Abstract
Until recently, allograft rejection was thought to be mediated primarily by alloreactive T cells. Consequently, immunosuppressive approaches focused on inhibition of T cell activation. While short-term graft survival has significantly improved and rejection rates have dropped, acute rejection has not been eliminated and chronic rejection remains the major threat to long-term graft survival. Increased attention to humoral immunity in experimental systems and in the clinic has revealed that donor specific antibodies (DSA) can mediate and promote acute and chronic rejection. Herein, we detail the effects of alloantibody, particularly HLA antibody, binding to graft vascular and other cells, and briefly summarize the experimental methods used to assess such outcomes.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Zhang Q, Cecka JM, Gjertson DW, Ge P, Rose ML, Patel JK et al (2011) HLA and MICA: targets of antibody-mediated rejection in heart transplantation. Transplantation 91:1153–1158
Cardarelli F, Pascual M, Tolkoff-Rubin N, Delmonico FL, Wong W, Schoenfeld DA et al (2005) Prevalence and significance of anti-HLA and donor-specific antibodies long-term after renal transplantation. Transpl Int 18:532–540
Everly MJ, Everly JJ, Arend LJ, Brailey P, Susskind B, Govil A et al (2009) Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss. Am J Transplant 9:1063–1071
Lachmann N, Terasaki PI, Schonemann C (2006) Donor-specific HLA antibodies in chronic renal allograft rejection: a prospective trial with a four-year follow-up. Clin Transpl 171–199
Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P et al (2009) Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation 87:1505–1513
Otten HG, Verhaar MC, Borst HP, Hene RJ, Zuilen AD (2012) Pretransplant donor-specific HLA class-I and -II antibodies are associated with an increased risk for kidney graft failure. Am J Transplant 12(6):1618–1623
Song EY, Lee YJ, Hyun J, Kim YS, Ahn C, Ha J et al (2012) Clinical relevance of pretransplant HLA class II donor-specific antibodies in renal transplantation patients with negative T-cell cytotoxicity crossmatches. Ann Lab Med 32:139–144
Bishara A, Brautbar C, Eid A, Scherman L, Ilan Y, Safadi R (2002) Is presensitization relevant to liver transplantation outcome? Hum Immunol 63:742–750
Appel JZ III, Hartwig MG, Davis RD, Reinsmoen NL (2005) Utility of peritransplant and rescue intravenous immunoglobulin and extracorporeal immunoadsorption in lung transplant recipients sensitized to HLA antigens. Hum Immunol 66:378–386
Bond G, Reyes J, Mazariegos G, Wu T, Schaefer N, Demetris J et al (2000) The impact of positive T-cell lymphocytotoxic crossmatch on intestinal allograft rejection and survival. Transplant Proc 32:1197–1198
Campbell PM, Salam A, Ryan EA, Senior P, Paty BW, Bigam D et al (2007) Pretransplant HLA antibodies are associated with reduced graft survival after clinical islet transplantation. Am J Transplant 7:1242–1248
Wu T, Abu-Elmagd K, Bond G, Demetris AJ (2004) A clinicopathologic study of isolated intestinal allografts with preformed IgG lymphocytotoxic antibodies. Hum Pathol 35:1332–1339
Barocci S, Valente U, Nocera A (2007) Detection and analysis of HLA class I and class II specific alloantibodies in the sera of dialysis recipients waiting for a renal retransplantation. Clin Transplant 21:47–56
OPTN 2004 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, MI
Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A et al (2005) Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol 16:2804–2812
Nath DS, Angaswamy N, Basha HI, Phelan D, Moazami N, Ewald GA et al (2010) Donor-specific antibodies to human leukocyte antigens are associated with and precede antibodies to major histocompatibility complex class I-related chain A in antibody-mediated rejection and cardiac allograft vasculopathy after human cardiac transplantation. Hum Immunol 71:1191–1196
Kimball PM, Baker MA, Wagner MB, King A (2011) Surveillance of alloantibodies after transplantation identifies the risk of chronic rejection. Kidney Int 79:1131–1137
Ho EK, Vlad G, Vasilescu ER, de la Torre L, Colovai AI, Burke E et al (2010) Pre- and posttransplantation allosensitization in heart allograft recipients: major impact of de novo alloantibody production on allograft survival. Hum Immunol 72:5–10
Wu GW, Kobashigawa JA, Fishbein MC, Patel JK, Kittleson MM, Reed EF et al (2009) Asymptomatic antibody-mediated rejection after heart transplantation predicts poor outcomes. J Heart Lung Transplant 28:417–422
Tsai HL, Island ER, Chang JW, Gonzalez-Pinto I, Tryphonopoulos P, Nishida S et al (2011) Association between donor-specific antibodies and acute rejection and resolution in small bowel and multivisceral transplantation. Transplantation 92:709–715
Gonzalez-Pinto IM, Tzakis AG, Tsai HL, Chang JW, Tryphonopoulos P, Nishida S et al (2010) Association between panel reactive antibodies and acute small bowel rejection: analysis of a series of 324 intestinal transplants. Transplant Proc 42:4269–4271
Farmer DG, Venick RS, Colangelo J, Esmailian Y, Yersiz H, Duffy JP et al (2010) Pretransplant predictors of survival after intestinal transplantation: analysis of a single-center experience of more than 100 transplants. Transplantation 90:1574–1580
Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ et al (2012) Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant 12:1157–1167
Smith RN, Kawai T, Boskovic S, Nadazdin O, Sachs DH, Cosimi AB et al (2008) Four stages and lack of stable accommodation in chronic alloantibody-mediated renal allograft rejection in Cynomolgus monkeys. Am J Transplant 8:1662–1672
Aubert V, Venetz JP, Pantaleo G, Pascual M (2009) Low levels of human leukocyte antigen donor-specific antibodies detected by solid phase assay before transplantation are frequently clinically irrelevant. Hum Immunol 70:580–583
Hosenpud JD, Everett JP, Morris TE, Mauck KA, Shipley GD, Wagner CR (1995) Cardiac allograft vasculopathy. Association with cell-mediated but not humoral alloimmunity to donor-specific vascular endothelium. Circulation 92:205–211
Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE et al (2007) Banff ’05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant 7:518–526
Berry GJ, Angelini A, Burke MM, Bruneval P, Fishbein MC, Hammond E et al (2011) The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: evolution and current status (2005–2011). J Heart Lung Transplant 30:601–611
Kozlowski T, Rubinas T, Nickeleit V, Woosley J, Schmitz J, Collins D et al (2011) Liver allograft antibody-mediated rejection with demonstration of sinusoidal C4d staining and circulating donor-specific antibodies. Liver Transpl 17:357–368
Mulder A, Kardol MJ, Arn JS, Eijsink C, Franke ME, Schreuder GM et al (2010) Human monoclonal HLA antibodies reveal interspecies crossreactive swine MHC class I epitopes relevant for xenotransplantation. Mol Immunol 47:809–815
Zhang X, Rozengurt E, Reed EF (2010) HLA class I molecules partner with integrin beta4 to stimulate endothelial cell proliferation and migration. Sci Signal 3:ra85
Russell PS, Chase CM, Winn HJ, Colvin RB (1994) Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity. J Immunol 152:5135–5141
Yacoub-Youssef H, Marcheix B, Calise D, Thiers JC, Benoist H, Blaes N et al (2005) Use of human mesenteric arteries to study chronic vascular rejection in SCID/beige mice reconstituted with human spleen cells. Transplant Proc 37:75–76
Marcheix B, Yacoub-Youssef H, Calise D, Thiers JC, Therville N, Benoist H et al (2006) Multiple human mesenteric arterial grafts from the same donor to study human chronic vascular rejection in humanized SCID/beige mice. J Heart Lung Transplant 25:675–682
Lorber MI, Wilson JH, Robert ME, Schechner JS, Kirkiles N, Qian HY et al (1999) Human allogeneic vascular rejection after arterial transplantation and peripheral lymphoid reconstitution in severe combined immunodeficient mice. Transplantation 67:897–903
Baldwin WM III, Valujskikh A, Fairchild RL (2010) Antibody-mediated rejection: emergence of animal models to answer clinical questions. Am J Transplant 10:1135–1142
Wehner JR, Morrell CN, Rodriguez ER, Fairchild RL, Baldwin WM III (2009) Immunological challenges of cardiac transplantation: the need for better animal models to answer current clinical questions. J Clin Immunol 29:722–729
Russell PS, Chase CM, Colvin RB (1997) Alloantibody- and T cell-mediated immunity in the pathogenesis of transplant arteriosclerosis: lack of progression to sclerotic lesions in B cell-deficient mice. Transplantation 64:1531–1536
Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738
Hughes PD, Cohney SJ (2011) Modifiers of complement activation for prevention of antibody-mediated injury to allografts. Curr Opin Organ Transplant 16:425–433
Hegde S, Mellon JK, Hargrave SL, Niederkorn JY (2002) Effect of alloantibodies on corneal allograft survival. Invest Ophthalmol Vis Sci 43:1012–1018
Nozaki T, Amano H, Bickerstaff A, Orosz CG, Novick AC, Tanabe K et al (2007) Antibody-mediated rejection of cardiac allografts in CCR5-deficient recipients. J Immunol 179:5238–5245
Colvin RB (2007) Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J Am Soc Nephrol 18:1046–1056
Murata K, Fox-Talbot K, Qian Z, Takahashi K, Stahl GL, Baldwin WM III et al (2007) Synergistic deposition of C4d by complement-activating and non-activating antibodies in cardiac transplants. Am J Transplant 7:2605–2614
Mauiyyedi S, Pelle PD, Saidman S, Collins AB, Pascual M, Tolkoff-Rubin NE et al (2001) Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. J Am Soc Nephrol 12:574–582
Satoskar AA, Lehman AM, Nadasdy GM, Sedmak DD, Pesavento TE, Henry ML et al (2008) Peritubular capillary C4d staining in late acute renal allograft rejection—is it relevant? Clin Transplant 22:61–67
Sis B, Grynoch R, Murray AG, Campbell P, Solez K (2008) Antibody-mediated rejection with a striking interstitial monocyte/macrophage infiltration in a renal allograft under FTY720 treatment. Am J Kidney Dis 51:127–130
Fedson SE, Daniel SS, Husain AN (2008) Immunohistochemistry staining of C4d to diagnose antibody-mediated rejection in cardiac transplantation. J Heart Lung Transplant 27:372–379
Ionescu DN, Girnita AL, Zeevi A, Duquesnoy R, Pilewski J, Johnson B et al (2005) C4d deposition in lung allografts is associated with circulating anti-HLA alloantibody. Transpl Immunol 15:63–68
Arias LF, Fernandez R, Fernandez D, Jaramillo JC, Gil M, Lopez Garcia-Asenjo JA (2010) C4D immunostaining in surveillance endomyocardial biopsies from well-functioning heart allografts. Transplant Proc 42:1793–1796
Troxell ML, Higgins JP, Kambham N (2006) Evaluation of C4d staining in liver and small intestine allografts. Arch Pathol Lab Med 130:1489–1496
Wasowska BA, Qian Z, Cangello DL, Behrens E, Van Tran K, Layton J et al (2001) Passive transfer of alloantibodies restores acute cardiac rejection in IgKO mice. Transplantation 71:727–736
Canet E, Devalliere J, Gerard N, Karam G, Giral M, Charreau B et al (2012) Profiling posttransplant circulating antibodies in kidney transplantation using donor endothelial cells. Transplantation 93:257–264
Honger G, Hopfer H, Arnold ML, Spriewald BM, Schaub S, Amico P (2011) Pretransplant IgG subclasses of donor-specific human leukocyte antigen antibodies and development of antibody-mediated rejection. Transplantation 92:41–47
Kaneku H, O’Leary JG, Taniguchi M, Susskind BM, Terasaki PI, Klintmalm GB (2012) Donor-specific HLA antibodies of IgG3 subclass are associated with chronic rejection and graft loss after liver transplantation. Liver Transpl 18(8):984–992
Chen G, Sequeira F, Tyan DB (2011) Novel C1q assay reveals a clinically relevant subset of human leukocyte antigen antibodies independent of immunoglobulin G strength on single antigen beads. Hum Immunol 72:849–858
Chin C, Chen G, Sequeria F, Berry G, Siehr S, Bernstein D et al (2011) Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients. J Heart Lung Transplant 30:158–163
Lobashevsky A, Rosner K, Goggins W, Higgins N (2010) Subtypes of immunoglobulin (Ig)-G antibodies against donor class II HLA and cross-match results in three kidney transplant candidates. Transpl Immunol 23:81–85
Tambur AR, Bray RA, Takemoto SK, Mancini M, Costanzo MR, Kobashigawa JA et al (2000) Flow cytometric detection of HLA-specific antibodies as a predictor of heart allograft rejection. Transplantation 70:1055–1059
Honger G, Wahrmann M, Amico P, Hopfer H, Bohmig GA, Schaub S (2010) C4d-fixing capability of low-level donor-specific HLA antibodies is not predictive for early antibody-mediated rejection. Transplantation 89:1471–1475
Hirohashi T, Uehara S, Chase CM, DellaPelle P, Madsen JC, Russell PS et al (2010) Complement independent antibody-mediated endarteritis and transplant arteriopathy in mice. Am J Transplant 10:510–517
Kirby JA, Givan AL, Shenton BK, Talbot D, Forsythe JL, Lennard TW et al (1990) Renal allograft rejection. Possible involvement of antibody-dependent cell-mediated cytotoxicity. Transplantation 50:225–229
Yard B, Spruyt-Gerritse M, Claas F, Thorogood J, Bruijn JA, Paape ME et al (1993) The clinical significance of allospecific antibodies against endothelial cells detected with an antibody-dependent cellular cytotoxicity assay for vascular rejection and graft loss after renal transplantation. Transplantation 55:1287–1293
Wasik M, Gradowska L, Lao M, Rowinska D, Orlowski T (1978) Study of antibody dependent cellular cytotoxicity (ADCC). II. ADCC activity in renal graft recipients and acute accelerated graft rejection. Arch Immunol Ther Exp (Warsz) 26:311–314
Miltenburg AM, Meijer-Paape ME, Weening JJ, Daha MR, van Es LA, van der Woude FJ (1989) Induction of antibody-dependent cellular cytotoxicity against endothelial cells by renal transplantation. Transplantation 48:681–688
Hirohashi T, Chase CM, Della Pelle P, Sebastian D, Alessandrini A, Madsen JC et al (2012) A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant 12:313–321
Uehara S, Chase CM, Cornell LD, Madsen JC, Russell PS, Colvin RB (2007) Chronic cardiac transplant arteriopathy in mice: relationship of alloantibody, C4d deposition and neointimal fibrosis. Am J Transplant 7:57–65
Hidalgo LG, Sis B, Sellares J, Campbell PM, Mengel M, Einecke G et al (2010) NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: evidence for NK cell involvement in antibody-mediated rejection. Am J Transplant 10:1812–1822
Narayanan K, Jaramillo A, Phelan DL, Mohanakumar T (2004) Pre-exposure to sub-saturating concentrations of HLA class I antibodies confers resistance to endothelial cells against antibody complement-mediated lysis by regulating Bad through the phosphatidylinositol 3-kinase/Akt pathway. Eur J Immunol 34:2303–2312
Narayanan K, Jendrisak MD, Phelan DL, Mohanakumar T (2006) HLA class I antibody mediated accommodation of endothelial cells via the activation of PI3K/cAMP dependent PKA pathway. Transpl Immunol 15:187–197
Iwasaki K, Miwa Y, Haneda M, Uchida K, Nakao A, Kobayashi T (2010) Significance of HLA class I antibody-induced antioxidant gene expression for endothelial cell protection against complement attack. Biochem Biophys Res Commun 391:1210–1215
Jin YP, Fishbein MC, Said JW, Jindra PT, Rajalingam R, Rozengurt E et al (2004) Anti-HLA class I antibody-mediated activation of the PI3K/Akt signaling pathway and induction of Bcl-2 and Bcl-xL expression in endothelial cells. Hum Immunol 65:291–302
Fukami N, Ramachandran S, Narayanan K, Liu W, Nath DS, Jendrisak M et al (2012) Mechanism of accommodation in a sensitized human leukocyte antigen transgenic murine cardiac transplant model. Transplantation 93:364–372
Coupel S, Leboeuf F, Boulday G, Soulillou JP, Charreau B (2004) RhoA activation mediates phosphatidylinositol 3-kinase-dependent proliferation of human vascular endothelial cells: an alloimmune mechanism of chronic allograft nephropathy. J Am Soc Nephrol 15:2429–2439
Jin YP, Korin Y, Zhang X, Jindra PT, Rozengurt E, Reed EF (2007) RNA interference elucidates the role of focal adhesion kinase in HLA class I-mediated focal adhesion complex formation and proliferation in human endothelial cells. J Immunol 178:7911–7922
Jin YP, Jindra PT, Gong KW, Lepin EJ, Reed EF (2005) Anti-HLA class I antibodies activate endothelial cells and promote chronic rejection. Transplantation 79:S19–S21
Jindra PT, Jin YP, Rozengurt E, Reed EF (2008) HLA class I antibody-mediated endothelial cell proliferation via the mTOR pathway. J Immunol 180:2357–2366
Jin YP, Singh RP, Du ZY, Rajasekaran AK, Rozengurt E, Reed EF (2002) Ligation of HLA class I molecules on endothelial cells induces phosphorylation of Src, paxillin, and focal adhesion kinase in an actin-dependent manner. J Immunol 168:5415–5423
Li F, Zhang X, Jin YP, Mulder A, Reed EF (2011) Antibody ligation of human leukocyte antigen class I molecules stimulates migration and proliferation of smooth muscle cells in a focal adhesion kinase-dependent manner. Hum Immunol 72:1150–1159
Galvani S, Auge N, Calise D, Thiers JC, Canivet C, Kamar N et al (2009) HLA class I antibodies provoke graft arteriosclerosis in human arteries transplanted into SCID/beige mice. Am J Transplant 9:2607–2614
Galvani S, Trayssac M, Auge N, Thiers JC, Calise D, Krell HW et al (2011) A key role for matrix metalloproteinases and neutral sphingomyelinase-2 in transplant vasculopathy triggered by anti-HLA antibody. Circulation 124:2725–2734
Ziegler ME, Souda P, Jin YP, Whitelegge JP, Reed EF (2012) Characterization of the endothelial cell cytoskeleton following HLA class I ligation. PLoS One 7:e29472
Lepin EJ, Jin YP, Barwe SP, Rozengurt E, Reed EF (2004) HLA class I signal transduction is dependent on Rho GTPase and ROK. Biochem Biophys Res Commun 323:213–217
Reznik SI, Jaramillo A, Zhang L, Patterson GA, Cooper JD, Mohanakumar T (2000) Anti-HLA antibody binding to HLA class I molecules induces proliferation of airway epithelial cells: a potential mechanism for bronchiolitis obliterans syndrome. J Thorac Cardiovasc Surg 119:39–45
Jindra PT, Hsueh A, Hong L, Gjertson D, Shen XD, Gao F et al (2008) Anti-MHC class I antibody activation of proliferation and survival signaling in murine cardiac allografts. J Immunol 180:2214–2224
Lepin EJ, Zhang Q, Zhang X, Jindra PT, Hong LS, Ayele P et al (2006) Phosphorylated S6 ribosomal protein: a novel biomarker of antibody-mediated rejection in heart allografts. Am J Transplant 6:1560–1571
Bian H, Harris PE, Mulder A, Reed EF (1997) Anti-HLA antibody ligation to HLA class I molecules expressed by endothelial cells stimulates tyrosine phosphorylation, inositol phosphate generation, and proliferation. Hum Immunol 53:90–97
Bian H, Harris PE, Reed EF (1998) Ligation of HLA class I molecules on smooth muscle cells with anti-HLA antibodies induces tyrosine phosphorylation, fibroblast growth factor receptor expression and cell proliferation. Int Immunol 10:1315–1323
Bian H, Reed EF (1999) Alloantibody-mediated class I signal transduction in endothelial cells and smooth muscle cells: enhancement by IFN-gamma and TNF-alpha. J Immunol 163:1010–1018
Bieri M, Oroszlan M, Farkas A, Ligeti N, Bieri J, Mohacsi P (2009) Anti-HLA I antibodies induce VEGF production by endothelial cells, which increases proliferation and paracellular permeability. Int J Biochem Cell Biol 41:2422–2430
Jaramillo A, Zhang L, Mohanakumar T (2001) Binding of anti-HLA class I antibodies to airway epithelial cells induces activation and growth factor production and indirectly upregulates lung fibroblast proliferation. J Heart Lung Transplant 20:166
Fishbein MC, Kobashigawa J (2004) Biopsy-negative cardiac transplant rejection: etiology, diagnosis, and therapy. Curr Opin Cardiol 19:166–169
Kitchens WH, Chase CM, Uehara S, Cornell LD, Colvin RB, Russell PS et al (2007) Macrophage depletion suppresses cardiac allograft vasculopathy in mice. Am J Transplant 7:2675–2682
Liu W, Xiao X, Demirci G, Madsen J, Li XC (2012) Innate NK cells and macrophages recognize and reject allogeneic nonself in vivo via different mechanisms. J Immunol 188:2703–2711
Lowenstein CJ, Morrell CN, Yamakuchi M (2005) Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med 15:302–308
Yamakuchi M, Kirkiles-Smith NC, Ferlito M, Cameron SJ, Bao C, Fox-Talbot K et al (2007) Antibody to human leukocyte antigen triggers endothelial exocytosis. Proc Natl Acad Sci USA 104:1301–1306
Saini D, Angaswamy N, Tiriveedhi V, Fukami N, Ramachandran S, Hachem R et al (2012) Synergistic effect of antibodies to human leukocyte antigens and defensins in pathogenesis of bronchiolitis obliterans syndrome after human lung transplantation. J Heart Lung Transplant 29:1330–1336
Taylor PM, Rose ML, Yacoub MH (1989) Expression of MHC antigens in normal human lungs and transplanted lungs with obliterative bronchiolitis. Transplantation 48:506–510
Taylor PM, Rose ML, Yacoub MH, Pigott R (1992) Induction of vascular adhesion molecules during rejection of human cardiac allografts. Transplantation 54:451–457
Yamazaki S, Isobe M, Suzuki J, Tojo S, Horie S, Okubo Y et al (1998) Role of selectin-dependent adhesion in cardiac allograft rejection. J Heart Lung Transplant 17:1007–1016
Shi C, Feinberg MW, Zhang D, Patel A, Sim CU, Dong ZM et al (1999) Donor MHC and adhesion molecules in transplant arteriosclerosis. J Clin Invest 103:469–474
Raisky O, Morrison KJ, Obadia JF, McGregor J, Yacoub MH, Rose ML (2001) Acute rejection and cardiac graft vasculopathy in the absence of donor-derived ICAM-1 or P-selectin. J Heart Lung Transplant 20:340–349
Furuyama T, Komori K, Shimokawa H, Matsumoto Y, Uwatoku T, Hirano K et al (2006) Long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits. J Vasc Surg 43:1249–1256
Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Kaibuchi K et al (2004) Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice. Circ Res 94:46–52
Ohki S, Iizuka K, Ishikawa S, Kano M, Dobashi K, Yoshii A et al (2001) A highly selective inhibitor of Rho-associated coiled-coil forming protein kinase, Y-27632, prolongs cardiac allograft survival of the BALB/c-to-C3H/He mouse model. J Heart Lung Transplant 20:956–963
Hiemann NE, Wellnhofer E, Lehmkuhl HB, Knosalla C, Hetzer R, Meyer R (2011) Everolimus prevents endomyocardial remodeling after heart transplantation. Transplantation 92:1165–1172
Chen Song S, Zhong S, Xiang Y, Li JH, Guo H, Wang WY et al (2011) Complement inhibition enables renal allograft accommodation and long-term engraftment in presensitized nonhuman primates. Am J Transplant 11:2057–2066
Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG et al (2011) Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 11:2405–2413
Meng HL, Jin XB, Li XT, Wang HW, Lu JJ (2009) Impact of human leukocyte antigen matching and recipients’ panel reactive antibodies on two-year outcome in presensitized renal allograft recipients. Chin Med J (Engl) 122:420–426
Muczynski KA, Ekle DM, Coder DM, Anderson SK (2003) Normal human kidney HLA-DR-expressing renal microvascular endothelial cells: characterization, isolation, and regulation of MHC class II expression. J Am Soc Nephrol 14:1336–1348
Muczynski KA, Cotner T, Anderson SK (2001) Unusual expression of human lymphocyte antigen class II in normal renal microvascular endothelium. Kidney Int 59:488–497
Geppert TD, Lipsky PE (1985) Antigen presentation by interferon-gamma-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expression. J Immunol 135:3750–3762
McDouall RM, Yacoub M, Rose ML (1996) Isolation, culture, and characterisation of MHC class II-positive microvascular endothelial cells from the human heart. Microvasc Res 51:137–152
McDouall RM, Batten P, McCormack A, Yacoub MH, Rose ML (1997) MHC class II expression on human heart microvascular endothelial cells: exquisite sensitivity to interferon-gamma and natural killer cells. Transplantation 64:1175–1180
Salom RN, Maguire JA, Hancock WW (1998) Endothelial activation and cytokine expression in human acute cardiac allograft rejection. Pathology 30:24–29
Deng MC, Bell S, Huie P, Pinto F, Hunt SA, Stinson EB et al (1995) Cardiac allograft vascular disease. Relationship to microvascular cell surface markers and inflammatory cell phenotypes on endomyocardial biopsy. Circulation 91:1647–1654
Hasegawa S, Becker G, Nagano H, Libby P, Mitchell RN (1998) Pattern of graft- and host-specific MHC class II expression in long-term murine cardiac allografts: origin of inflammatory and vascular wall cells. Am J Pathol 153:69–79
Wang YC, Mayne A, Sell KW, Ahmed-Ansari A (1990) The influence of MHC and non-MHC genes on the nature of murine cardiac allograft rejection. I. Kinetic analysis of mononuclear cell infiltrate and MHC-class I/class II expression in donor tissue. Transplantation 50:313–324
Xu R, Burdick JF, Scott A, Beschorner WE, Adler W, Kittur DS (1992) Graft-specific MHC class II gene expression in response to allogeneic stimulus in heterotopic murine cardiac allografts. Immunology 75:361–365
Truman JP, Garban F, Choqueux C, Charron D, Mooney N (1996) HLA class II signaling mediates cellular activation and programmed cell death. Exp Hematol 24:1409–1415
Truman JP, Choqueux C, Charron D, Mooney N (1996) HLA class II molecule signal transduction leads to either apoptosis or activation via two different pathways. Cell Immunol 172:149–157
Truman JP, Ericson ML, Choqueux-Seebold CJ, Charron DJ, Mooney NA (1994) Lymphocyte programmed cell death is mediated via HLA class II DR. Int Immunol 6:887–896
Kato-Kogoe N, Ohyama H, Nishimura F, Meguro M, Yoshizawa S, Okada Y et al (2010) Fibroblasts stimulated via HLA-II molecules produce prostaglandin E(2) and regulate cytokine production from helper T cells. Lab Invest 90:1747–1756
Okada Y, Meguro M, Ohyama H, Yoshizawa S, Takeuchi-Hatanaka K, Kato N et al (2009) Human leukocyte histocompatibility antigen class II-induced cytokines from human gingival fibroblasts promote proliferation of human umbilical vein endothelial cells: potential association with enhanced angiogenesis in chronic periodontal inflammation. J Periodontal Res 44:103–109
Meguro M, Nishimura F, Ohyama H, Takashiba S, Murayama Y, Matsushita S (2003) Ligation of IFN-gamma-induced HLA-DR molecules on fibroblasts induces RANTES expression via c-Jun N-terminal kinase (JNK) pathway. Cytokine 22:107–115
Yoshizawa S, Meguro M, Ohyama H, Takeuchi-Hatanaka K, Matsushita S, Takashiba S et al (2007) Focal adhesion kinase mediates human leukocyte histocompatibility antigen class II-induced signaling in gingival fibroblasts. J Periodontal Res 42:572–579
Thaunat O, Graff-Dubois S, Fabien N, Duthey A, Attuil-Audenis V, Nicoletti A et al (2012) A stepwise breakdown of B-cell tolerance occurs within renal allografts during chronic rejection. Kidney Int 81:207–219
Le Bas-Bernardet S, Hourmant M, Coupel S, Bignon JD, Soulillou JP, Charreau B (2003) Non-HLA-type endothelial cell reactive alloantibodies in pre-transplant sera of kidney recipients trigger apoptosis. Am J Transplant 3:167–177
Jackson AM, Lucas DP, Melancon JK, Desai NM (2011) Clinical relevance and IgG subclass determination of non-HLA antibodies identified using endothelial cell precursors isolated from donor blood. Transplantation 92:54–60
Perrey C, Brenchley PE, Johnson RW, Martin S (1998) An association between antibodies specific for endothelial cells and renal transplant failure. Transpl Immunol 6:101–106
Jaramillo A, Naziruddin B, Zhang L, Reznik SI, Smith MA, Aloush AA et al (2001) Activation of human airway epithelial cells by non-HLA antibodies developed after lung transplantation: a potential etiological factor for bronchiolitis obliterans syndrome. Transplantation 71:966–976
Ferry BL, Welsh KI, Dunn MJ, Law D, Proctor J, Chapel H et al (1997) Anti-cell surface endothelial antibodies in sera from cardiac and kidney transplant recipients: association with chronic rejection. Transpl Immunol 5:17–24
Qin Z, Lavingia B, Zou Y, Stastny P (2011) Antibodies against nucleolin in recipients of organ transplants. Transplantation 92:829–835
Bates RL, Frampton G, Rose ML, Murphy JJ (2003) High diversity of non-human leukocyte antigens in transplant-associated coronary artery disease. Transplantation 75:1347–1350
Panigrahi A, Gupta N, Siddiqui JA, Margoob A, Bhowmik D, Guleria S et al (2007) Post transplant development of MICA and anti-HLA antibodies is associated with acute rejection episodes and renal allograft loss. Hum Immunol 68:362–367
Zou Y, Stastny P, Susal C, Dohler B, Opelz G (2007) Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med 357:1293–1300
Nath DS, Ilias Basha H, Tiriveedhi V, Alur C, Phelan D, Ewald GA et al (2010) Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy. J Heart Lung Transplant 29:1277–1285
Dragun D (2008) Humoral responses directed against non-human leukocyte antigens in solid-organ transplantation. Transplantation 86:1019–1025
Acevedo LM, Barillas S, Weis SM, Gothert JR, Cheresh DA (2008) Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 111:2674–2680
Ationu A (1998) Identification of endothelial antigens relevant to transplant coronary artery disease from a human endothelial cell cDNA expression library. Int J Mol Med 1:1007–1010
Linke AT, Marchant B, Marsh P, Frampton G, Murphy J, Rose ML (2001) Screening of a HUVEC cDNA library with transplant-associated coronary artery disease sera identifies RPL7 as a candidate autoantigen associated with this disease. Clin Exp Immunol 126:173–179
Kalache S, Dinavahi R, Pinney S, Mehrotra A, Cunningham MW, Heeger PS (2011) Anticardiac myosin immunity and chronic allograft vasculopathy in heart transplant recipients. J Immunol 187:1023–1030
Jurcevic S, Ainsworth ME, Pomerance A, Smith JD, Robinson DR, Dunn MJ et al (2001) Antivimentin antibodies are an independent predictor of transplant-associated coronary artery disease after cardiac transplantation. Transplantation 71:886–892
Alvarez-Marquez A, Aguilera I, Gentil MA, Caro JL, Bernal G, Fernandez Alonso J et al (2009) Donor-specific antibodies against HLA, MICA, and GSTT1 in patients with allograft rejection and C4d deposition in renal biopsies. Transplantation 87:94–99
Alvarez-Marquez A, Aguilera I, Blanco RM, Pascual D, Encarnacion-Carrizosa M, Alvarez-Lopez MR et al (2008) Positive association of anticytoskeletal endothelial cell antibodies and cardiac allograft rejection. Hum Immunol 69:143–148
Dragun D, Muller DN, Brasen JH, Fritsche L, Nieminen-Kelha M, Dechend R et al (2005) Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med 352:558–569
Walther T, Jank A, Heringer-Walther S, Horn LC, Stepan H (2008) Angiotensin II type 1 receptor has impact on murine placentation. Placenta 29:905–909
Walther T, Stepan H (2007) Agonist autoantibodies against the angiotensin AT1 receptor in renal and hypertensive disorders. Curr Hypertens Rep 9:128–132
Papa ND, Raschi E, Moroni G, Panzeri P, Borghi MO, Ponticelli C et al (1999) Anti-endothelial cell IgG fractions from systemic lupus erythematosus patients bind to human endothelial cells and induce a pro-adhesive and a pro-inflammatory phenotype in vitro. Lupus 8:423–429
Muller Kobold AC, van Wijk RT, Franssen CF, Molema G, Kallenberg CG, Tervaert JW (1999) In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener’s granulomatosis and microscopic polyangiitis. Clin Exp Rheumatol 17:433–440
Del Papa N, Guidali L, Sironi M, Shoenfeld Y, Mantovani A, Tincani A et al (1996) Anti-endothelial cell IgG antibodies from patients with Wegener’s granulomatosis bind to human endothelial cells in vitro and induce adhesion molecule expression and cytokine secretion. Arthritis Rheum 39:758–766
Derhaag JG, Duijvestijn AM, Damoiseaux JG, van Breda Vriesman PJ (2000) Effects of antibody reactivity to major histocompatibility complex (MHC) and non-MHC alloantigens on graft endothelial cells in heart allograft rejection. Transplantation 69:1899–1906
Diujvestijn AM, Derhaag JG, van Breda Vriesman PJ (2000) Complement activation by anti-endothelial cell antibodies in MHC-mismatched and MHC-matched heart allograft rejection: anti-MHC-, but not anti non-MHC alloantibodies are effective in complement activation. Transpl Int 13:363–371
Mahesh B, Leong HS, McCormack A, Sarathchandra P, Holder A, Rose ML (2007) Autoantibodies to vimentin cause accelerated rejection of cardiac allografts. Am J Pathol 170:1415–1427
Tambur AR, Pamboukian SV, Costanzo MR, Herrera ND, Dunlap S, Montpetit M et al (2005) The presence of HLA-directed antibodies after heart transplantation is associated with poor allograft outcome. Transplantation 80:1019–1025
Lau CL, Palmer SM, Posther KE, Howell DN, Reinsmoen NL, Massey HT et al (2000) Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients. Ann Thorac Surg 69:1520–1524
Angaswamy N, Saini D, Ramachandran S, Nath DS, Phelan D, Hachem R et al (2010) Development of antibodies to human leukocyte antigen precedes development of antibodies to major histocompatibility class I-related chain A and are significantly associated with development of chronic rejection after human lung transplantation. Hum Immunol 71:560–565
Panigrahi A, Siddiqui JA, Rai A, Margoob A, Khaira A, Bhowmik D et al (2007) Allosensitization to HLA and MICA is an important measure of renal graft outcome. Clin Transpl 211–217
Panigrahi A, Gupta N, Siddiqui JA, Margoob A, Bhowmik D, Guleria S et al (2007) Monitoring of anti-HLA and anti-Major histocompatibility complex class I related chain A antibodies in living related renal donor transplantation. Transplant Proc 39:759–760
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Valenzuela, N.M., Reed, E.F. (2013). Antibodies in Transplantation: The Effects of HLA and Non-HLA Antibody Binding and Mechanisms of Injury. In: Zachary, A., Leffell, M. (eds) Transplantation Immunology. Methods in Molecular Biology, vol 1034. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-493-7_2
Download citation
DOI: https://doi.org/10.1007/978-1-62703-493-7_2
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-492-0
Online ISBN: 978-1-62703-493-7
eBook Packages: Springer Protocols