KEY POINTS * In addition to the well-known role of T cells in the rejection of allografts, antibodies that are produced by the host and are specific for the donor graft (that is,

alloantibodies) can mediate graft rejection, which can occur at almost any time after transplantation and cause rapid or slow graft dysfunction. * The target antigens are the MHC class I and

class II molecules and the ABO blood-group antigens, as well as potentially other minor alloantigens at the endothelial-cell surface. * Complement component 4d (C4d), a breakdown product of

complement activation, can be detected in tissues that are undergoing antibody-mediated rejection, even though no immunoglobulin can be detected. The presence of C4d has proved to be a more

these cases develop over many years and probably involve distinct stages of pathogenesis. * In some settings, antibody and complement do not seem to have adverse effects on endothelial

cells, a phenomenon that is known as accommodation. Understanding the molecular basis for this might provide a strategy to inhibit the consequences of antibody-mediated rejection. *

Innovative therapies that have the potential to more specifically target B cells and plasma cells are under evaluation for the prevention or treatment of antibody-mediated rejection.

ABSTRACT Recent studies show that alloantibodies mediate a substantial proportion of graft-rejection episodes, contributing to both early and late graft loss. Rejection that is caused by

antibody is mediated by different mechanisms from rejection that is caused by T cells, thereby requiring other approaches to treatment and prevention. Antibody induces rejection acutely

through the fixation of complement, resulting in tissue injury and coagulation. In addition, complement activation recruits macrophages and neutrophils, causing additional endothelial

injury. Antibody and complement also induce gene expression by endothelial cells, which is thought to remodel arteries and basement membranes, leading to fixed and irreversible anatomical

lesions that permanently compromise graft function. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS TRANSLATING B CELL IMMUNOLOGY TO THE TREATMENT OF ANTIBODY-MEDIATED ALLOGRAFT

REJECTION Article 02 January 2024 TISSUE-SPECIFIC ENDOTHELIAL CELL HETEROGENEITY CONTRIBUTES TO UNEQUAL INFLAMMATORY RESPONSES Article Open access 21 January 2021 INTERFERON-Γ AND ITS

RESPONSE ARE DETERMINANTS OF ANTIBODY-MEDIATED REJECTION AND CLINICAL OUTCOMES IN PATIENTS AFTER RENAL TRANSPLANTATION Article 22 January 2024 REFERENCES * Manning, D. D., Reed, N. D. &

Shaffer, C. F. Maintenance of skin xenografts of widely divergent phylogenetic origin of congenitally athymic (nude) mice. _J. Exp. Med._ 138, 488–494 (1973). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Pascual, M. et al. in _Clinical Transplants 2001_ 123–130 (UCLA Immunogenetics Center, Los Angeles, 2002). Google Scholar  * Gorer, P. The detection of antigenic

differences in mouse erythrocytes by the employment of immune sera. _Br. J. Exp. Pathol._ 17, 42–50 (1936). CAS  PubMed Central  Google Scholar  * Gerlag, P. G., Koene, R. A., Hagemann, J.

F. & Wijdeveld, P. G. Hyperacute rejection of skin allografts in the mouse. Sensitivity of ingrowing skin grafts to the action of alloantibody and rabbit complement. _Transplantation_

20, 308–313 (1975). Article  CAS  PubMed  Google Scholar  * Jooste, S. V., Colvin, R. B., Soper, W. D. & Winn, H. J. The vascular bed as the primary target in the destruction of skin

grafts by antiserum. I. Resistance of freshly placed xenografts of skin to antiserum. _J. Exp. Med._ 154, 1319–1331 (1981). Article  CAS  PubMed  PubMed Central  Google Scholar  * Jeannet,

M., Pinn, V. W., Flax, M. H., Winn, H. J. & Russell, P. S. Humoral antibodies in renal allotransplantation in man. _N. Engl. J. Med._ 282, 111–117 (1970). Article  CAS  PubMed  Google

Scholar  * Russell, P. S., Chase, C. M. & Colvin, R. B. 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 (1997). Article  CAS  PubMed  Google Scholar  * Halloran, P. F., Schlaut, J., Solez, K. & Srinivasa, N. S. The

significance of the anti-class I antibody response. II. Clinical and pathologic features of renal transplants with anti-class I-like antibody. _Transplantation_ 53, 550–555 (1992). Article 

CAS  PubMed  Google Scholar  * Feucht, H. E. et al. Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection. _Clin. Exp. Immunol._ 86, 464–470

(1991). Article  CAS  PubMed  PubMed Central  Google Scholar  * Collins, A. B. et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d

deposits in peritubular capillaries. _J. Am. Soc. Nephrol._ 10, 2208–2214 (1999). THIS WAS THE FIRST PAPER TO SHOW THAT THE PRESENCE OF C4D IN THE PERITUBULAR CAPILLARIES OF RENAL ALLOGRAFTS

IS ASSOCIATED WITH CIRCULATING DONOR-HLA-SPECIFIC ANTIBODIES AND DISTINCTIVE HISTOLOGICAL FEATURES. CAS  PubMed  Google Scholar  * Pei, R., Lee, J. H., Shih, N. J., Chen, M. & Terasaki,

P. I. Single human leukocyte antigen flow cytometry beads for accurate identification of human leukocyte antigen antibody specificities. _Transplantation_ 75, 43–49 (2003). Article  CAS 

PubMed  Google Scholar  * Jaramillo, A. et al. Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a

possible mechanism for bronchiolitis obliterans syndrome. _Hum. Immunol._ 64, 521–529 (2003). Article  CAS  PubMed  Google Scholar  * Takemoto, S. K. et al. National conference to assess

antibody-mediated rejection in solid organ transplantation. _Am. J. Transplant._ 4, 1033–1041 (2004). Article  CAS  PubMed  Google Scholar  * Racusen, L. C. et al. Antibody-mediated

rejection criteria — an addition to the Banff 97 classification of renal allograft rejection. _Am. J. Transplant._ 3, 708–714 (2003). Article  PubMed  Google Scholar  * Mauiyyedi, S. et al.

Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. _J. Am. Soc. Nephrol._ 13, 779–787 (2002). PubMed  Google Scholar  *

Nickeleit, V., Zeiler, M., Gudat, F., Thiel, G. & Mihatsch, M. J. Detection of the complement degradation product C4d in renal allografts: diagnostic and therapeutic implications. _J.

Am. Soc. Nephrol._ 13, 242–251 (2002). CAS  PubMed  Google Scholar  * Herzenberg, A. M., Gill, J. S., Djurdjev, O. & Magil, A. B. C4d deposition in acute rejection: an independent

long-term prognostic factor. _J. Am. Soc. Nephrol._ 13, 234–241 (2002). CAS  PubMed  Google Scholar  * Lorenz, M. et al. Risk factors for capillary C4d deposition in kidney allografts:

evaluation of a large study cohort. _Transplantation_ 78, 447–452 (2004). Article  PubMed  Google Scholar  * Trpkov, K. et al. Pathologic features of acute renal allograft rejection

associated with donor-specific antibody: analysis using the Banff grading schema. _Transplantation_ 61, 1586–1592 (1996). Article  CAS  PubMed  Google Scholar  * Bohmig, G. A. et al.

Capillary C4d deposition in kidney allografts: a specific marker of alloantibody-dependent graft injury. _J. Am. Soc. Nephrol._ 13, 1091–1099 (2002). CAS  PubMed  Google Scholar  * Magil, A.

B. & Tinckam, K. Monocytes and peritubular capillary C4d deposition in acute renal allograft rejection. _Kidney Int._ 63, 1888–1893 (2003). Article  CAS  PubMed  Google Scholar  *

Lederer, S. R. et al. Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts. _Kidney Int._ 59, 334–341 (2001). THIS IS A RECENT PAPER BY

THE RESEARCH GROUP OF HELMUT FEUCHT, WHO WAS THE FIRST TO STAIN RENAL ALLOGRAFTS FOR C4D AND SHOW THAT IT PREDICTED A POOR PROGNOSIS (REPORTED IN REFERENCE 9). Article  CAS  PubMed  Google

Scholar  * Haas, M., Ratner, L. E. & Montgomery, R. A. C4d staining of perioperative renal transplant biopsies. _Transplantation_ 74, 711–717 (2002). Article  CAS  PubMed  Google Scholar

  * Rotman, S., Collins, A. B. & Colvin, R. B. C4d deposition in allografts: current concepts and interpretation. _Transplant. Rev._ (in the press). * Hammond, E. H. et al. Vascular

(humoral) rejection in heart transplantation: pathologic observations and clinical implications. _J. Heart Transplant._ 8, 430–443 (1989). CAS  PubMed  Google Scholar  * John, R. et al.

Immunologic sensitization in recipients of left ventricular assist devices. _J. Thorac. Cardiovasc. Surg._ 125, 578–591 (2003). Article  PubMed  Google Scholar  * Smith, R. N. et al. C4d

deposition in cardiac allografts correlates with alloantibody. _J. Heart Lung Transplant._ 24, 1202–1210 (2005). THIS PAPER SHOWS THAT C4D DEPOSITION IN MYOCARDIAL CAPILLARIES IS ASSOCIATED

WITH CIRCULATING HLA-SPECIFIC ANTIBODIES RATHER THAN ISCHAEMIA. Article  PubMed  Google Scholar  * Michaels, P. J. et al. Humoral rejection in cardiac transplantation: risk factors,

hemodynamic consequences and relationship to transplant coronary artery disease. _J. Heart Lung Transplant._ 22, 58–69 (2003). Article  PubMed  Google Scholar  * Reed, E. F. et al.

Monitoring of soluble HLA alloantigens and anti-HLA antibodies identifies heart allograft recipients at risk of transplant-associated coronary artery disease. _Transplantation_ 61, 566–572

(1996). Article  CAS  PubMed  Google Scholar  * Behr, T. M. et al. Detection of humoral rejection in human cardiac allografts by assessing the capillary deposition of complement fragment C4d

in endomyocardial biopsies. _J. Heart Lung Transplant._ 18, 904–912 (1999). Article  CAS  PubMed  Google Scholar  * Magro, C. M. et al. Use of C4d as a diagnostic adjunct in lung allograft

biopsies. _Am. J. Transplant._ 3, 1143–1154 (2003). Article  CAS  PubMed  Google Scholar  * Krukemeyer, M. G. et al. Description of B lymphocytes and plasma cells, complement, and

chemokines/receptors in acute liver allograft rejection. _Transplantation_ 78, 65–70 (2004). Article  CAS  PubMed  Google Scholar  * Terasaki, P. I. & Ozawa, M. Predicting kidney graft

failure by HLA antibodies: a prospective trial. _Am. J. Transplant._ 4, 438–443 (2004). Article  CAS  PubMed  Google Scholar  * Piazza, A. et al. Impact of donor-specific antibodies on

chronic rejection occurrence and graft loss in renal transplantation: posttransplant analysis using flow cytometric techniques. _Transplantation_ 71, 1106–1112 (2001). Article  CAS  PubMed 

Google Scholar  * Pelletier, R. P. et al. Clinical significance of MHC-reactive alloantibodies that develop after kidney or kidney–pancreas transplantation. _Am. J. Transplant._ 2, 134–141

(2002). Article  CAS  PubMed  Google Scholar  * Worthington, J. E., Martin, S., Al-Husseini, D. M., Dyer, P. A. & Johnson, R. W. Posttransplantation production of donor HLA-specific

antibodies as a predictor of renal transplant outcome. _Transplantation_ 75, 1034–1040 (2003). THIS REPORT SHOWS THAT CIRCULATING ANTIBODIES THAT ARE SPECIFIC FOR DONOR HLA CLASS I OR CLASS

II ANTIGENS PREDICT THE SUBSEQUENT DEVELOPMENT OF CHRONIC REJECTION OF A RENAL ALLOGRAFT. Article  CAS  PubMed  Google Scholar  * Mauiyyedi, S. et al. Chronic humoral rejection:

identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. _J. Am. Soc. Nephrol._ 12, 574–582 (2001). THE PAPER IDENTIFIES AND

ESTABLISHES THE IMMUNOPATHOLOGICAL CRITERIA FOR A NEW FORM OF CHRONIC RENAL-ALLOGRAFT REJECTION THAT IS MEDIATED BY ANTIBODIES. CAS  PubMed  Google Scholar  * Regele, H. et al. Capillary

deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to

chronic allograft rejection. _J. Am. Soc. Nephrol._ 13, 2371–2380 (2002). THIS WAS THE FIRST PAPER TO SHOW THAT THE PRESENCE OF C4D IN THE PERITUBULAR CAPILLARIES OF RENAL ALLOGRAFTS

PRECEDES THE DEVELOPMENT OF CHRONIC ALLOGRAFT GLOMERULOPATHY. IT ALSO SHOWS THAT C4D DEPOSITION CORRELATES WITH LAMINATION OF THE PERITUBULAR CAPILLARY BASEMENT MEMBRANE. Article  PubMed 

Google Scholar  * Vongwiwatana, A., Gourishankar, S., Campbell, P. M., Solez, K. & Halloran, P. F. Peritubular capillary changes and C4d deposits are associated with transplant

glomerulopathy but not IgA nephropathy. _Am. J. Transplant._ 4, 124–129 (2004). Article  PubMed  Google Scholar  * Sijpkens, Y. W. et al. Immunologic risk factors and glomerular C4d deposits

in chronic transplant glomerulopathy. _Kidney Int._ 65, 2409–2418 (2004). Article  CAS  PubMed  Google Scholar  * Erlich, H. A., Opelz, G. & Hansen, J. HLA DNA typing and

transplantation. _Immunity_ 14, 347–356 (2001). Article  CAS  PubMed  Google Scholar  * Race, R. R. & Sanger, R. _Blood Groups in Man_ (Blackwell Scientific, Oxford, 1958). Google

Scholar  * Chao, N. J. Minors come of age: minor histocompatibility antigens and graft-versus-host disease. _Biol. Blood Marrow Transplant._ 10, 215–223 (2004). Article  CAS  PubMed  Google

Scholar  * Derhaag, J. G., Duijvestijn, A. M., Damoiseaux, J. G. & van Breda Vriesman, P. J. 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 (2000). Article  CAS  PubMed  Google Scholar  * Wu, G. D. et al. Vascular endothelial

cell apoptosis induced by anti-donor non-MHC antibodies: a possible injury pathway contributing to chronic allograft rejection. _J. Heart Lung Transplant._ 21, 1174–1187 (2002). Article 

PubMed  Google Scholar  * Kooijmans-Coutinho, M. F. et al. Interstitial rejection, vascular rejection, and diffuse thrombosis of renal allografts. Predisposing factors, histology,

immunohistochemistry, and relation to outcome. _Transplantation_ 61, 1338–1344 (1996). Article  CAS  PubMed  Google Scholar  * Sumitran-Holgersson, S., Wilczek, H. E., Holgersson, J. &

Soderstrom, K. Identification of the nonclassical HLA molecules, MICA, as targets for humoral immunity associated with irreversible rejection of kidney allografts. _Transplantation_ 74,

268–277 (2002). Article  CAS  PubMed  Google Scholar  * Mizutani, K. et al. Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure. _Am. J. Transplant._

5, 1–8 (2005). Article  CAS  Google Scholar  * Dragun, D. et al. Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. _N. Engl. J. Med._ 352, 558–569 (2005).

Article  CAS  PubMed  Google Scholar  * Jurcevic, S. et al. Antivimentin antibodies are an independent predictor of transplant-associated coronary artery disease after cardiac

transplantation. _Transplantation_ 71, 886–892 (2001). Article  CAS  PubMed  Google Scholar  * Morgun, A. et al. Pre- and post-transplant anti-myosin and anti-heat shock protein antibodies

and cardiac transplant outcome. _J. Heart Lung Transplant._ 23, 204–209 (2004). Article  PubMed  Google Scholar  * Austen, W. G. Jr et al. Murine hindlimb reperfusion injury can be initiated

by a self-reactive monoclonal IgM. _Surgery_ 136, 401–406 (2004). Article  PubMed  Google Scholar  * Mitchison, N. A. T-cell–B-cell cooperation. _Nature Rev. Immunol._ 4, 308–312 (2004).

Article  CAS  Google Scholar  * Baratin, M., Bonin, K. & Daniel, C. Peripheral priming of alloreactive T cells by the direct pathway of allorecognition. _Eur. J. Immunol._ 34, 3305–3314

(2004). Article  CAS  PubMed  Google Scholar  * Steele, D. J. et al. Two levels of help for B cell alloantibody production. _J. Exp. Med._ 183, 699–703 (1996). Article  CAS  PubMed  Google

Scholar  * Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. _N. Engl. J. Med._ 350, 2572–2581 (2004). Article  CAS  PubMed 

Google Scholar  * Asiedu, C. K., Dong, S. S., Lobashevsky, A., Jenkins, S. M. & Thomas, J. M. Tolerance induced by anti-CD3 immunotoxin plus 15-deoxyspergualin associates with

donor-specific indirect pathway unresponsiveness. _Cell. Immunol._ 223, 103–112 (2003). Article  CAS  PubMed  Google Scholar  * Epstein, M. M., Di Rosa, F., Jankovic, D., Sher, A. &

Matzinger, P. Successful T cell priming in B cell-deficient mice. _J. Exp. Med._ 182, 915–922 (1995). Article  CAS  PubMed  Google Scholar  * Williams, G. S., Oxenius, A., Hengartner, H.,

Benoist, C. & Mathis, D. CD4+ T cell responses in mice lacking MHC class II molecules specifically on B cells. _Eur. J. Immunol._ 28, 3763–3772 (1998). Article  CAS  PubMed  Google

Scholar  * Shapiro-Shelef, M. & Calame, K. Regulation of plasma-cell development. _Nature Rev. Immunol._ 5, 230–242 (2005). Article  CAS  Google Scholar  * Kerjaschki, D. et al.

Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. _J. Am. Soc. Nephrol._ 15, 603–612 (2004). Article  CAS  PubMed 

Google Scholar  * Sarwal, M. et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. _N. Engl. J. Med._ 349, 125–138 (2003). Article  CAS 

PubMed  Google Scholar  * Cassese, G. et al. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. _Eur. J. Immunol._ 31, 2726–2732 (2001). Article  CAS 

PubMed  Google Scholar  * Desvaux, D. et al. γ-Interferon expression and poor clinical outcome. _Nephrol. Dial. Transplant._ 19, 933–939 (2004). Article  CAS  PubMed  Google Scholar  *

Hidalgo, L. G. & Halloran, P. F. Role of IFN-γ in allograft rejection. _Crit. Rev. Immunol._ 22, 317–349 (2002). Article  CAS  PubMed  Google Scholar  * Auchincloss, H. Jr & Sachs,

D. H. Xenogeneic transplantation. _Annu. Rev. Immunol._ 16, 433–470 (1998). Article  CAS  PubMed  Google Scholar  * Wasowska, B. A. et al. Passive transfer of alloantibodies restores acute

cardiac rejection in IgKO mice. _Transplantation_ 71, 727–736 (2001). Article  CAS  PubMed  Google Scholar  * Rahimi, S. et al. Non-complement- and complement-activating antibodies synergize

to cause rejection of cardiac allografts. _Am. J. Transplant._ 4, 326–334 (2004). Article  CAS  PubMed  Google Scholar  * Menoret, S. et al. Characterization of human CD55 and CD59

transgenic pigs and kidney xenotransplantation in the pig-to-baboon combination. _Transplantation_ 77, 1468–1471 (2004). Article  CAS  PubMed  Google Scholar  * Azimzadeh, A. et al.

Hyperacute lung rejection in the pig-to-human model. 2. Synergy between soluble and membrane complement inhibition. _Xenotransplantation_ 10, 120–131 (2003). Article  CAS  PubMed  Google

Scholar  * Prodinger, W. M., Wurzner, R., Stoiber, H. & Dierich, M. P. in _Fundamentals of Immunology_ (ed. Paul, W. E.) 1077–1103 (Lippincott Williams & Wilkins, Philadelphia,

2003). Google Scholar  * van den Elsen, J. M. et al. X-ray crystal structure of the C4d fragment of human complement component C4. _J. Mol. Biol._ 322, 1103–1115 (2002). Article  CAS  PubMed

  Google Scholar  * Baldwin, W. M. 3rd, Kasper, E. K., Zachary, A. A., Wasowska, B. A. & Rodriguez, E. R. Beyond C4d: other complement-related diagnostic approaches to antibody-mediated

rejection. _Am. J. Transplant._ 4, 311–318 (2004). Article  CAS  PubMed  Google Scholar  * Sund, S. et al. Complement activation in early protocol kidney graft biopsies after living-donor

transplantation. _Transplantation_ 75, 1204–1213 (2003). Article  CAS  PubMed  Google Scholar  * Nakashima, S., Qian, Z., Rahimi, S., Wasowska, B. A. & Baldwin, W. M. 3rd. Membrane

attack complex contributes to destruction of vascular integrity in acute lung allograft rejection. _J. Immunol._ 169, 4620–4627 (2002). Article  CAS  PubMed  Google Scholar  * Saadi, S.

& Platt, J. L. Humoral rejection and endothelial cell activation, 2001. _Xenotransplantation_ 9, 239–241 (2002). Article  PubMed  Google Scholar  * Albrecht, E. A. et al. C5a-induced

gene expression in human umbilical vein endothelial cells. _Am. J. Pathol._ 164, 849–859 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * Monsinjon, T. et al. Regulation by

complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells. _FASEB J._ 17, 1003–1014 (2003). Article  CAS  PubMed  Google Scholar  * Saadi, S.,

Holzknecht, R. A., Patte, C. P. & Platt, J. L. Endothelial cell activation by pore-forming structures: pivotal role for interleukin-1α. _Circulation_ 101, 1867–1873 (2000). Article  CAS

  PubMed  Google Scholar  * Benzaquen, L. R., Nicholson-Weller, A. & Halperin, J. A. Terminal complement proteins C5b–9 release basic fibroblast growth factor and platelet-derived growth

factor from endothelial cells. _J. Exp. Med._ 179, 985–992 (1994). Article  CAS  PubMed  Google Scholar  * Selvan, R. S., Kapadia, H. B. & Platt, J. L. Complement-induced expression of

chemokine genes in endothelium: regulation by IL-1-dependent and -independent mechanisms. _J. Immunol._ 161, 4388–4395 (1998). CAS  PubMed  Google Scholar  * Kilgore, K. S. et al. Sublytic

concentrations of the membrane attack complex of complement induce endothelial interleukin-8 and monocyte chemoattractant protein-1 through nuclear factor-κB activation. _Am. J. Pathol._

150, 2019–2031 (1997). CAS  PubMed  PubMed Central  Google Scholar  * Ikeda, K. et al. C5a induces tissue factor activity on endothelial cells. _Thromb. Haemost._ 77, 394–398 (1997). Article

  CAS  PubMed  Google Scholar  * Saadi, S., Holzknecht, R. A., Patte, C. P., Stern, D. M. & Platt, J. L. Complement-mediated regulation of tissue factor activity in endothelium. _J. Exp.

Med._ 182, 1807–1814 (1995). Article  CAS  PubMed  Google Scholar  * Dempsey, P. W., Allison, M. E., Akkaraju, S., Goodnow, C. C. & Fearon, D. T. C3d of complement as a molecular

adjuvant: bridging innate and acquired immunity. _Science_ 271, 348–350 (1996). Article  CAS  PubMed  Google Scholar  * Qian, Z. et al. C6 produced by macrophages contributes to cardiac

allograft rejection. _Am. J. Pathol._ 155, 1293–1302 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ota, H. et al. Terminal complement components mediate release of von

Willebrand factor and adhesion of platelets in arteries of allografts. _Transplantation_ 79, 276–281 (2005). Article  CAS  PubMed  Google Scholar  * Pratt, J. R., Basheer, S. A. & Sacks,

S. H. Local synthesis of complement component C3 regulates acute renal transplant rejection. _Nature Med._ 8, 582–587 (2002). Article  CAS  PubMed  Google Scholar  * Smith, J. D., Lawson,

C., Yacoub, M. H. & Rose, M. L. Activation of NF-κB in human endothelial cells induced by monoclonal and allospecific HLA antibodies. _Int. Immunol._ 12, 563–571 (2000). Article  CAS 

PubMed  Google Scholar  * Jin, Y. P. et al. 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 (2002). THIS IS THE MOST RECENT IN A SERIES OF PAPERS FROM THIS RESEARCH GROUP. IT IDENTIFIES THE ACTIVATION PATHWAYS IN ENDOTHELIAL CELLS THAT ARE

TRIGGERED BY HLA-SPECIFIC ANTIBODIES. Article  CAS  PubMed  Google Scholar  * Yuan, F. F. et al. Association of Fcγ receptor IIA polymorphisms with acute renal-allograft rejection.

_Transplantation_ 78, 766–769 (2004). Article  CAS  PubMed  Google Scholar  * Koch, C. A., Khalpey, Z. I. & Platt, J. L. Accommodation: preventing injury in transplantation and disease.

_J. Immunol._ 172, 5143–5148 (2004). Article  CAS  PubMed  Google Scholar  * Alexandre, G. P. J. et al. Present experience in a series of 26 ABO-incompatible living donor renal allografts.

_Transplant. Proc._ 19, 4538–4544 (1987). CAS  PubMed  Google Scholar  * Shishido, S. et al. ABO-incompatible living-donor kidney transplantation in children. _Transplantation_ 72, 1037–1042

(2001). Article  CAS  PubMed  Google Scholar  * Ogawa, H. et al. Mouse-heart grafts expressing an incompatible carbohydrate antigen. II. Transition from accommodation to tolerance.

_Transplantation_ 77, 366–373 (2004). Article  CAS  PubMed  Google Scholar  * Soares, M. P., Brouard, S., Smith, R. N. & Bach, F. H. Heme oxygenase-1, a protective gene that prevents the

rejection of transplanted organs. _Immunol. Rev._ 184, 275–285 (2001). Article  CAS  PubMed  Google Scholar  * Tabata, T. et al. Accommodation after lung xenografting from hamster to rat.

_Transplantation_ 75, 607–612 (2003). Article  CAS  PubMed  Google Scholar  * Salama, A. D. et al. Transplant accommodation in highly sensitized patients: a potential role for Bcl-xL and

alloantibody. _Am. J. Transplant._ 1, 260–269 (2001). THIS PAPER SHOWS ANTIBODY-INDUCED INCREASES IN ENDOTHELIAL-CELL EXPRESSION OF BCL-X L , A POTENTIAL MOLECULAR MECHANISM OF ACCOMMODATION

IN HUMAN RENAL TRANSPLANTS. Article  CAS  PubMed  Google Scholar  * Narayanan, K., Jaramillo, A., Phelan, D. L. & Mohanakumar, T. 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 (2004). Article  PubMed  Google Scholar  * Park, W. D. et al. Accommodation in ABO-incompatible kidney allografts, a novel mechanism of self-protection against

antibody-mediated injury. _Am. J. Transplant._ 3, 952–960 (2003). Article  CAS  PubMed  Google Scholar  * Lee, P. C. et al. All chronic rejection failures of kidney transplants were preceded

by the development of HLA antibodies. _Transplantation_ 74, 1192–1194 (2002). Article  CAS  PubMed  Google Scholar  * Mason, J. C. et al. Decay-accelerating factor induction on vascular

endothelium by vascular endothelial growth factor (VEGF) is mediated via a VEGF receptor-2 (VEGF-R2)- and protein kinase C-α/ε (PKCα/ε)-dependent cytoprotective signaling pathway and is

inhibited by cyclosporin A. _J. Biol. Chem._ 279, 41611–41618 (2004). Article  CAS  PubMed  Google Scholar  * Shimizu, I. et al. DAF prevents acute humoral rejection induced by low titres of

anti-αGal antibodies in GAL KO mice. _Transplantation_ (in the press). * Grubbs, B. C., Benson, B. A. & Dalmasso, A. P. Characteristics of CD59 up-regulation induced in porcine

endothelial cells by αGal ligation and its association with protection from complement. _Xenotransplantation_ 10, 387–397 (2003). Article  PubMed  Google Scholar  * Williams, J. M. et al.

Acute vascular rejection and accommodation: divergent outcomes of the humoral response to organ transplantation. _Transplantation_ 78, 1471–1478 (2004). Article  PubMed  Google Scholar  *

Hillebrands, J. L. et al. Origin of neointimal endothelium and α-actin-positive smooth muscle cells in transplant arteriosclerosis. _J. Clin. Invest._ 107, 1411–1422 (2001). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Koestner, S. C. et al. Histo-blood group type change of the graft from B to O after ABO mismatched heart transplantation. _Lancet_ 363, 1523–1525

(2004). Article  PubMed  Google Scholar  * Lagaaij, E. L. et al. Endothelial cell chimerism after renal transplantation and vascular rejection. _Lancet_ 357, 33–37 (2001). Article  CAS 

PubMed  Google Scholar  * Mohiuddin, M. M., Ogawa, H., Yin, D. P., Shen, J. & Galili, U. Antibody-mediated accommodation of heart grafts expressing an incompatible carbohydrate antigen.

_Transplantation_ 75, 258–262 (2003). THIS REPORT DESCRIBES A PILOT STUDY OF GENE EXPRESSION IN ABO-INCOMPATIBLE HUMAN CARDIAC ALLOGRAFTS WITH ACCOMMODATION. Article  CAS  PubMed  Google

Scholar  * Toyoda, M., Petrosyan, A., Pao, A. & Jordan, S. C. Immunomodulatory effects of combination of pooled human gammaglobulin and rapamycin on cell proliferation and apoptosis in

the mixed lymphocyte reaction. _Transplantation_ 78, 1134–1138 (2004). Article  CAS  PubMed  Google Scholar  * Jordan, S. C. et al. Intravenous immune globulin treatment inhibits crossmatch

positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. _Transplantation_ 76, 631–636 (2003). Article  CAS  PubMed  Google Scholar

  * Frank, M. M., Miletic, V. D. & Jiang, H. Immunoglobulin in the control of complement action. _Immunol. Res._ 22, 137–146 (2000). Article  CAS  PubMed  Google Scholar  * Vieira, C. A.

et al. Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics. _Transplantation_ 77, 542–548 (2004).

THIS PAPER DESCRIBES ENCOURAGING RESULTS FROM A PHASE I CLINICAL TRIAL OF RITUXIMAB IN PRE-SENSITIZED PATIENTS WHO ARE AWAITING A RENAL TRANSPLANT. IT SHOWS SOME EFFICACY AT THE INHIBITION

OF PRESUMED PRE-EXISTING MEMORY B CELLS AND LONG-LIVED PLASMA CELLS. Article  CAS  PubMed  Google Scholar  * Gloor, J. M. et al. Overcoming a positive crossmatch in living-donor kidney

transplantation. _Am. J. Transplant._ 3, 1017–1023 (2003). Article  PubMed  Google Scholar  * Tyden, G., Kumlien, G. & Fehrman, I. Successful ABO-incompatible kidney transplantations

without splenectomy using antigen-specific immunoadsorption and rituximab. _Transplantation_ 76, 730–731 (2003). Article  PubMed  Google Scholar  * McHeyzer-Williams, L. J. &

McHeyzer-Williams, M. G. Antigen-specific memory B cell development. _Annu. Rev. Immunol._ 23, 487–513 (2005). Article  CAS  PubMed  Google Scholar  * Craxton, A., Magaletti, D., Ryan, E. J.

& Clark, E. A. Macrophage- and dendritic cell-dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF. _Blood_ 101, 4464–4471 (2003). Article  CAS  PubMed

  Google Scholar  * Gross, J. A. et al. TACI–Ig neutralizes molecules critical for B cell development and autoimmune disease: impaired B cell maturation in mice lacking BLyS. _Immunity_ 15,

289–302 (2001). Article  CAS  PubMed  Google Scholar  * O'Connor, B. P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. _J. Exp. Med._ 199, 91–98

(2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * West, L. J. et al. ABO-incompatible heart transplantation in infants. _N. Engl. J. Med._ 344, 793–800 (2001). Article  CAS 

PubMed  Google Scholar  * Fan, X. et al. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. _Nature Med._ 10, 1227–1233 (2004). Article  CAS  PubMed  Google

Scholar  * Knechtle, S. J. et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. _Am. J. Transplant._ 3, 722–730 (2003). Article  CAS 

PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pathology, Warren 225, Massachusetts General Hospital, Harvard Medical School, Boston,

02140, Massachusetts, USA Robert B. Colvin & R. Neal Smith Authors * Robert B. Colvin View author publications You can also search for this author inPubMed Google Scholar * R. Neal

Smith View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Robert B. Colvin. ETHICS DECLARATIONS COMPETING INTERESTS

The authors declare no competing financial interests. RELATED LINKS RELATED LINKS DATABASES ENTREZ GENE BCL-2 BCL-XL C4d CCL2 CCL5 CD59 CXCL8 DAF E-selectin HO1 ICAM1 IL-1α IL-6 PDGF tissue

factor VCAM1 GLOSSARY * ACUTE REJECTION The rapid (within days) clinical deterioration of graft function, which can occur days to years after transplantation. It can be caused by

T-cell-dependent reactivity to donor alloantigen (that is, cellular rejection) and/or alloantibody reactivity to donor antigens on the endothelium (that is, antibody-mediated rejection). *

CHRONIC REJECTION The slow (within months to years) clinical deterioration of graft function. It can be caused by T-cell- and/or antibody-mediated reaction to donor alloantigens, which

results in a slow, progressive decline in graft function and is typically associated with stenotic intimal hyperplasia of the arteries. * PRE-SENSITIZATION Immunological reactivity to a

donor that is present before transplantation: for example, as a result of a previous transplant, pregnancy or blood transfusion. It is typically detected by the measurement of serum antibody

that is specific for donor cells or surrogate targets. * SERUM CREATININE Creatinine is a component of urine and the final product in the metabolism of creatine. An increase in serum

concentration is used as a marker of kidney dysfunction. * _DE NOVO_ ANTIBODIES Antibodies that first appear after transplantation (that is, the patient is not pre-sensitized). *

NEO-LYMPHOID ORGAN The organization within a tissue of high endothelial venules, lymphoid follicles and dendritic cells. This can be mediated by persistent inflammation. * COMPLEMENT-FIXING

ANTIBODIES Not all antibodies fix or activate complement. In humans, IgM and the IgG subclasses IgG1 and IgG3 readily fix complement, whereas IgG2 is less effective. The IgG subclass IgG4

and other classes of immunoglobulin do not fix complement or activate the classical complement pathway. * ENDOTHELIAL-CELL ACTIVATION Marked by phenotypic changes that usually include MHC

class II expression, tissue-factor activity and increased leukocyte adhesion to the endothelium, all of which are induced by interferon. This often occurs together with morphological

changes, including hypertrophy (indicated by a cuboidal appearance), increased biosynthesis and increased permeability. * ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC). A mechanism by

which natural killer (NK) cells kill other cells: for example, virus-infected target cells that are coated with antibodies. The Fc portions of the coating antibodies interact with the Fc

receptor that is expressed by NK cells (FcγRIII; CD16), thereby initiating a signalling cascade that results in the release of cytotoxic granules (containing perforin and granzyme B), which

induce apoptosis of the antibody-coated cell. * INTRAVENOUS IMMUNOGLOBULIN Immunoglobulin that is pooled from a large number of individuals. It is used as a replacement for patients who have

been depleted of immunoglobulins and for the immunomodulatory treatment of patients with some immune disorders. * MIXED LYMPHOCYTE REACTION A tissue-culture technique for testing T-cell

reactivity. The proliferation of responder T cells (in this case, recipient T cells) that is induced by exposure to inactivated stimulator cells (in this case, donor T cells) is determined

by measuring the incorporation of 3H-thymidine into the DNA of dividing cells. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Colvin, R., Smith, R.

Antibody-mediated organ-allograft rejection. _Nat Rev Immunol_ 5, 807–817 (2005). https://doi.org/10.1038/nri1702 Download citation * Published: 20 September 2005 * Issue Date: 01 October

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