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    Rejections After TransplantationVessels, Primarily Mediate Immune Cutting Edge: Lymphatic Vessels, Not Blood

    CursiefenBachmann, Grit Zahn, Stanley Wiegand, Lu Chen and Claus Tina Dietrich, Felix Bock, Don Yuen, Deniz Hos, Bjrn O. 10.4049/jimmunol.0903180December 2009;

    2010; 184:535-539; Prepublished online 16J Immunol


    , 7 of which you can access for free at: cites 26 articlesThis article


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  • Cutting Edge: Lymphatic Vessels, Not Blood Vessels,Primarily Mediate Immune Rejections AfterTransplantationTina Dietrich,*,,1 Felix Bock,*,,1 Don Yuen,x Deniz Hos,* Bjorn O. Bachmann,*Grit Zahn,{ Stanley Wiegand,|| Lu Chen,x and Claus Cursiefen*,

    The purpose of this study was to determine the relativeimportance of blood vessels (hemangiogenesis) versuslymphatic vessels (lymphangiogenesis) in mediating im-munological responses after transplantation. Using themurine model of corneal transplantation, graft survivalwas compared in differentially prevascularized and avas-cular recipient beds. Donor corneas (C57BL/6) weretransplanted into uninflamed or inflamed avascular,prehemvascularized only or prehemvascularized andprelymphvascularized recipient murine eyes (BALB/C).Selective inhibition of lymphangiogenesis was achievedusing antivascular endothelial growth factor receptor 3Abs and anti-integrin a5 small molecules. Grafts placedinto only prehemvascularized recipient beds had a sim-ilarly good graft survival compared with grafts placedinto completely avascular, normal recipients, whereasthe pre-existence of lymphatic vessels significantlydeteriorated corneal graft survival (p , 0.05). Lym-phatic vessels seem to contribute significantly to graftrejection after (corneal) transplantation. That may al-low for selective, temporary, perioperative antilym-phangiogenic treatment to promote graft survivalwithout affecting blood vessels, even after solid organtransplantation. The Journal of Immunology, 2010,184: 535539.

    Immune-mediated graft rejections remain the mostcommon cause for graft failure after organ and tissuetransplantation. A great medical need exists for phar-

    macologic strategies to promote graft survival without undulycompromising the health of the recipient (for review see Ref. 1).The three structural components of the immune system

    allowing for immune responses against foreign tissue aftertransplantation are afferent lymphatic vessels (afferent arm ofthe immune reflex arc), regional lymph nodes (central

    processing unit), and efferent blood vessels (efferent arm ofthe immune reflex arc) (2).Lymphatic vessels allow the transport of APCs with foreign

    tissue Ags and soluble antigenic material to the regional lymphnode and, thereby, constitute one of the earliest events in theimmune-cascade leading to rejection. The precise relative im-portance of lymphatic vessels (afferent arm) versus bloodvessels (efferent arm) for immune reactions after trans-plantation is unclear. However, every solid organ or vascular-ized tissue transplantation is accompanied by hemangiogenesisand lymphangiogenesis across the wound edges. In fact, lym-phatic vessels have been identified in allogenic grafts after heartand kidney transplantation, where their presence seems to berelated to graft rejection (37).In this study, we try to unravel the relative importance of pre-

    existing hemangiogenesis versus lymphangiogenesis for im-mune responses after transplantation. To do that, we used themurine model of corneal transplantation. Corneal trans-plantation (also called keratoplasty) is the most frequentlyperformed tissue transplantation, with .40,000 surgeries peryear in the United States. In addition, corneal transplantationcan experimentally serve as a model for allogenic trans-plantation, which allows for the analysis of the impact oflymphatic and blood vessels on the graft outcome, because ofthe corneas normal avascularity. Corneal hemangiogenesisand lymphangiogenesis occurring before as well as after cornealtransplantation significantly increase the risk for immune re-jection (8). The rate of immune rejections in patient eyes withavascular graft beds is 10%, whereas the rate in prevascu-larized, so-called high-risk patient eyes increases to 50100% (9). Lymphatic vessels and blood vessels override the so-called immune privilege of the normally avascular cornea.Itwas shownthat a combinedmodulationofhemangiogenesis

    and lymphangiogenesis by vascular endothelial growth factor(VEGF)-TrapR1R2 after normal-risk corneal transplantationimproved graft survival in the murine model of corneal

    *Department of Ophthalmology, University of Erlangen-Nurnberg, Erlangen;Department of Ophthalmology, University Medical Center, Regensburg, Germany;Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02101; xCenterfor Eye Disease and Development, Program in Vision Science and School of Optometry,University of California, Berkeley, Berkeley, CA 94701; {Jerini AG, Berlin, Germany;and ||Regeneron Pharmaceuticals, Tarrytown, NY 10591

    1T.D. and F.B. contributed equally to this work and should be considered cosenior authors.

    Received for publication October 2, 2009. Accepted for publication November 14, 2009.

    This work was supported by the Interdisciplinary Centre for Clinical Research Erlangen(A9), the German Research Foundation (Sonderforschungsbereich SFB 643: B10), andthe National Institutes of Health.

    Address correspondence and reprint requests to Dr. Claus Cursiefen at the currentaddress: Department of Ophthalmology, University of Erlangen-Nurnberg, Schwaba-chanlage 6, 91054 Erlangen, Germany. E-mail address:

    Abbreviations used in this paper: VEGF, vascular endothelial growth factor; VEGFR,vascular endothelial growth factor receptor.

    Copyright 2010 by TheAmerican Association of Immunologists, Inc. 0022-1767/10/$16.00

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  • transplantation (8). Blocking lymphangiogenesis preferentiallyover hemangiogenesis may lead to inhibition of the induction ofan immune response and, at the same time, blood vessels couldstill support the graft with nutrients and enable wound healing(essential in solid organ transplants).Therefore, it is important to identify ways to preferentially

    block lymphangiogenesis to promote graft survival. Until veryrecently, specific inhibition of lymphangiogenesis was notpossible. We and other investigators identified ways to pref-erentially inhibit lymphangiogenesis over hemangiogenesis bya dose-dependent, systemic integrin a5b1 blockade with smallmolecule inhibitors (JSM6427) (10, 11). We found thatpreferential inhibition of lymphangiogenesis is possible byintegrin a5b1 inhibition using an intermediate dose (10). Inaddition, we recently found a preferential inhibitory effect ofthe anti-VEGF receptor (VEGFR)3 Ab mF4-31C1 on cor-neal inflammatory lymphangiogenesis in the murine model ofsuture-induced neovascularization (12).We used these two novel pharmacologic functional assays to

    create new models of differentially vascularized allogenictransplantation in corneal host beds. These contained onlyblood vessels (alymphatic), blood and lymphatic vessels(high-risk), or no vessels (normal-risk) prior to trans-plantation. The purpose of this study was to determinewhether the high-risk status of corneal allografts in vascular-ized host beds is defined by the lymphatic or blood vessels andwhether preferential inhibition of lymphangiogenesis prior totransplantation is able to improve graft survival by interferingwith sensitization and immune rejection.

    Materials and MethodsMice and anesthesia

    Six- to 8-wk-old female C57BL/6mice were used as graft donors; aged-matchedfemale BALB/C mice (Charles River Germany, Sulzfeld, Germany) were usedas recipients. All animals were treated in accordance with the Association forResearch in Vision and Ophthalmology Statement for the Use of Animals inOphthalmic and Vision Research. For surgical procedures, mice were anes-thetize


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