T cells and acute renal allograft rejection

Robertson, Helen Lee; Wong, Wai Keong; Burt, Alastair D.; Mohamed, Mostafa; Talbot, David; Kirby, John A.

doi:10.1016/s0041-1345(00)02441-6

Cited by 6 publications

(7 citation statements)

References 4 publications

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“…Hadley et al [35,36] reported that up to 63 % of T cells infiltrating renal allografts undergoing a late rejection crisis expressed aEb7 and that the cells were localized mainly in the tubular epithelium. Similar findings were reported by Robertson et al [83,84] who observed a correlation between the prevalence of …”

Section: Allograftssupporting

confidence: 91%

Integrin αEβ7: Molecular Features and Functional Significance in the Immune System

Hadley

Higgins

2014

Advances in Experimental Medicine and Biology

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Alpha E beta 7 (αEβ7) is an α-I domain-containing integrin that is highly expressed by a variety of leukocyte populations at mucosal sites including intraepithelial T cells, dendritic cells, mast cells, and T regulatory cells (Treg). Expression depends largely or solely on transforming growth factor beta (TGF-β) isoforms. The best characterized ligand for αEβ7 is E-cadherin on epithelial cells, though there is evidence of a second ligand in the human system. An exposed acidic residue on the distal aspect of E-cadherin domain 1 interacts with the MIDAS site in the αE α-I domain. By binding to E-cadherin, αEβ7 contributes to mucosal specific retention of leukocytes within epithelia. Studies on αE knockout mice have identified an additional important function for this integrin in allograft rejection and have also indicated that it may have a role in immunoregulation. Recent studies point to a multifaceted role for αEβ7 in regulating both innate and acquired immune responses to foreign antigen.

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Section: Allograftssupporting

confidence: 91%

Integrin αEβ7: Molecular Features and Functional Significance in the Immune System

Hadley

Higgins

2014

Advances in Experimental Medicine and Biology

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“…Moreover, gene knockout experiments document that CD103 expression is required for destruction of cellular epithelial allografts (pancreatic islets) by CD8 ϩ T cells (12). Clinical observational studies indicate that CD8 effector populations expressing CD103 accumulate within the graft renal tubular epithelium at the time of graft dysfunction (13)(14)(15), leading to speculation that CD103 ϩ CD8 ϩ effectors play a central role in promoting tubular injury following allogeneic renal transplantation. The goal of the present study was to directly test this hypothesis.…”

Section: T He Infiltration Of Cd8mentioning

confidence: 99%

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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“…IFNγ induces PD-L1 and IDO on RTECs (88,89), and PD-L1 can induce the generation of allogeneic Foxp3 + Tregs (90). Finally, RTECs are known to produce and activate TGFβ (91), which is an inducer of Foxp3+ Treg (92) and tolerogenic pDC (93) generation. High levels of TGFβ have been documented in accepted DBA/2 kidneys (17,18).…”

Section: Introductionmentioning

confidence: 99%

Organ-specific differences in achieving tolerance

Madariaga¹,

Kreisel

Madsen

2015

Current Opinion in Organ Transplantation

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Purpose of review When it comes to tolerance induction, kidney allografts behave differently from heart allografts which behave differently from lung allografts. Here, we examine how and why different organ allografts respond differently to the same tolerance induction protocol. Recent findings Allograft tolerance has been achieved in experimental and clinical kidney transplantation. However, inducing tolerance in experimental recipients of heart and lung allografts has proven to be more challenging. New protocols being developed in nonhuman primates based on mixed chimerism and co-transplantation of tolerogenic organs may provide mechanistic insights to help overcome these challenges. Summary Tolerance induction protocols that are successful in patients transplanted with “tolerance-prone” organs such as kidneys and livers will most likely not succeed in recipients of “tolerance-resistant” organs such as hearts and lungs. Separate clinical trials using more robust tolerance protocols will be required to achieve tolerance in heart and lung recipients.

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Relationship between TGFβ1, intratubular CD103 positive T cells and acute renal allograft rejection

Cited by 6 publications

References 4 publications

Integrin αEβ7: Molecular Features and Functional Significance in the Immune System

Integrin αEβ7: Molecular Features and Functional Significance in the Immune System

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

Organ-specific differences in achieving tolerance

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