Analysis of dendritic cells and ischemia-reperfusion changes in postimplantation renal allograft biopsies may serve as predictors of subsequent rejection episodes

Published:March 13, 2018DOI:
      Ischemia-reperfusion injury increases allograft immunogenicity and enhances myeloid dendritic cell maturation and trafficking to recipient’s secondary lymphoid tissue. Here, we used postreperfusion biopsies from patients who received kidney allografts from deceased donors between 2006 and 2009 to assess the impact of ischemia-reperfusion damage and myeloid dendritic cell density on subsequent allograft rejection episodes. Histologic changes of severe ischemia-reperfusion damage in postreperfusion biopsies were found to be associated with subsequent rejection episodes and suboptimal allograft survival. Using BDCA-1 as a marker of myeloid dendritic cells, postreperfusion biopsies from deceased donors had lower dendritic cell density compared to postreperfusion biopsies from living donors or normal controls. This suggests a rapid emigration of donor dendritic cells out of the allograft. In our cohort, low dendritic cell density was associated with a subsequent increase in rejection episodes. However, it appears that the donor’s cause of death also influenced dendritic cell density. Therefore, we assessed the additive impact of severe ischemia-reperfusion changes and low dendritic cell density on subsequent rejection. The aforementioned combination was a powerful and independent predictor of allograft rejection. Thus, our data highlight the prognostic value of histopathologic changes associated with ischemia-reperfusion in postreperfusion biopsies and suggest a rapid posttransplant emigration of myeloid dendritic cells out of the allograft to enhance alloimmunity. These findings may provide a rationale for minimizing ischemia-reperfusion injury and therapeutic targeting of donor-derived dendritic cells to promote rejection-free allograft survival.


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        • Gaston R.S.
        Our evolving understanding of late kidney allograft failure.
        Curr Opin Organ Transplant. 2011; 16: 594-599
        • Modena B.D.
        • Kurian S.M.
        • Gaber L.W.
        • et al.
        Gene expression in biopsies of acute rejection and interstitial fibrosis/tubular atrophy reveals highly shared mechanisms that correlate with worse long-term outcomes.
        Am J Transplant. 2016; 16: 1982-1998
        • Black S.C.
        • Rodger I.W.
        Methods for studying experimental myocardial ischemic and reperfusion injury.
        J Pharmacol Toxicol Methods. 1996; 35: 179-190
        • Pratschke J.
        • Kofla G.
        • Wilhelm M.J.
        • et al.
        Improvements in early behavior of rat kidney allografts after treatment of the brain-dead donor.
        Ann Surg. 2001; 234: 732-740
        • Chalasani G.
        • Li Q.
        • Konieczny B.T.
        • et al.
        The allograft defines the type of rejection (acute versus chronic) in the face of an established effector immune response.
        J Immunol. 2004; 172: 7813-7820
        • Wang Y.
        • Wu J.
        • Jiang B.
        • et al.
        Relationship between ischemia/reperfusion injury and acute rejection of allogeneic liver transplant in rats.
        Transplant Proc. 2014; 46: 50-55
        • Fuquay R.
        • Renner B.
        • Kulik L.
        • et al.
        Renal ischemia-reperfusion injury amplifies the humoral immune response.
        J Am Soc Nephrol. 2013; 24: 1063-1072
        • Imamura R.
        • Isaka Y.
        • Sandoval R.M.
        • et al.
        Intravital two-photon microscopy assessment of renal protection efficacy of siRNA for p53 in experimental rat kidney transplantation models.
        Cell Transplant. 2010; 19: 1659-1670
        • Schmitz V.
        • Schaser K.D.
        • Olschewski P.
        • et al.
        In vivo visualization of early microcirculatory changes following ischemia/reperfusion injury in human kidney transplantation.
        Eur Surg Res. 2008; 40: 19-25
        • Land W.G.
        Injury to allografts: innate immune pathways to acute and chronic rejection.
        Saudi J Kidney Dis Transpl. 2005; 6: 520-539
        • Jurewicz M.
        • Takakura A.
        • Augello A.
        • et al.
        Ischemic injury enhances dendritic cell immunogenicity via TLR4 and NF-kappa B activation.
        J Immunol. 2010; 184: 2939-2948
        • Batal I.
        • Azzi J.
        • Mounayar M.
        • et al.
        The mechanisms of up-regulation of dendritic cell activity by oxidative stress.
        J Leukoc Biol. 2014; 96: 283-293
        • Shoskes D.A.
        • Halloran P.F.
        Delayed graft function in renal transplantation: etiology, management and long-term significance.
        J Urol. 1996; 155: 1831-1840
        • Li L.
        • Okusa M.D.
        Macrophages, dendritic cells, and kidney ischemia-reperfusion injury.
        Semin Nephrol. 2010; 30: 268-277
        • Menke J.
        • Sollinger D.
        • Schamberger B.
        • et al.
        The effect of ischemia/reperfusion on the kidney graft.
        Curr Opin Organ Transplant. 2014; 19: 395-400
        • Loverre A.
        • Ditonno P.
        • Crovace A.
        • et al.
        Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin.
        J Am Soc Nephrol. 2004; 15: 2675-2686
        • Land W.G.
        The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation.
        Transplantation. 2005; 79: 505-514
        • Land W.
        Postischemic reperfusion injury and cytokines.
        Transplant Proc. 1998; 30: 4237-4238
        • Ponticelli C.
        Ischaemia-reperfusion injury: a major protagonist in kidney transplantation.
        Nephrol Dial Transplant. 2014; 29: 1134-1140
        • Qayumi A.K.
        • Nikbakht-Sangari M.N.
        • Godin D.V.
        • et al.
        The relationship of ischemia-reperfusion injury of transplanted lung and the up-regulation of major histocompatibility complex II on host peripheral lymphocytes.
        J Thorac Cardiovasc Surg. 1998; 115: 978-989
        • Siedlecki A.
        • Irish W.
        • Brennan D.C.
        Delayed graft function in the kidney transplant.
        Am J Transplant. 2011; 11: 2279-2296
        • Sutton T.A.
        • Mang H.E.
        • Campos S.B.
        • et al.
        Injury of the renal microvascular endothelium alters barrier function after ischemia.
        Am J Physiol Renal Physiol. 2003; 285: F191-F198
        • Sutton T.A.
        Alteration of microvascular permeability in acute kidney injury.
        Microvasc Res. 2009; 77: 4-7
        • Jushinskis J.
        • Trushkov S.
        • Bicans J.
        • et al.
        Risk factors for the development of delayed graft function in deceased donor renal transplants.
        Transplant Proc. 2009; 41: 746-748
        • Cho S.I.
        • Olsson C.A.
        • Bradley J.W.
        • et al.
        Regional program for kidney preservation and transplantation in New England.
        Am J Surg. 1976; 131: 428-433
        • Lechler R.I.
        • Batchelor J.R.
        Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells.
        J Exp Med. 1982; 155: 31-41
        • Larsen C.P.
        • Austyn J.M.
        • Morris P.J.
        The role of graft-derived dendritic leukocytes in the rejection of vascularized organ allografts. Recent findings on the migration and function of dendritic leukocytes after transplantation.
        Ann Surg. 1990; 212 (discussion 316–307): 308-315
        • Larsen C.P.
        • Morris P.J.
        • Austyn J.M.
        Migration of dendritic leukocytes from cardiac allografts into host spleens. A novel pathway for initiation of rejection.
        J Exp Med. 1990; 171: 307-314
        • Zhuang Q.
        • Liu Q.
        • Divito S.J.
        • et al.
        Graft-infiltrating host dendritic cells play a key role in organ transplant rejection.
        Nat Commun. 2016; 7: 12623
        • Batal I.
        • De Serres S.A.
        • Safa K.
        • et al.
        Dendritic cells in kidney transplant biopsy samples are associated with t cell infiltration and poor allograft survival.
        J Am Soc Nephrol. 2015; 26: 3102-3113
        • Segerer S.
        • Heller F.
        • Lindenmeyer M.T.
        • et al.
        Compartment specific expression of dendritic cell markers in human glomerulonephritis.
        Kidney Int. 2008; 74: 37-46
        • Woltman A.M.
        • de Fijter J.W.
        • Zuidwijk K.
        • et al.
        Quantification of dendritic cell subsets in human renal tissue under normal and pathological conditions.
        Kidney Int. 2007; 71: 1001-1008
        • Loverre A.
        • Capobianco C.
        • Stallone G.
        • et al.
        Ischemia-reperfusion injury-induced abnormal dendritic cell traffic in the transplanted kidney with delayed graft function.
        Kidney Int. 2007; 72: 994-1003
        • Fiore N.
        • Castellano G.
        • Blasi A.
        • et al.
        Immature myeloid and plasmacytoid dendritic cells infiltrate renal tubulointerstitium in patients with lupus nephritis.
        Mol Immunol. 2008; 45: 259-265
        • Yapici U.
        • Kers J.
        • Slavujevic-Letic I.
        • et al.
        Intragraft blood dendritic cell antigen-1-positive myeloid dendritic cells increase during BK polyomavirus-associated nephropathy.
        J Am Soc Nephrol. 2016; 27: 2502-2510
        • Garcia-Vallejo J.J.
        • van Kooyk Y.
        DC-SIGN: the strange case of Dr. Jekyll and Mr. Hyde.
        Immunity. 2015; 42: 983-985
        • Conde P.
        • Rodriguez M.
        • van der Touw W.
        • et al.
        DC-SIGN(+) macrophages control the induction of transplantation tolerance.
        Immunity. 2015; 42: 1143-1158
        • Kassianos A.J.
        • Wang X.
        • Sampangi S.
        • et al.
        Increased tubulointerstitial recruitment of human CD141hi CLEC9A+ and CD1c+ myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease.
        Am J Physiol Renal Physiol. 2013; 305: F1391-F1401
        • Marafioti T.
        • Paterson J.C.
        • Ballabio E.
        • et al.
        Novel markers of normal and neoplastic human plasmacytoid dendritic cells.
        Blood. 2008; 111: 3778-3792
        • Patel V.I.
        • Metcalf J.P.
        Identification and characterization of human dendritic cell subsets in the steady state: a review of our current knowledge.
        J Investig Med. 2016; 64: 833-847
        • Yatim K.M.
        • Gosto M.
        • Humar R.
        • et al.
        Renal dendritic cells sample blood-borne antigen and guide T-cell migration to the kidney by means of intravascular processes.
        Kidney Int. 2016; 90: 818-827
        • Soos T.J.
        • Sims T.N.
        • Barisoni L.
        • et al.
        CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney.
        Kidney Int. 2006; 70: 591-596
        • Gunzer M.
        • Friedl P.
        • Niggemann B.
        • et al.
        Migration of dendritic cells within 3-D collagen lattices is dependent on tissue origin, state of maturation, and matrix structure and is maintained by proinflammatory cytokines.
        J Leukoc Biol. 2000; 67: 622-629
        • Ueno T.
        • Tanaka K.
        • Jurewicz M.
        • et al.
        Divergent role of donor dendritic cells in rejection versus tolerance of allografts.
        J Am Soc Nephrol. 2009; 20: 535-544
        • Land W.G.
        Emerging role of innate immunity in organ transplantation part II: potential of damage-associated molecular patterns to generate immunostimulatory dendritic cells.
        Transplant Rev (Orlando). 2012; 26: 73-87
        • Roussey-Kesler G.
        • Brouard S.
        • Ballet C.
        • et al.
        Exhaustive depletion of graft resident dendritic cells: marginally delayed rejection but strong alteration of graft infiltration.
        Transplantation. 2005; 80: 506-513
        • Racusen L.C.
        • Solez K.
        • Colvin R.B.
        • et al.
        The Banff 97 working classification of renal allograft pathology.
        Kidney Int. 1999; 55: 713-723
        • Racusen L.C.
        • Colvin R.B.
        • Solez K.
        • et al.
        Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection.
        Am J Transplant. 2003; 3: 708-714
        • Solez K.
        • Colvin R.B.
        • Racusen L.C.
        • et al.
        Banff 07 classification of renal allograft pathology: updates and future directions.
        Am J Transplant. 2008; 8: 753-760
        • Levey A.S.
        • Coresh J.
        • Greene T.
        • et al.
        Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate.
        Ann Intern Med. 2006; 145: 247-254
        • Lau C.L.
        • Zhao Y.
        • Kim J.
        • et al.
        Enhanced fibrinolysis protects against lung ischemia-reperfusion injury.
        J Thorac Cardiovasc Surg. 2009; 137: 1241-1248
        • Schoots I.G.
        • Levi M.
        • Roossink E.H.
        • et al.
        Local intravascular coagulation and fibrin deposition on intestinal ischemia-reperfusion in rats.
        Surgery. 2003; 133: 411-419
        • Gwinner W.
        • Hinzmann K.
        • Erdbruegger U.
        • et al.
        Acute tubular injury in protocol biopsies of renal grafts: prevalence, associated factors and effect on long-term function.
        Am J Transplant. 2008; 8: 1684-1693