CD103 mRNA levels in urinary cells predict acute rejection of renal allografts1

Ding, Ruchuang; Li, Baogui; Muthukumar, Thangamani; Dadhania, Darshana; Medeiros-Domingo, Mara; Hartono, Choli; Serur, David; Seshan, Surya V.; Sharma, Vijay Kumar; Kapur, Sandip; Suthanthiran, Manikkam

doi:10.1097/01.tp.0000064210.92444.b5

Cited by 94 publications

(80 citation statements)

References 19 publications

(19 reference statements)

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“…Regardless, these data document that an important component of the anti-graft response is not detectable by conventional immune monitoring approaches, which typically rely on sampling of peripheral blood. An alternative approach for detection of CD103 ϩ CD8 ϩ effectors is suggested by Ding et al (49), who have shown that CD103-expressing cells are detectable in the urine of renal transplant patients and that such levels correlate with rejection episodes. It now will be important to determine whether such assays possess the sensitivity and specificity to reliably predict tubular injury.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Reverse transcription to cDNA was performed by using TaqMan Reverse Transcription reagents (Applied Biosystems). Oligonucleotide primers and fluorogenic probes were designed and synthesized and tested for efficiency and validity for the measurement of mRNA levels of Suppressor of cytokine signaling1 (SOCS1), Suppressor of cytokine signaling2 (SOCS2), tissue necrosis factor ␣ (TNF␣), Complement 3 (C3), Ceruloplasmin (Cp), C-reactive protein (CRP), Guanylate nucleotide binding protein-1 (GBP1), interleukin-1␤ (IL-1␤), plasminogen activator inhibitor type-1 (PAI-1), Serum amyloid A-1 (SAA-), and transforming growth factor-␤ (TGF␤) (32). To measure mRNA levels of the internal control GAPDH transcript, a commercially available probe and primer mix (Applied Biosystems) were used.…”

Section: Rt-pcr Methodsmentioning

confidence: 99%

Modification of adverse inflammation is required to cure new-onset type 1 diabetic hosts

Koulmanda

Budo

Bonner-Weir

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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In nonobese diabetic (NOD) mice with overt new-onset type 1 diabetes mellitus (T1DM), short-term treatment with a ''tripletherapy'' regimen [rapamycin plus agonist IL-2-related and antagonist-type, mutant IL-15-related Ig fusion proteins (IL-2.Ig and mutIL-15.Ig)] halts autoimmune destruction of insulinproducing beta cells and restores both euglycemia and immune tolerance to beta cells. Increases in the mass of insulin-producing beta cells or circulating insulin levels were not linked to the restoration of euglycemia. Instead, the restoration of euglycemia was linked to relief from an inflammatory state that impaired the host's response to insulin. Both restoration of immune tolerance to beta cells and relief from the adverse metabolic effects of an inflammatory state in insulin-sensitive tissues appear essential for permanent restoration of normoglycemia in this T1DM model. Thus, this triple-therapy regimen, possessing both toleranceinducing and select antiinflammatory properties, may represent a prototype for therapies able to restore euglycemia and selftolerance in T1DM.autoimmunity ͉ diabetes ͉ NOD mice ͉ tolerance ͉ transplantation

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“…These observations include significantly increased levels of granzyme B and perforin, two cytotoxic effector molecules, in cells that were derived from rejection-associated urine compared with samples that were obtained in the absence of ACR, chronic allograft nephropathy, toxicity, or acute tubular necrosis (40). Other markers of the cytotoxic T cell pathway that are overexpressed in urine pellets during ACR episodes include the serine proteinase inhibitor-9 (PI-9), a natural antagonist of granzyme B (41), and CD103, expressed on alloreactive cytotoxic CD8 ϩ T cells (42). Along this theme, protein and transcript expression of the IFN-␥-inducible chemokine IP-10 and the chemokine receptor CXCR3 are elevated in the urine sediments of recipients with ACR (43), with variable predictive characteristics depending on the cutoff values used.…”

Section: What Can Urine Tell Us?mentioning

confidence: 99%

Beyond Histology

Mannon¹,

Kirk²

2006

Clinical Journal of the American Society of Nephrology

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Kidney biopsy is the gold standard procedure for the assessment of allograft dysfunction. The differential diagnosis for both acute and chronic dysfunction can encompass a number of different causes, and a biopsy frequently can suggest a specific cause. However, many of these causes are difficult to distinguish on morphologic basis alone, and the information that is obtained from a biopsy is limited with regard to functional and prognostic importance. Additional methods therefore are needed to guide the diagnosis and the treatment of allograft dysfunction, and numerous methods have been studied. Potential markers include protein and gene expression profiles in the peripheral blood, the urine, and the graft itself, all compartments that are relevant to the alloimmune response. Recent comprehensive sequencing of the human genome has led to an unprecedented opportunity to develop these genetic and proteomic techniques, and ongoing evaluations of potential tests have led to an improved understanding of the complexity of immune responses. The future challenge for promising tests is validation in larger patient populations to facilitate their addition to the diagnostic armamentarium.

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CD103 mRNA levels in urinary cells predict acute rejection of renal allografts1

Cited by 94 publications

References 19 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

Modification of adverse inflammation is required to cure new-onset type 1 diabetic hosts

Beyond Histology

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