FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2890836726> ?p ?o ?g. }

• W2890836726 endingPage "1140" @default.
• W2890836726 startingPage "1127" @default.
• W2890836726 abstract "Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited nephropathy. To date, therapies alleviating the disease have largely focused on targeting abnormalities in renal epithelial cell signaling. ADPKD has many hallmarks of cancer, where targeting T cells has brought novel therapeutic interventions. However, little is known about the role and therapeutic potential of T cells in ADPKD. Here, we used an orthologous ADPKD model, Pkd1 p.R3277C (RC), to begin to define the role of T cells in disease progression. Using flow cytometry, we found progressive increases in renal CD8+ and CD4+ T cells, correlative with disease severity, but with selective activation of CD8+ T cells. By immunofluorescence, T cells specifically localized to cystic lesions and increased levels of T-cell recruiting chemokines (CXCL9/CXCL10) were detected by qPCR/in situ hybridization in the kidneys of mice, patients, and ADPKD epithelial cell lines. Importantly, immunodepletion of CD8+ T cells from one to three months in C57Bl/6 Pkd1RC/RC mice resulted in worsening of ADPKD pathology, decreased apoptosis, and increased proliferation compared to IgG-control, consistent with a reno-protective role of CD8+ T cells. Thus, our studies suggest a functional role for T cells, specifically CD8+ T cells, in ADPKD progression. Hence, targeting this pathway using immune-oncology agents may represent a novel therapeutic approach for ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited nephropathy. To date, therapies alleviating the disease have largely focused on targeting abnormalities in renal epithelial cell signaling. ADPKD has many hallmarks of cancer, where targeting T cells has brought novel therapeutic interventions. However, little is known about the role and therapeutic potential of T cells in ADPKD. Here, we used an orthologous ADPKD model, Pkd1 p.R3277C (RC), to begin to define the role of T cells in disease progression. Using flow cytometry, we found progressive increases in renal CD8+ and CD4+ T cells, correlative with disease severity, but with selective activation of CD8+ T cells. By immunofluorescence, T cells specifically localized to cystic lesions and increased levels of T-cell recruiting chemokines (CXCL9/CXCL10) were detected by qPCR/in situ hybridization in the kidneys of mice, patients, and ADPKD epithelial cell lines. Importantly, immunodepletion of CD8+ T cells from one to three months in C57Bl/6 Pkd1RC/RC mice resulted in worsening of ADPKD pathology, decreased apoptosis, and increased proliferation compared to IgG-control, consistent with a reno-protective role of CD8+ T cells. Thus, our studies suggest a functional role for T cells, specifically CD8+ T cells, in ADPKD progression. Hence, targeting this pathway using immune-oncology agents may represent a novel therapeutic approach for ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) is the most common, potentially lethal monogenic nephropathy caused predominantly by mutations to either PKD1 or PKD2.1Grantham J.J. Mechanisms of progression in autosomal dominant polycystic kidney disease.Kidney Int Suppl. 1997; 63: S93-S97PubMed Google Scholar, 2Grantham J.J. Chapman A.B. Torres V.E. Volume progression in autosomal dominant polycystic kidney disease: the major factor determining clinical outcomes.Clin J Am Soc Nephrol. 2006; 1: 148-157Crossref PubMed Scopus (234) Google Scholar, 3Heyer C.M. Sundsbak J.L. Abebe K.Z. et al.Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2016; 27: 2872-2884Crossref PubMed Scopus (107) Google Scholar, 4Porath B. Gainullin V.G. Cornec-Le Gall E. et al.Mutations in GANAB, encoding the glucosidase IIalpha subunit, cause autosomal-dominant polycystic kidney and liver disease.Am J Hum Genet. 2016; 98: 1193-1207Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar ADPKD accounts for 8% to 10% of patients receiving renal replacement therapy for end-stage renal disease (ESRD) worldwide5Grantham J.J. Clinical practice. Autosomal dominant polycystic kidney disease.N Engl J Med. 2008; 359: 1477-1485Crossref PubMed Scopus (410) Google Scholar and affects roughly 1:400 to 1:1000 people.6Iglesias C.G. Torres V.E. Offord K.P. et al.Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980.Am J Kidney Dis. 1983; 2: 630-639Abstract Full Text PDF PubMed Scopus (299) Google Scholar, 7Peters D.J. Sandkuijl L.A. Genetic heterogeneity of polycystic kidney disease in Europe.Contrib Nephrol. 1992; 97: 128-139Crossref PubMed Google Scholar The disease is characterized by dysregulated growth of renal epithelial cells leading to progressive, bilateral fluid-filled renal cysts and resulting in ESRD in about 50% of patients by middle age.8Torres V.E. Harris P.C. Pirson Y. Autosomal dominant polycystic kidney disease.Lancet. 2007; 369: 1287-1301Abstract Full Text Full Text PDF PubMed Scopus (1025) Google Scholar, 9Grantham J.J. Torres V.E. Chapman A.B. et al.Volume progression in polycystic kidney disease.N Engl J Med. 2006; 354: 2122-2130Crossref PubMed Scopus (601) Google Scholar Extrarenal manifestations, such as liver and pancreatic cysts or cardiovascular abnormalities, further decrease quality of life and increase morbidity and mortality.10Rahman E. Niaz F.A. Al-Suwaida A. et al.Analysis of causes of mortality in patients with autosomal dominant polycystic kidney disease: a single center study.Saudi J Kidney Dis Transpl. 2009; 20: 806-810PubMed Google Scholar, 11Perrone R.D. Ruthazer R. Terrin N.C. Survival after end-stage renal disease in autosomal dominant polycystic kidney disease: contribution of extrarenal complications to mortality.Am J Kidney Dis. 2001; 38: 777-784Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Previous research focused on targeting pathways central to cyst pathology, such as cyclic adenosine monophosphate/protein kinase A, epidermal growth factor, and mammalian target of rapamycin,12Harris P.C. Torres V.E. Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease.J Clin Invest. 2014; 124: 2315-2324Crossref PubMed Scopus (214) Google Scholar have provided positive data in murine preclinical trials, but their efficacy in humans was modest at best.13Walz G. Budde K. Mannaa M. et al.Everolimus in patients with autosomal dominant polycystic kidney disease.N Engl J Med. 2010; 363: 830-840Crossref PubMed Scopus (456) Google Scholar, 14Serra A.L. Poster D. Kistler A.D. et al.Sirolimus and kidney growth in autosomal dominant polycystic kidney disease.N Engl J Med. 2010; 363: 820-829Crossref PubMed Scopus (449) Google Scholar, 15Torres V.E. Chapman A.B. Devuyst O. et al.Tolvaptan in patients with autosomal dominant polycystic kidney disease.N Engl J Med. 2012; 367: 2407-2418Crossref PubMed Scopus (1024) Google Scholar, 16Caroli A. Perico N. Perna A. et al.Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial.Lancet. 2013; 382: 1485-1495Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 17Irazabal M.V. Torres V.E. Experimental therapies and ongoing clinical trials to slow down progression of ADPKD.Curr Hypertens Rev. 2013; 9: 44-59Crossref PubMed Scopus (15) Google Scholar Hence the number of US Food and Drug Administration (FDA)–approved compounds for the treatment of ADPKD are limited, and ESRD is managed by either dialysis or kidney transplant.18Harris PC, Torres VE. Polycystic kidney disease, autosomal dominant. GeneReviews. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1246/. Published January 10, 2002; updated July 19, 2018. Accessed July 20, 2018.Google Scholar Thus an urgent need exists to explore new treatment options that can slow the progression of ADPKD and prevent advancement to ESRD. Whereas mutations in PKD1 or PKD2 mediate ADPKD initiation and progression,19Mochizuki T. Wu G. Hayashi T. et al.PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.Science. 1996; 272: 1339-1342Crossref PubMed Scopus (1176) Google Scholar, 20The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium.Cell. 1994; 77: 881-894Abstract Full Text PDF PubMed Scopus (755) Google Scholar observed intra- and interfamilial phenotypic heterogeneity, ranging from in utero onset21Zerres K. Rudnik-Schoneborn S. Deget F. Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk. German Working Group on Paediatric Nephrology (Arbeitsgemeinschaft fuer Padiatrische Nephrologie).J Med Genet. 1993; 30: 583-588Crossref PubMed Google Scholar, 22Bergmann C. Bruchle N.O. Frank V. et al.Perinatal deaths in a family with autosomal dominant polycystic kidney disease and a PKD2 mutation.N Engl J Med. 2008; 359: 318-319Crossref PubMed Scopus (26) Google Scholar to adequate renal function at old age,23Hateboer N. v Dijk M.A. Bogdanova N. et al.Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group.Lancet. 1999; 353: 103-107Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar exceeds genic effects,3Heyer C.M. Sundsbak J.L. Abebe K.Z. et al.Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2016; 27: 2872-2884Crossref PubMed Scopus (107) Google Scholar, 24Harris P.C. Rossetti S. Determinants of renal disease variability in ADPKD.Adv Chronic Kidney Dis. 2010; 17: 131-139Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar suggesting that additional, nongenetic factors contribute to disease progression. Further, the functional role of the PKD1 and PKD2 proteins, polycystin-1 and polycystin-2, while extensively studied, remains elusive, leaving many open questions regarding the mechanisms that drive cystogenesis.25Torres V.E. Harris P.C. Autosomal dominant polycystic kidney disease: the last 3 years.Kidney Int. 2009; 76: 149-168Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar, 26Nauli S.M. Alenghat F.J. Luo Y. et al.Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.Nat Genet. 2003; 33: 129-137Crossref PubMed Scopus (1625) Google Scholar, 27Delling M. Indzhykulian A.A. Liu X. et al.Primary cilia are not calcium-responsive mechanosensors.Nature. 2016; 531: 656-660Crossref PubMed Scopus (241) Google Scholar, 28Delling M. DeCaen P.G. Doerner J.F. et al.Primary cilia are specialized calcium signalling organelles.Nature. 2013; 504: 311-314Crossref PubMed Scopus (329) Google Scholar Although ADPKD historically has been considered a “neoplasia in disguise,”29Grantham J.J. Polycystic kidney disease: neoplasia in disguise.Am J Kidney Dis. 1990; 15: 110-116Abstract Full Text PDF PubMed Scopus (135) Google Scholar the significant similarities between ADPKD and cancer have been rediscovered more recently.30Seeger-Nukpezah T. Geynisman D.M. Nikonova A.S. et al.The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease.Nat Rev Nephrol. 2015; 11: 515-534Crossref PubMed Scopus (85) Google Scholar In fact, many of the cancer hallmarks as defined by Hanahan and Weinberg31Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (43056) Google Scholar are applicable to ADPKD (e.g., sustained proliferation,12Harris P.C. Torres V.E. Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease.J Clin Invest. 2014; 124: 2315-2324Crossref PubMed Scopus (214) Google Scholar, 30Seeger-Nukpezah T. Geynisman D.M. Nikonova A.S. et al.The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease.Nat Rev Nephrol. 2015; 11: 515-534Crossref PubMed Scopus (85) Google Scholar, 32Nadasdy T. Laszik Z. Lajoie G. et al.Proliferative activity of cyst epithelium in human renal cystic diseases.J Am Soc Nephrol. 1995; 5: 1462-1468Crossref PubMed Google Scholar genomic instability,33Battini L. Macip S. Fedorova E. et al.Loss of polycystin-1 causes centrosome amplification and genomic instability.Hum Mol Genet. 2008; 17: 2819-2833Crossref PubMed Scopus (66) Google Scholar, 34Li M. Qin S. Wang L. et al.Genomic instability in patients with autosomal-dominant polycystic kidney disease.J Int Med Res. 2013; 41: 169-175Crossref PubMed Scopus (8) Google Scholar, 35Brasier J.L. Henske E.P. Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis.J Clin Invest. 1997; 99: 194-199Crossref PubMed Scopus (225) Google Scholar deregulated cellular energetics,36Rowe I. Chiaravalli M. Mannella V. et al.Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy.Nat Med. 2013; 19: 488-493Crossref PubMed Scopus (311) Google Scholar, 37Warner G. Hein K.Z. Nin V. et al.Food restriction ameliorates the development of polycystic kidney disease.J Am Soc Nephrol. 2016; 27: 1437-1447Crossref PubMed Scopus (99) Google Scholar and inflammation/avoiding immune destruction38Zheng D. Wolfe M. Cowley Jr., B.D. et al.Urinary excretion of monocyte chemoattractant protein-1 in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2003; 14: 2588-2595Crossref PubMed Scopus (95) Google Scholar, 39Li X. Magenheimer B.S. Xia S. et al.A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease.Nat Med. 2008; 14: 863-868Crossref PubMed Scopus (116) Google Scholar, 40Ta M.H. Harris D.C. Rangan G.K. Role of interstitial inflammation in the pathogenesis of polycystic kidney disease.Nephrology (Carlton). 2013; 18: 317-330Crossref PubMed Scopus (54) Google Scholar, 41Karihaloo A. Koraishy F. Huen S.C. et al.Macrophages promote cyst growth in polycystic kidney disease.J Am Soc Nephrol. 2011; 22: 1809-1814Crossref PubMed Scopus (148) Google Scholar, 42Swenson-Fields K.I. Vivian C.J. Salah S.M. et al.Macrophages promote polycystic kidney disease progression.Kidney Int. 2013; 83: 855-864Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 43Vogler C. Homan S. Pung A. et al.Clinical and pathologic findings in two new allelic murine models of polycystic kidney disease.J Am Soc Nephrol. 1999; 10: 2534-2539PubMed Google Scholar, 44Zeier M. Fehrenbach P. Geberth S. et al.Renal histology in polycystic kidney disease with incipient and advanced renal failure.Kidney Int. 1992; 42: 1259-1265Abstract Full Text PDF PubMed Scopus (135) Google Scholar, 45McPherson E.A. Luo Z. Brown R.A. et al.Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2004; 15: 493-500Crossref PubMed Scopus (67) Google Scholar, 46Bernhardt W.M. Wiesener M.S. Weidemann A. et al.Involvement of hypoxia-inducible transcription factors in polycystic kidney disease.Am J Pathol. 2007; 170: 830-842Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 47Werder A.A. Amos M.A. Nielsen A.H. et al.Comparative effects of germfree and ambient environments on the development of cystic kidney disease in CFWwd mice.J Lab Clin Med. 1984; 103: 399-407PubMed Google Scholar). Importantly, interstitial inflammation has been reported in human patients with ADPKD, as well as in animal models of the disease.40Ta M.H. Harris D.C. Rangan G.K. Role of interstitial inflammation in the pathogenesis of polycystic kidney disease.Nephrology (Carlton). 2013; 18: 317-330Crossref PubMed Scopus (54) Google Scholar In concordance with an inflammatory response, increased levels of pro-inflammatory cytokines, such as monocyte chemoattractant protein-1 and tumor necrosis factor–α, were detected in cyst fluid of patients with ADPKD, and anti-inflammatory therapies have been shown to attenuate disease progression in animal models.38Zheng D. Wolfe M. Cowley Jr., B.D. et al.Urinary excretion of monocyte chemoattractant protein-1 in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2003; 14: 2588-2595Crossref PubMed Scopus (95) Google Scholar, 39Li X. Magenheimer B.S. Xia S. et al.A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease.Nat Med. 2008; 14: 863-868Crossref PubMed Scopus (116) Google Scholar, 40Ta M.H. Harris D.C. Rangan G.K. Role of interstitial inflammation in the pathogenesis of polycystic kidney disease.Nephrology (Carlton). 2013; 18: 317-330Crossref PubMed Scopus (54) Google Scholar Furthermore, macrophage infiltration can be observed in orthologous and nonorthologous ADPKD models at advanced disease stage,41Karihaloo A. Koraishy F. Huen S.C. et al.Macrophages promote cyst growth in polycystic kidney disease.J Am Soc Nephrol. 2011; 22: 1809-1814Crossref PubMed Scopus (148) Google Scholar, 42Swenson-Fields K.I. Vivian C.J. Salah S.M. et al.Macrophages promote polycystic kidney disease progression.Kidney Int. 2013; 83: 855-864Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 43Vogler C. Homan S. Pung A. et al.Clinical and pathologic findings in two new allelic murine models of polycystic kidney disease.J Am Soc Nephrol. 1999; 10: 2534-2539PubMed Google Scholar and a few reports show CD4+ T cells, mast cells, and neutrophils in the interstitium of patients with ADPKD.44Zeier M. Fehrenbach P. Geberth S. et al.Renal histology in polycystic kidney disease with incipient and advanced renal failure.Kidney Int. 1992; 42: 1259-1265Abstract Full Text PDF PubMed Scopus (135) Google Scholar, 45McPherson E.A. Luo Z. Brown R.A. et al.Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2004; 15: 493-500Crossref PubMed Scopus (67) Google Scholar, 46Bernhardt W.M. Wiesener M.S. Weidemann A. et al.Involvement of hypoxia-inducible transcription factors in polycystic kidney disease.Am J Pathol. 2007; 170: 830-842Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar Additionally, historic data showed that murine PKD models raised in germ-free environments present with milder cystic disease,47Werder A.A. Amos M.A. Nielsen A.H. et al.Comparative effects of germfree and ambient environments on the development of cystic kidney disease in CFWwd mice.J Lab Clin Med. 1984; 103: 399-407PubMed Google Scholar suggesting a role for the immune system in PKD. In fact, it was shown that M2-like macrophages can promote cyst growth in murine models of autosomal recessive PKD (ARPKD) and ADPKD and that their depletion slows renal and hepatic cystogenesis.41Karihaloo A. Koraishy F. Huen S.C. et al.Macrophages promote cyst growth in polycystic kidney disease.J Am Soc Nephrol. 2011; 22: 1809-1814Crossref PubMed Scopus (148) Google Scholar, 42Swenson-Fields K.I. Vivian C.J. Salah S.M. et al.Macrophages promote polycystic kidney disease progression.Kidney Int. 2013; 83: 855-864Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 48Locatelli L. Cadamuro M. Spirli C. et al.Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.Hepatology. 2016; 63: 965-982Crossref PubMed Scopus (64) Google Scholar However, to date, no research in the literature addresses the role of the adaptive immune system in ADPKD initiation and progression. Targeting adaptive immunity has become a central focus in developing new therapeutic approaches in multiple malignancies.49Callahan M.K. Wolchok J.D. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy.J Leukoc Biol. 2013; 94: 41-53Crossref PubMed Scopus (263) Google Scholar, 50Topalian S.L. Drake C.G. Pardoll D.M. Immune checkpoint blockade: a common denominator approach to cancer therapy.Cancer Cell. 2015; 27: 450-461Abstract Full Text Full Text PDF PubMed Scopus (2644) Google Scholar In many cancers, increased numbers of tumor-infiltrating T cells are associated with better prognosis,51Restifo N.P. Dudley M.E. Rosenberg S.A. Adoptive immunotherapy for cancer: harnessing the T cell response.Nat Rev Immunol. 2012; 12: 269-281Crossref PubMed Scopus (1223) Google Scholar consistent with a role for these cells in inhibiting tumor progression. However, the role of different T-cell subtypes is complex because of their heterogeneity.52DeNardo D.G. Andreu P. Coussens L.M. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity.Cancer Metastasis Rev. 2010; 29: 309-316Crossref PubMed Scopus (372) Google Scholar As such, different populations have either pro-tumorigenic (e.g., regulatory T cells [Tregs]) or antitumorigenic (e.g., CD8+ T cell) roles. Additionally, cancers have developed multiple cellular and molecular pathways to suppress T-cell functions. Strategies targeting the interaction of specific T cells with cancer cells have shown recent clinical success, leading to FDA approval of checkpoint inhibitors that target the interactions of programmed cell death protein-1 (PD-1) with its ligand PD-L1, resulting in reactivation of antitumor CD8+ T cells.53Ribas A. Hamid O. Daud A. et al.Association of pembrolizumab with tumor response and survival among patients with advanced melanoma.JAMA. 2016; 315: 1600-1609Crossref PubMed Scopus (734) Google Scholar, 54Long G.V. Weber J.S. Larkin J. et al.Nivolumab for patients with advanced melanoma treated beyond progression: analysis of 2 phase 3 clinical trials.JAMA Oncol. 2017; 3: 1511-1519Crossref PubMed Scopus (117) Google Scholar The progress made in the field of cancer research, specifically the function of T cells in tumorigenesis, may yield new ideas and avenues for ADPKD research. Thus, an essential first step forward is to understand the role of T cells in ADPKD progression. Here, we characterized T-cell subpopulations in an orthologous mouse model of ADPKD that reproduces critical features of the human disease, including a slow rate of progression. We found that T cells increase in correlation with disease severity and localize specifically to cystic lesions. Importantly, our results define a functional role for CD8+ T cells in inhibiting ADPKD progression, highlighting the potential to adapt cancer immunotherapy strategies to ADPKD. The homozygous Pkd1 p.R3277C (Pkd1RC/RC)55Hopp K. Ward C.J. Hommerding C.J. et al.Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity.J Clin Invest. 2012; 122: 4257-4273Crossref PubMed Scopus (242) Google Scholar model genetically and physiologically mimics human ADPKD. It harbors a knock-in mutation that mimics a hypomorphic allele identified in ADPKD families56Rossetti S. Kubly V.J. Consugar M.B. et al.Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease.Kidney Int. 2009; 75: 848-855Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar and presents over time in the C57Bl/6 background with slowly progressive disease with moderate increases in percent kidney weight/body weight (%KW/BW), renal cystic/fibrotic area (index), chronic inflammation (increased renal interleukin-6/decreased interleukin-10 levels), as well as mild renal function decline (Supplementary Figure S1; Supplementary Table S1). To evaluate how the cystic microenvironment (CME), specifically T cells, differ between C57Bl/6 wild type (WT) and Pkd1RC/RC mice and to correlate changes in the adaptive immune system profile with cystogenesis progression, we used flow cytometry analysis of renal single cell suspensions and analyzed mice at 3, 6, and 9 months of age. In Pkd1RC/RC C57Bl/6 mice at 3 and 6 months, when the cystic disease is mild/moderate, respectively, we detected a statistically significant increase in immune cells (CD45+) and T cells (T-cell receptor β+ [TCRβ+]) in Pkd1RC/RC compared with WT mice, but the most striking increase occurred at 9 months of age, the investigated time point at which PKD is most severe (Figure 1a and b; Supplementary Figure S1; Supplementary Table S1). The same pattern was observed for both cytotoxic T cells (CD8+) and helper T cells (CD4+, Figure 1c and d; Supplementary Table S1). Importantly, as shown by immunofluorescence, T cells (CD3+, CD4+, CD8+) specifically localized around cystic lesions even at mild stages of cystogenesis (3 months) when the global increase of T-cell number in the kidney was modest (Figure 1e and f; Supplementary Figure S2). At 9 months a more diffuse increase of T cells was notable by immunofluorescence, characterized by increased localization to noncystic areas, likely accounting for the striking increase in T-cell number at 9 months observed by flow cytometry (Figure 1b and e). This finding likely reflects the adaptive immune system’s response to increasing tubular atrophy and interstitial expansion/inflammation that can be observed in 9-month-old Pkd1RC/RC C57Bl/6 mice, despite the slowly progressive/mild disease (Supplementary Figure S1C). Importantly, the increase in T-cell numbers between C57Bl/6 WT and Pkd1RC/RC mice was specific to kidney disease, as no changes were observed in spleens (Supplementary Figure S3). The Pkd1RC/RC model presents with varying disease severity in different mouse strains, being mildest in the C57Bl/6 and significantly more severe in the 129/S6 and Balb/c backgrounds as measured by percent kidney weight/body weight, renal cystic/fibrotic area (index), renal function, and cytokine levels (Supplementary Figure S1; Supplementary Table S1). Interestingly, among these strains, only renal cyst size but not cyst number varies significantly, suggesting that variances in the rate of cyst progression rather than cyst initiation drive disease severity differences, indicative of a microenvironmental role in disease pathology (Supplementary Figure S1F and G). To evaluate whether T-cell number increases correlate to disease severity, we performed comparable experiments in 129/S6 and Balb/c Pkd1RC/RC mice as for the C57Bl/6 background. We observed similar changes in the adaptive immune system in 129/S6 and Balb/c Pkd1RC/RC mice (Figure 2; Supplementary Figure S4). However, the overall increase in CD45+ and T-cell subpopulations (TCRβ+, CD8+, and CD4+) compared with WT was much larger in the 129/S6 and Balb/c Pkd1RC/RC models than in the C57Bl/6 Pkd1RC/RC model, correlating with the more severe disease in these strains. This outcome was notable by flow cytometry (Figure 2a–d; Supplementary Figure S4; Supplementary Table S1), as well as by immunofluorescence (Figure 2e; Supplementary Figures S2 and S4; Supplementary Table S1). To evaluate the rise in T-cell numbers mechanistically, we performed quantitative polymerase chain reaction for interferon (IFN)-γ, a cytokine produced by activated T cells,57Nakajima C. Uekusa Y. Iwasaki M. et al.A role of interferon-gamma (IFN-gamma) in tumor immunity: T cells with the capacity to reject tumor cells are generated but fail to migrate to tumor sites in IFN-gamma-deficient mice.Cancer Res. 2001; 61: 3399-3405PubMed Google Scholar and T-cell recruiting chemokines (Cxcl9, Cxcl1058Marshall A. Celentano A. Cirillo N. et al.Tissue-specific regulation of CXCL9/10/11 chemokines in keratinocytes: implications for oral inflammatory disease.PLoS One. 2017; 12: e0172821Crossref PubMed Scopus (35) Google Scholar, 59Lucca L.E. Hafler D.A. Resisting fatal attraction: a glioma oncometabolite prevents CD8+ T cell recruitment.J Clin Invest. 2017; 127: 1218-1220Crossref PubMed Scopus (12) Google Scholar). Levels of all 3 gene products were increased in the kidney as disease progressed (Figure 3a–c; Supplementary Table S1). In cancer, CXCL9 and CXCL10 induce lymphocyte infiltration and lead to suppression of tumor growth because of the infiltration of primarily CD8+ and Th1 CD4+ T cells.60Tokunaga R. Zhang W. Naseem M. et al.CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation—a target for novel cancer therapy.Cancer Treat Rev. 2017; 63: 40-47Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar, 61Bronger H. Singer J. Windmuller C. et al.CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer.Br J Cancer. 2016; 115: 553-563Crossref PubMed Scopus (148) Google Scholar Upon further investigation, in situ hybridization of Balb/c Pkd1RC/RC renal sections revealed that Cxcl9/Cxcl10 are produced primarily in cystic regions, and co-immunofluorescence staining for CD3 showed that T cells co-localize near the cystic regions that produce Cxcl9/Cxcl10 (Figure 3d). From a closer examination of these data, it is apparent that while multiple cells may be producing these chemokines, significant numbers of epithelial cells stained positive, highlighting that the cystic epithelium plays an active role in T-cell recruitment (Figure 3d, inset). To determine if this mechanism of T-cell recruitment is relevant to human disease, we performed in situ hybridization for CXCL9 and CXCL10 on human ESRD ADPKD and ARPKD formalin-fixed-paraffin-embedded kidneys. As in mice, CD3+ T cells co-localized to regions with high CXCL9/CXCL10 levels, and both of these chemokines were produced by the cystic epithelium (Figure 3e). In both ADPKD and ARPKD, we observed similar increases in CXCL9/CXCL10 levels and overall T-cell infiltrate to cystic regions, which were significantly higher compared with normal human kidney tissue. Because CXCL9/CXCL10 production by cancer cells has been reported previously and predicts tumor outcome,62Kistner L. Doll D. Holtorf A. et al" @default.
• W2890836726 created "2018-09-27" @default.
• W2890836726 creator A5001705661 @default.
• W2890836726 creator A5002238355 @default.
• W2890836726 creator A5014699103 @default.
• W2890836726 creator A5032236530 @default.
• W2890836726 creator A5036228407 @default.
• W2890836726 creator A5040401945 @default.
• W2890836726 creator A5044275756 @default.
• W2890836726 creator A5052417193 @default.
• W2890836726 creator A5053952407 @default.
• W2890836726 creator A5064713352 @default.
• W2890836726 creator A5076891434 @default.
• W2890836726 creator A5080064369 @default.
• W2890836726 creator A5087878429 @default.
• W2890836726 creator A5089539218 @default.
• W2890836726 date "2018-12-01" @default.
• W2890836726 modified "2023-10-04" @default.
• W2890836726 title "CD8+ T cells modulate autosomal dominant polycystic kidney disease progression" @default.
• W2890836726 cites W1551136355 @default.
• W2890836726 cites W1584313983 @default.
• W2890836726 cites W1594650921 @default.
• W2890836726 cites W1812059588 @default.
• W2890836726 cites W1966289658 @default.
• W2890836726 cites W1971220062 @default.
• W2890836726 cites W1980334968 @default.
• W2890836726 cites W1984459365 @default.
• W2890836726 cites W1991634527 @default.
• W2890836726 cites W1999095798 @default.
• W2890836726 cites W2000619967 @default.
• W2890836726 cites W2003784194 @default.
• W2890836726 cites W2004630197 @default.
• W2890836726 cites W2005026678 @default.
• W2890836726 cites W2016547342 @default.
• W2890836726 cites W2018529989 @default.
• W2890836726 cites W2043904711 @default.
• W2890836726 cites W2048168245 @default.
• W2890836726 cites W2053062434 @default.
• W2890836726 cites W2053094829 @default.
• W2890836726 cites W2055919784 @default.
• W2890836726 cites W2065928247 @default.
• W2890836726 cites W2066671159 @default.
• W2890836726 cites W2073941052 @default.
• W2890836726 cites W2078789307 @default.
• W2890836726 cites W2080307184 @default.
• W2890836726 cites W2082060108 @default.
• W2890836726 cites W2083917318 @default.
• W2890836726 cites W2085346322 @default.
• W2890836726 cites W2086082652 @default.
• W2890836726 cites W2094982034 @default.
• W2890836726 cites W2095869636 @default.
• W2890836726 cites W2096538221 @default.
• W2890836726 cites W2110300199 @default.
• W2890836726 cites W2111222260 @default.
• W2890836726 cites W2112591804 @default.
• W2890836726 cites W2112643254 @default.
• W2890836726 cites W2117692326 @default.
• W2890836726 cites W2119615058 @default.
• W2890836726 cites W2120923776 @default.
• W2890836726 cites W2121026194 @default.
• W2890836726 cites W2123332237 @default.
• W2890836726 cites W2124951764 @default.
• W2890836726 cites W2127766722 @default.
• W2890836726 cites W2129253605 @default.
• W2890836726 cites W2130066229 @default.
• W2890836726 cites W2130211846 @default.
• W2890836726 cites W2130848313 @default.
• W2890836726 cites W2133223520 @default.
• W2890836726 cites W2139409703 @default.
• W2890836726 cites W2140394797 @default.
• W2890836726 cites W2143108257 @default.
• W2890836726 cites W2143772132 @default.
• W2890836726 cites W2152155935 @default.
• W2890836726 cites W2153747318 @default.
• W2890836726 cites W2159432951 @default.
• W2890836726 cites W2168769452 @default.
• W2890836726 cites W2168922778 @default.
• W2890836726 cites W2171481006 @default.
• W2890836726 cites W2171821069 @default.
• W2890836726 cites W2172223249 @default.
• W2890836726 cites W2190376035 @default.
• W2890836726 cites W2213687129 @default.
• W2890836726 cites W2280100400 @default.
• W2890836726 cites W2282558901 @default.
• W2890836726 cites W2311871350 @default.
• W2890836726 cites W2338494814 @default.
• W2890836726 cites W2339322884 @default.
• W2890836726 cites W2397573860 @default.
• W2890836726 cites W2418233049 @default.
• W2890836726 cites W2488042065 @default.
• W2890836726 cites W2531627693 @default.
• W2890836726 cites W2547347902 @default.
• W2890836726 cites W2560367415 @default.
• W2890836726 cites W2572174216 @default.
• W2890836726 cites W2594688214 @default.
• W2890836726 cites W2595719683 @default.
• W2890836726 cites W265806298 @default.
• W2890836726 cites W2725298133 @default.

• next