Understanding Ocular Surface Inflammation in Tears Before and After Autologous Cultivated Limbal Epithelial Stem Cell Transplantation
Tóm tắt
We aimed to determine the expression of inflammatory cytokines in the tears of patients with unilateral total limbal stem cell deficiency (TLSCD) caused by chemical burns before and after autologous cultivated limbal epithelial stem cell transplantation (CLET). Tear samples were collected from both eyes of 23 patients with unilateral TLSCD and 11 healthy controls, at fixed timepoints before and after CLET. Dissolved molecules were extracted from Schirmer’s strips using a standardised method and analysed on an array plate of ten inflammatory cytokines (V-Plex Proinflammatory Panel 1 Human Kit, MSD). IL1β expression was significantly elevated in the TLSCD eye compared with the unaffected eye at baseline (p < 0.0001) but decreased to normal 3 months post-CLET (p = 0.22). IL6 and IL8 were unaffected at baseline but significantly elevated in the TLSCD eyes at 1 month post-CLET (p = 0.001 and p < 0.0001, respectively). IL6 returned to normal at 3 months and IL8 at 6 months post-CLET. There was a significant renewed increase in IL1β, IL6 and IL8 expression at 12 months post-CLET (p < 0.0001, p = 0.0001 and p = 0.0003, respectively). IFNγ, IL10 and IL12p70 expression were significantly reduced in both eyes of patients with unilateral TLSCD at all timepoints. IL1β is a specific marker of inflammation in TLSCD eyes that could be therapeutically targeted pre-CLET to improve stem cell engraftment. At 12 months post-CLET the spike in levels of IL1β, IL6 and IL8 coincides with cessation of topical steroids, suggesting ongoing subclinical inflammation. We therefore recommend not discontinuing topical steroid treatment in cases where penetrating keratoplasty is indicated; however, further investigation is needed to ascertain this. European Union Drug Regulating Authorities Clinical Trials Database (EuDRACT 2011—000608-16); ISRCTN (International Standard Randomised Controlled Trial Number (isrctn51772481).
Tài liệu tham khảo
citation_journal_title=Am J Ophthalmol; citation_title=Important concepts for treating ocular surface and tear disorders; citation_author=SC Tseng, K Tsubota; citation_volume=124; citation_issue=6; citation_publication_date=1997; citation_pages=825-835; citation_doi=10.1016/S0002-9394(14)71700-3; citation_id=CR1
citation_journal_title=Br J Ophthalmol; citation_title=Towards a dynamic customised therapy for ocular surface dysfunctions; citation_author=P Aragona, M Rolando; citation_volume=97; citation_issue=8; citation_publication_date=2013; citation_pages=955-960; citation_doi=10.1136/bjophthalmol-2012-302568; citation_id=CR2
citation_journal_title=Cornea; citation_title=Effect of stromal inflammation on the outcome of limbal transplantation for corneal surface reconstruction; citation_author=RJ Tsai, SC Tseng; citation_volume=14; citation_issue=5; citation_publication_date=1995; citation_pages=439-449; citation_doi=10.1097/00003226-199509000-00001; citation_id=CR3
citation_journal_title=Ophthalmology; citation_title=Limbal stem cell transplantation in chronic inflammatory eye disease; citation_author=CM Samson, C Nduaguba, S Baltatzis, CS Foster; citation_volume=109; citation_issue=5; citation_publication_date=2002; citation_pages=862-868; citation_doi=10.1016/S0161-6420(02)00994-6; citation_id=CR4
citation_journal_title=Nat Cell Biol; citation_title=Chronic inflammation imposes aberrant cell fate in regenerating epithelia through mechanotransduction; citation_author=CS Nowell, PD Odermatt, L Azzolin, S Hohnel, EF Wagner, GE Fantner; citation_volume=18; citation_issue=2; citation_publication_date=2016; citation_pages=168-180; citation_doi=10.1038/ncb3290; citation_id=CR5
citation_journal_title=Invest Ophthalmol Vis Sci; citation_title=Characterization of corneal pannus removed from patients with total limbal stem cell deficiency; citation_author=EM Espana, MA Pascuale, H He, T Kawakita, VK Raju, CY Liu; citation_volume=45; citation_issue=9; citation_publication_date=2004; citation_pages=2961-2966; citation_doi=10.1167/iovs.03-1397; citation_id=CR6
citation_journal_title=Eye; citation_title=Ocular surface changes in limbal stem cell deficiency caused by chemical injury: a histologic study of excised pannus from recipients of cultured corneal epithelium; citation_author=A Fatima, G Iftekhar, VS Sangwan, GK Vemuganti; citation_volume=22; citation_issue=9; citation_publication_date=2007; citation_pages=1161-1167; citation_doi=10.1038/sj.eye.6702895; citation_id=CR7
citation_journal_title=Ophthalmology; citation_title=Characterization of the corneal surface in limbal stem cell deficiency and after transplantation of cultivated limbal epithelium; citation_author=M Pauklin, K-P Steuhl, D Meller; citation_volume=116; citation_issue=6; citation_publication_date=2009; citation_pages=1048-1056; citation_doi=10.1016/j.ophtha.2009.01.005; citation_id=CR8
citation_journal_title=Stem Cells; citation_title=Successful clinical implementation of corneal epithelial stem cell therapy for treatment of unilateral limbal stem cell deficiency; citation_author=S Kolli, S Ahmad, M Lako, F Figueiredo; citation_volume=28; citation_issue=3; citation_publication_date=2010; citation_pages=597-610; citation_doi=10.1002/stem.276; citation_id=CR9
citation_journal_title=BioMed Res Int; citation_title=Quiescent and active tear protein profiles to predict vernal keratoconjunctivitis reactivation; citation_author=A Micera, A Zazzo, G Esposito, R Sgrulletta, VL Calder, S Bonini; citation_volume=2016; citation_publication_date=2016; citation_pages=10; citation_doi=10.1155/2016/9672082; citation_id=CR10
citation_journal_title=Invest Ophthalmol Vis Sci; citation_title=Correlation between human tear cytokine levels and cellular corneal changes in patients with bacterial keratitis by in vivo confocal microscopy; citation_author=T Yamaguchi, BM Calvacanti, A Cruzat, Y Qazi, S Ishikawa, A Osuka; citation_volume=55; citation_issue=11; citation_publication_date=2014; citation_pages=7457-7466; citation_doi=10.1167/iovs.14-15411; citation_id=CR11
citation_journal_title=Indian J Ophthalmol; citation_title=A pilot study on the infiltrating cells and cytokine levels in the tear of fungal keratitis patients; citation_author=M Vasanthi, NV Prajna, P Lalitha, K Mahadevan, V Muthukkaruppan; citation_volume=55; citation_issue=1; citation_publication_date=2007; citation_pages=27-31; citation_doi=10.4103/0301-4738.29491; citation_id=CR12
citation_journal_title=JAMA Ophthalmol; citation_title=Topical interleukin 1 receptor antagonist for treatment of dry eye disease: a randomized clinical trial; citation_author=F Amparo, MH Dastjerdi, A Okanobo, G Ferrari, L Smaga, P Hamrah; citation_volume=131; citation_issue=6; citation_publication_date=2013; citation_pages=715-723; citation_doi=10.1001/jamaophthalmol.2013.195; citation_id=CR13
citation_journal_title=N Engl J Med; citation_title=Acute-phase proteins and other systemic responses to inflammation; citation_author=C Gabay, I Kushner; citation_volume=340; citation_issue=6; citation_publication_date=1999; citation_pages=448-454; citation_doi=10.1056/NEJM199902113400607; citation_id=CR14
citation_journal_title=J Clin Invest; citation_title=Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein; citation_author=C Gabay, MF Smith, D Eidlen, WP Arend; citation_volume=99; citation_issue=12; citation_publication_date=1997; citation_pages=2930-2940; citation_doi=10.1172/JCI119488; citation_id=CR15
citation_journal_title=Annu Rev Immunol; citation_title=Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity; citation_author=G Trinchieri; citation_volume=13; citation_publication_date=1995; citation_pages=251-276; citation_doi=10.1146/annurev.iy.13.040195.001343; citation_id=CR16
citation_journal_title=Scand J Immunol; citation_title=Innate IFN-gamma production by subsets of natural killer cells, natural killer T cells and gammadelta T cells in response to dying bacterial-infected macrophages; citation_author=K Kubota; citation_volume=71; citation_issue=3; citation_publication_date=2010; citation_pages=199-209; citation_doi=10.1111/j.1365-3083.2009.02366.x; citation_id=CR17
citation_journal_title=Immunol Res; citation_title=Cell type-specific regulation of IL-10 expression in inflammation and disease; citation_author=C Hedrich, J Bream; citation_volume=47; citation_issue=1–3; citation_publication_date=2010; citation_pages=185-206; citation_doi=10.1007/s12026-009-8150-5; citation_id=CR18
citation_title=Chapter 2: acute and chronic inflammation induces disease pathogenesis; citation_inbook_title=Molecular pathology; citation_publication_date=2009; citation_pages=25-40; citation_id=CR19; citation_author=V Dolgachev; citation_author=LN Lukacs; citation_publisher=Academic Press
citation_title=Chapter 9: Cytokines; citation_inbook_title=Immunology: understanding the immune system; citation_publication_date=2009; citation_id=CR20; citation_author=KD Elgert; citation_publisher=Wiley
citation_journal_title=Cornea; citation_title=Bilateral alterations in corneal nerves, dendritic cells, and tear cytokine levels in ocular surface disease; citation_author=T Yamaguchi, P Hamrah, J Shimazaki; citation_volume=35; citation_issue=Suppl 1; citation_publication_date=2016; citation_pages=S65-s70; citation_doi=10.1097/ICO.0000000000000989; citation_id=CR21
citation_journal_title=Invest Ophthalmol Vis Sci; citation_title=Contralateral clinically unaffected eyes of patients with unilateral infectious keratitis demonstrate a sympathetic immune response; citation_author=A Cruzat, WA Schrems, LM Schrems-Hoesl, BM Cavalcanti, N Baniasadi, D Witkin; citation_volume=56; citation_issue=11; citation_publication_date=2015; citation_pages=6612-6620; citation_doi=10.1167/iovs.15-16560; citation_id=CR22
citation_journal_title=Invest Ophthalmol Vis Sci; citation_title=In vivo confocal microscopy demonstrates bilateral loss of endothelial cells in unilateral herpes simplex keratitis; citation_author=RT Muller, R Pourmirzaie, D Pavan-Langston, BM Cavalcanti, S Aggarwal, C Colon; citation_volume=56; citation_issue=8; citation_publication_date=2015; citation_pages=4899-4906; citation_doi=10.1167/iovs.15-16527; citation_id=CR23
citation_journal_title=Invest Ophthalmol Vis Sci; citation_title=Inflammation and the nervous system: the connection in the cornea in patients with infectious keratitis; citation_author=A Cruzat, D Witkin, N Baniasadi, L Zheng, JB Ciolino, UV Jurkunas; citation_volume=52; citation_issue=8; citation_publication_date=2011; citation_pages=5136-5143; citation_doi=10.1167/iovs.10-7048; citation_id=CR24
citation_journal_title=Ocul Surf; citation_title=In vivo confocal microscopy detects bilateral changes of corneal immune cells and nerves in unilateral herpes zoster ophthalmicus; citation_author=B Cavalcanti, A Cruzat, A Sahin, D Pavan-Langston, E Samayoa, P Hamrah; citation_volume=16; citation_issue=1; citation_publication_date=2018; citation_pages=101-111; citation_doi=10.1016/j.jtos.2017.09.004; citation_id=CR25
citation_journal_title=Yonsei Med J; citation_title=Inflammatory cytokine and osmolarity changes in the tears of dry eye patients treated with topical 1% methylprednisolone; citation_author=JH Lee, K Min, SK Kim, EK Kim, T Kim; citation_volume=55; citation_issue=1; citation_publication_date=2014; citation_pages=203-208; citation_doi=10.3349/ymj.2014.55.1.203; citation_id=CR26
citation_journal_title=Stem Cells; citation_title=Outcomes of penetrating keratoplasty following autologous cultivated limbal epithelial stem cell transplantation; citation_author=GS Figueiredo, B Salvador-Culla, OJ Baylis, HS Mudhar, M Lako, FC Figueiredo; citation_volume=36; citation_issue=6; citation_publication_date=2018; citation_pages=925-931; citation_doi=10.1002/stem.2803; citation_id=CR27