Skip to main content
SpringerLink
Log in

Immunobiology of Transplantation

  • Chapter
  • First Online:
Pathology of Transplantation

Abstract

Although the immune system effectively provides protection from foreign pathogens, it creates a major barrier for transplantation. To understand the processes involved in rejection of a transplanted allograft, a fundamental understanding of the immune system and its function in transplant-directed immune responses is required. This chapter reviews the basic immunologic concepts, factors, and mechanisms that contribute to transplant rejection and regulation of alloimmune responses. Key transplantation antigens that can elicit an immune response against the graft are reviewed. The role of adaptive and innate immunity in allograft rejection is described in detail. In addition, potential mechanisms that can regulate alloimmune responses and induce transplant tolerance are discussed. For simplicity, concepts will be explained in the context of solid organ transplantation, where the graft is recognized as foreign and attacked by the host’s immune system. The unique complexities of hematopoietic stem cell transplantation (HSCT) will be discussed separately. This chapter should provide pathologists and clinicians an understanding of basic concepts in transplant-related immunobiology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ABOi:

ABO incompatible

ADCC:

Antibody-dependent cellular cytotoxicity

aGvHD:

Acute graft-versus-host disease

AMR:

Antibody-mediated rejection

APC:

Antigen-presenting cell

ASC:

Antibody-secreting cell

BAFF:

B-cell-activating factor

BCL:

B-cell lymphoma

BCR:

B-cell receptor

Breg:

Regulatory B-cell

cGvHD:

Chronic graft-versus-host disease

CTLA:

Cytotoxic T-lymphocyte-associated antigen

DAMP:

Damage-associated molecular pattern

DC:

Dendritic cell

DN:

Double negative

DSA:

Donor-specific antibody

Fab:

Antigen-binding fragment

Fc:

Crystallizable fragment

FDC:

Follicular dendritic cell

FOXP3:

Forkhead box P3

GC:

Germinal center

GvHD:

Graft-versus-host disease

GvL:

Graft versus leukemia

HLA:

Human leukocyte antigen

HSCT:

Hematopoietic stem cell transplantation

ICOS:

Inducible T-cell co-stimulator

IFN:

Interferon

Ig:

Immunoglobulin

iNKT-cell:

Invariant natural killer T-cell

iNOS:

Inducible nitric oxide synthase

I/R:

Ischemia/reperfusion

IL:

Interleukin

KIR:

Killer cell immunoglobulin-like

MBL:

Mannose-binding lectin

mDC:

Myeloid DC

MDSC:

Myeloid-derived suppressor cell

MHC:

Major histocompatibility complex

MICA/MICB:

Major histocompatibility complex class I-related chain A and B

Mregs:

Regulatory macrophages

mTEC:

Medullary thymic epithelial cell

mTOR:

Mammalian target of rapamycin

MyD88:

Myeloid differentiation factor 88

MZ:

Marginal zone

NK-cell:

Natural killer cell

NKG:

Natural killer group

NKT-cell:

Natural killer T-cell

PAMP:

Pathogen-associated molecular pattern

PD(-L):

Programmed cell death protein (-ligand)

pDC:

Plasmacytoid DC

PDGF:

Platelet-derived growth factor

PRR:

Pattern recognition receptor

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SHM:

Somatic hypermutation

STAT:

Signal transducer and activator of transcription

Tcm-cell:

Central memory T-cell

TCR:

T-cell receptor

TD:

T-cell dependent

Tem-cell:

Effector memory T-cell

Tfh:

Follicular T helper

TGF:

Transforming growth factor

Th:

T helper

TI:

T-cell independent

TIM:

T-cell immunoglobulin and mucin domain

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

Treg:

Regulatory T-cell

References

  1. Neefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 2011;11(12):823–36.

    CAS  PubMed  Google Scholar 

  2. Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res. 2015;43(Database issue):D423–31.

    Article  PubMed  Google Scholar 

  3. Springer GF, Horton RE. Blood group isoantibody stimulation in man by feeding blood group-active bacteria. J Clin Invest. 1969;48(7):1280–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fong SW, Qaqundah BY, Taylor WF. Developmental patterns of ABO isoagglutinins in normal children correlated with the effects of age, sex, and maternal isoagglutinins. Transfusion. 1974;14(6):551–9.

    Article  CAS  PubMed  Google Scholar 

  5. Muramatsu M, Gonzalez HD, Cacciola R, Aikawa A, Yaqoob MM, Puliatti C. ABO incompatible renal transplants: Good or bad? World J Transplant. 2014;4(1):18–29.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tanabe M, Kawachi S, Obara H, Shinoda M, Hibi T, Kitagawa Y, et al. Current progress in ABO-incompatible liver transplantation. Eur J Clin Invest. 2010;40(10):943–9.

    Article  PubMed  Google Scholar 

  7. West LJ. ABO-incompatible hearts for infant transplantation. Curr Opin Organ Transplant. 2011;16(5):548–54.

    Article  CAS  PubMed  Google Scholar 

  8. Heffron T, Welch D, Pillen T, Asolati M, Smallwood G, Hagedorn P, et al. Successful ABO-incompatible pediatric liver transplantation utilizing standard immunosuppression with selective postoperative plasmapheresis. Liver Transpl. 2006;12(6):972–8.

    Article  PubMed  Google Scholar 

  9. Nath DS, Ilias Basha H, Tiriveedhi V, Alur C, Phelan D, Ewald GA, et al. 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. 2010;29(11):1277–85.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kalache S, Dinavahi R, Pinney S, Mehrotra A, Cunningham MW, Heeger PS. Anticardiac myosin immunity and chronic allograft vasculopathy in heart transplant recipients. J Immunol. 2011;187(2):1023–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Burlingham WJ, Love RB, Jankowska-Gan E, Haynes LD, Xu Q, Bobadilla JL, et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007;117(11):3498–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Goers TA, Ramachandran S, Aloush A, Trulock E, Patterson GA, Mohanakumar T. De novo production of K-alpha1 tubulin-specific antibodies: role in chronic lung allograft rejection. J Immunol. 2008;180(7):4487–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dragun D, Muller DN, Brasen JH, Fritsche L, Nieminen-Kelha M, Dechend R, et al. Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med. 2005;352(6):558–69.

    Article  CAS  PubMed  Google Scholar 

  14. Joosten SA, Sijpkens YW, van Ham V, Trouw LA, van der Vlag J, van den Heuvel B, et al. Antibody response against the glomerular basement membrane protein agrin in patients with transplant glomerulopathy. Am J Transplant. 2005;5(2):383–93.

    Article  CAS  PubMed  Google Scholar 

  15. Tan JC, Wadia PP, Coram M, Grumet FC, Kambham N, Miller K, et al. H-Y antibody development associates with acute rejection in female patients with male kidney transplants. Transplantation. 2008;86(1):75–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zou Y, Stastny P, Susal C, Dohler B, Opelz G. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med. 2007;357(13):1293–300.

    Article  CAS  PubMed  Google Scholar 

  17. Quiroga I, Salio M, Koo DD, Cerundolo L, Shepherd D, Cerundolo V, et al. Expression of MHC class I-related chain B (MICB) molecules on renal transplant biopsies. Transplantation. 2006;81(8):1196–203.

    Article  CAS  PubMed  Google Scholar 

  18. Suarez-Alvarez B, Lopez-Vazquez A, Gonzalez MZ, Fdez-Morera JL, Diaz-Molina B, Blanco-Gelaz MA, et al. The relationship of anti-MICA antibodies and MICA expression with heart allograft rejection. Am J Transplant. 2007;7(7):1842–8.

    Article  CAS  PubMed  Google Scholar 

  19. Afzali B, Lombardi G, Lechler RI. Pathways of major histocompatibility complex allorecognition. Curr Opin Organ Transplant. 2008;13(4):438–44.

    Article  PubMed  Google Scholar 

  20. Herrera OB, Golshayan D, Tibbott R, Salcido Ochoa F, James MJ, Marelli-Berg FM, et al. A novel pathway of alloantigen presentation by dendritic cells. J Immunol. 2004;173(8):4828–37.

    Article  CAS  PubMed  Google Scholar 

  21. Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice. J Immunol. 1999;162(1):352–8.

    CAS  PubMed  Google Scholar 

  22. van Besouw NM, Zuijderwijk JM, Vaessen LM, Balk AH, Maat AP, van der Meide PH, et al. The direct and indirect allogeneic presentation pathway during acute rejection after human cardiac transplantation. Clin Exp Immunol. 2005;141(3):534–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol. 2001;166(2):973–81.

    Article  CAS  PubMed  Google Scholar 

  24. Valujskikh A, Hartig C, Heeger PS. Indirectly primed CD8+ T cells are a prominent component of the allogeneic T-cell repertoire after skin graft rejection in mice. Transplantation. 2001;71(3):418–21.

    Article  CAS  PubMed  Google Scholar 

  25. Csencsits K, Wood SC, Lu G, Magee JC, Eichwald EJ, Chang CH, et al. Graft rejection mediated by CD4+ T cells via indirect recognition of alloantigen is associated with a dominant Th2 response. Eur J Immunol. 2005;35(3):843–51.

    Article  CAS  PubMed  Google Scholar 

  26. Pilat N, Sayegh MH, Wekerle T. Costimulatory pathways in transplantation. Semin Immunol. 2011;23(4):293–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rothstein DM, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Immunol Rev. 2003;196:85–108.

    Article  CAS  PubMed  Google Scholar 

  28. Wojciechowski D, Vincenti F. Belatacept in kidney transplantation. Curr Opin Organ Transplant. 2012;17(6):640–7.

    Article  CAS  PubMed  Google Scholar 

  29. Zhu J, Paul WE. Heterogeneity and plasticity of T helper cells. Cell Res. 2010;20(1):4–12.

    Article  PubMed  CAS  Google Scholar 

  30. Nakayamada S, Takahashi H, Kanno Y, O’Shea JJ. Helper T cell diversity and plasticity. Curr Opin Immunol. 2012;24(3):297–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhu J, Paul WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev. 2010;238(1):247–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. D’Elios MM, Josien R, Manghetti M, Amedei A, de Carli M, Cuturi MC, et al. Predominant Th1 cell infiltration in acute rejection episodes of human kidney grafts. Kidney Int. 1997;51(6):1876–84.

    Article  PubMed  Google Scholar 

  33. Al-Lamki RS, Wang J, Skepper JN, Thiru S, Pober JS, Bradley JR. Expression of tumor necrosis factor receptors in normal kidney and rejecting renal transplants. Lab Invest. 2001;81(11):1503–15.

    Article  CAS  PubMed  Google Scholar 

  34. de Groot-Kruseman HA, Mol WM, Niesters HG, Maat AP, van Gelder T, Balk AH, et al. Differential intragraft cytokine messenger RNA profiles during rejection and repair of clinical heart transplants. A longitudinal study. Transpl Int. 2003;16(1):9–14.

    Article  PubMed  Google Scholar 

  35. Hodge G, Hodge S, Chambers D, Reynolds PN, Holmes M. Acute lung transplant rejection is associated with localized increase in T-cell IFNgamma and TNFalpha proinflammatory cytokines in the airways. Transplantation. 2007;84(11):1452–8.

    Article  CAS  PubMed  Google Scholar 

  36. Grazia TJ, Plenter RJ, Weber SM, Lepper HM, Victorino F, Zamora MR, et al. Acute cardiac allograft rejection by directly cytotoxic CD4 T cells: parallel requirements for Fas and perforin. Transplantation. 2010;89(1):33–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bushell A, Niimi M, Morris PJ, Wood KJ. Evidence for immune regulation in the induction of transplantation tolerance: a conditional but limited role for IL-4. J Immunol. 1999;162(3):1359–66.

    CAS  PubMed  Google Scholar 

  38. Waaga AM, Gasser M, Kist-van Holthe JE, Najafian N, Muller A, Vella JP, et al. Regulatory functions of self-restricted MHC class II allopeptide-specific Th2 clones in vivo. J Clin Invest. 2001;107(7):909–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Barbara JA, Turvey SE, Kingsley CI, Spriewald BM, Hara M, Witzke O, et al. Islet allograft rejection can be mediated by CD4+, alloantigen experienced, direct pathway T cells of TH1 and TH2 cytokine phenotype. Transplantation. 2000;70(11):1641–9.

    Article  CAS  PubMed  Google Scholar 

  40. Nocera A, Tagliamacco A, De Palma R, Del Galdo F, Ferrante A, Fontana I, et al. Cytokine mRNA expression in chronically rejected human renal allografts. Clin Transplant. 2004;18(5):564–70.

    Article  PubMed  Google Scholar 

  41. Keane MP, Gomperts BN, Weigt S, Xue YY, Burdick MD, Nakamura H, et al. IL-13 is pivotal in the fibro-obliterative process of bronchiolitis obliterans syndrome. J Immunol. 2007;178(1):511–9.

    Article  CAS  PubMed  Google Scholar 

  42. Goldman M, Le Moine A, Braun M, Flamand V, Abramowicz D. A role for eosinophils in transplant rejection. Trends Immunol. 2001;22(5):247–51.

    Article  CAS  PubMed  Google Scholar 

  43. Singh RP, Hasan S, Sharma S, Nagra S, Yamaguchi DT, Wong DT, et al. Th17 cells in inflammation and autoimmunity. Autoimmun Rev. 2014;13(12):1174–81.

    Article  CAS  PubMed  Google Scholar 

  44. Laan M, Cui ZH, Hoshino H, Lotvall J, Sjostrand M, Gruenert DC, et al. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol. 1999;162(4):2347–52.

    CAS  PubMed  Google Scholar 

  45. Liu Z, Yang L, Cui Y, Wang X, Guo C, Huang Z, et al. Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(8):1133–44.

    Article  PubMed  Google Scholar 

  46. Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med. 2008;14(3):275–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Heidt S, Segundo DS, Chadha R, Wood KJ. The impact of Th17 cells on transplant rejection and the induction of tolerance. Curr Opin Organ Transplant. 2010;15(4):456–61.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Yoshida S, Haque A, Mizobuchi T, Iwata T, Chiyo M, Webb TJ, et al. Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants. Am J Transplant. 2006;6(4):724–35.

    Article  CAS  PubMed  Google Scholar 

  49. Fukami N, Ramachandran S, Saini D, Walter M, Chapman W, Patterson GA, et al. Antibodies to MHC class I induce autoimmunity: role in the pathogenesis of chronic rejection. J Immunol. 2009;182(1):309–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Van Kooten C, Boonstra JG, Paape ME, Fossiez F, Banchereau J, Lebecque S, et al. Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection. J Am Soc Nephrol. 1998;9(8):1526–34.

    PubMed  Google Scholar 

  51. Vanaudenaerde BM, De Vleeschauwer SI, Vos R, Meyts I, Bullens DM, Reynders V, et al. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant. 2008;8(9):1911–20.

    Article  CAS  PubMed  Google Scholar 

  52. Loong CC, Hsieh HG, Lui WY, Chen A, Lin CY. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol. 2002;197(3):322–32.

    Article  CAS  PubMed  Google Scholar 

  53. Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One. 2011;6(3), e17739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Conlon TM, Saeb-Parsy K, Cole JL, Motallebzadeh R, Qureshi MS, Rehakova S, et al. Germinal center alloantibody responses are mediated exclusively by indirect-pathway CD4 T follicular helper cells. J Immunol. 2012;188(6):2643–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. de Graav GN, Dieterich M, Hesselink DA, Boer K, Clahsen-van Groningen MC, Kraaijeveld R, et al. Follicular T helper cells and humoral reactivity in kidney transplant patients. Clin Exp Immunol. 2015;180(2):329–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells, and together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells. Nat Immunol. 2008;9(12):1347–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kaplan MH. Th9 cells: differentiation and disease. Immunol Rev. 2013;252(1):104–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Schmitt EG, Williams CB. Generation and function of induced regulatory T cells. Front Immunol. 2013;4:152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol. 2006;176(6):3321–9.

    Article  CAS  PubMed  Google Scholar 

  60. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B, et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol. 2008;181(4):2277–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood. 2005;105(3):1162–9.

    Article  CAS  PubMed  Google Scholar 

  63. Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol. 2007;8(12):1380–9.

    Article  CAS  PubMed  Google Scholar 

  64. Pot C, Apetoh L, Awasthi A, Kuchroo VK. Molecular pathways in the induction of interleukin-27-driven regulatory type 1 cells. J Interferon Cytokine Res. 2010;30(6):381–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Grossman WJ, Verbsky JW, Tollefsen BL, Kemper C, Atkinson JP, Ley TJ. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood. 2004;104(9):2840–8.

    Article  CAS  PubMed  Google Scholar 

  66. Lo DJ, Weaver TA, Kleiner DE, Mannon RB, Jacobson LM, Becker BN, et al. Chemokines and their receptors in human renal allotransplantation. Transplantation. 2011;91(1):70–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fahmy NM, Yamani MH, Starling RC, Ratliff NB, Young JB, McCarthy PM, et al. Chemokine and chemokine receptor gene expression indicates acute rejection of human cardiac transplants. Transplantation. 2003;75(1):72–8.

    Article  CAS  PubMed  Google Scholar 

  68. Agostini C, Calabrese F, Rea F, Facco M, Tosoni A, Loy M, et al. Cxcr3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection. Am J Pathol. 2001;158(5):1703–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Schenk AD, Rosenblum JM, Fairchild RL. Chemokine-directed strategies to attenuate allograft rejection. Clin Lab Med. 2008;28(3):441–54. vii.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Kreisel D, Krupnick AS, Gelman AE, Engels FH, Popma SH, Krasinskas AM, et al. Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: an alternative mechanism of allorecognition. Nat Med. 2002;8(3):233–9.

    Article  CAS  PubMed  Google Scholar 

  71. Grazia TJ, Pietra BA, Johnson ZA, Kelly BP, Plenter RJ, Gill RG. A two-step model of acute CD4 T-cell mediated cardiac allograft rejection. J Immunol. 2004;172(12):7451–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Choy JC. Granzymes and perforin in solid organ transplant rejection. Cell Death Differ. 2010;17(4):567–76.

    Article  CAS  PubMed  Google Scholar 

  73. Oh SI, Kim IW, Jung HC, Seo JW, Chae IH, Kim HS, et al. Correlation of Fas and Fas ligand expression with rejection status of transplanted heart in human. Transplantation. 2001;71(7):906–9.

    Article  CAS  PubMed  Google Scholar 

  74. Bittmann I, Muller C, Behr J, Groetzner J, Frey L, Lohrs U. Fas/FasL and perforin/granzyme pathway in acute rejection and diffuse alveolar damage after allogeneic lung transplantation-a human biopsy study. Virchows Arch. 2004;445(4):375–81.

    Article  PubMed  Google Scholar 

  75. Batista FD, Harwood NE. The who, how and where of antigen presentation to B cells. Nat Rev Immunol. 2009;9(1):15–27.

    Article  CAS  PubMed  Google Scholar 

  76. Pape KA, Catron DM, Itano AA, Jenkins MK. The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity. 2007;26(4):491–502.

    Article  CAS  PubMed  Google Scholar 

  77. Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu Rev Immunol. 2005;23:901–44.

    Article  CAS  PubMed  Google Scholar 

  78. Bergtold A, Desai DD, Gavhane A, Clynes R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity. 2005;23(5):503–14.

    Article  CAS  PubMed  Google Scholar 

  79. Yoshida K, van den Berg TK, Dijkstra CD. Two functionally different follicular dendritic cells in secondary lymphoid follicles of mouse spleen, as revealed by CR1/2 and FcR gamma II-mediated immune-complex trapping. Immunology. 1993;80(1):34–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Bekeredjian-Ding I, Jego G. Toll-like receptors—sentries in the B-cell response. Immunology. 2009;128(3):311–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Balin SJ, Platt JL, Cascalho M. New insights into the functions of B cells. Pediatr Transplant. 2008;12(5):510–5.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Vos Q, Lees A, Wu ZQ, Snapper CM, Mond JJ. B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms. Immunol Rev. 2000;176:154–70.

    Article  CAS  PubMed  Google Scholar 

  83. Rickert RC. Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex. Curr Opin Immunol. 2005;17(3):237–43.

    Article  CAS  PubMed  Google Scholar 

  84. Parker W, Yu PB, Holzknecht ZE, Lundberg K, Buckley RH, Platt JL. Specificity and function of “natural” antibodies in immunodeficient subjects: clues to B cell lineage and development. J Clin Immunol. 1997;17(4):311–21.

    Article  CAS  PubMed  Google Scholar 

  85. Natkunam Y. The biology of the germinal center. Hematology Am Soc Hematol Educ Program. 2007:210–5.

    Google Scholar 

  86. Allen CD, Okada T, Cyster JG. Germinal-center organization and cellular dynamics. Immunity. 2007;27(2):190–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol. 2013;13(2):118–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cinamon G, Zachariah MA, Lam OM, Foss Jr FW, Cyster JG. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol. 2008;9(1):54–62.

    Article  CAS  PubMed  Google Scholar 

  89. Attanavanich K, Kearney JF. Marginal zone, but not follicular B cells, are potent activators of naive CD4 T cells. J Immunol. 2004;172(2):803–11.

    Article  CAS  PubMed  Google Scholar 

  90. Bialecki E, Paget C, Fontaine J, Capron M, Trottein F, Faveeuw C. Role of marginal zone B lymphocytes in invariant NKT cell activation. J Immunol. 2009;182(10):6105–13.

    Article  CAS  PubMed  Google Scholar 

  91. Weill JC, Weller S, Reynaud CA. Human marginal zone B cells. Annu Rev Immunol. 2009;27:267–85.

    Article  CAS  PubMed  Google Scholar 

  92. Haas KM, Poe JC, Steeber DA, Tedder TF. B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. Immunity. 2005;23(1):7–18.

    Article  CAS  PubMed  Google Scholar 

  93. Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70. J Exp Med. 2011;208(1):67–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Covens K, Verbinnen B, Geukens N, Meyts I, Schuit F, Van Lommel L, et al. Characterization of proposed human B-1 cells reveals pre-plasmablast phenotype. Blood. 2013;121(26):5176–83.

    Article  CAS  PubMed  Google Scholar 

  95. Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015;42(4):607–12.

    Article  CAS  PubMed  Google Scholar 

  96. Flores-Borja F, Bosma A, Ng D, Reddy V, Ehrenstein MR, Isenberg DA, et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med. 2013;5(173):173ra23.

    Article  PubMed  CAS  Google Scholar 

  97. Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y, Kayama H, et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity. 2014;41(6):1040–51.

    Article  CAS  PubMed  Google Scholar 

  98. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221–41.

    Article  CAS  PubMed  Google Scholar 

  99. Maseda D, Smith SH, DiLillo DJ, Bryant JM, Candando KM, Weaver CT, et al. Regulatory B10 cells differentiate into antibody-secreting cells after transient IL-10 production in vivo. J Immunol. 2012;188(3):1036–48.

    Article  CAS  PubMed  Google Scholar 

  100. Pinto D, Montani E, Bolli M, Garavaglia G, Sallusto F, Lanzavecchia A, et al. A functional BCR in human IgA and IgM plasma cells. Blood. 2013;121(20):4110–4.

    Article  CAS  PubMed  Google Scholar 

  101. Calame KL. Plasma cells: finding new light at the end of B cell development. Nat Immunol. 2001;2(12):1103–8.

    Article  CAS  PubMed  Google Scholar 

  102. Smith KG, Hewitson TD, Nossal GJ, Tarlinton DM. The phenotype and fate of the antibody-forming cells of the splenic foci. Eur J Immunol. 1996;26(2):444–8.

    Article  CAS  PubMed  Google Scholar 

  103. Smith KG, Light A, O’Reilly LA, Ang SM, Strasser A, Tarlinton D. bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells. J Exp Med. 2000;191(3):475–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Radbruch A, Muehlinghaus G, Luger EO, Inamine A, Smith KG, Dorner T, et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol. 2006;6(10):741–50.

    Article  CAS  PubMed  Google Scholar 

  105. Yu X, Tsibane T, McGraw PA, House FS, Keefer CJ, Hicar MD, et al. Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors. Nature. 2008;455(7212):532–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cassese G, Arce S, Hauser AE, Lehnert K, Moewes B, Mostarac M, et al. Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J Immunol. 2003;171(4):1684–90.

    Article  CAS  PubMed  Google Scholar 

  107. O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199(1):91–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Daha NA, Banda NK, Roos A, Beurskens FJ, Bakker JM, Daha MR, et al. Complement activation by (auto-) antibodies. Mol Immunol. 2011;48(14):1656–65.

    Article  CAS  PubMed  Google Scholar 

  109. Nimmerjahn F, Ravetch JV. Antibody-mediated modulation of immune responses. Immunol Rev. 2010;236:265–75.

    Article  CAS  PubMed  Google Scholar 

  110. Puttarajappa C, Shapiro R, Tan HP. Antibody-mediated rejection in kidney transplantation: a review. J Transplant. 2012;2012:193724.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Chih S, Chruscinski A, Ross HJ, Tinckam K, Butany J, Rao V. Antibody-mediated rejection: an evolving entity in heart transplantation. J Transplant. 2012;2012:210210.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Hachem R. Antibody-mediated lung transplant rejection. Curr Respir Care Rep. 2012;1(3):157–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hubscher SG. Antibody-mediated rejection in the liver allograft. Curr Opin Organ Transplant. 2012;17(3):280–6.

    CAS  PubMed  Google Scholar 

  114. Collins AB, Schneeberger EE, Pascual MA, Saidman SL, Williams WW, Tolkoff-Rubin N, et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol. 1999;10(10):2208–14.

    CAS  PubMed  Google Scholar 

  115. Magro CM, Pope Harman A, Klinger D, Orosz C, Adams P, Waldman J, et al. Use of C4d as a diagnostic adjunct in lung allograft biopsies. Am J Transplant. 2003;3(9):1143–54.

    Article  CAS  PubMed  Google Scholar 

  116. Rodriguez ER, Skojec DV, Tan CD, Zachary AA, Kasper EK, Conte JV, et al. Antibody-mediated rejection in human cardiac allografts: evaluation of immunoglobulins and complement activation products C4d and C3d as markers. Am J Transplant. 2005;5(11):2778–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Sis B, Grynoch R, Murray AG, Campbell P, Solez K. Antibody-mediated rejection with a striking interstitial monocyte/macrophage infiltration in a renal allograft under FTY720 treatment. Am J Kidney Dis. 2008;51(1):127–30.

    Article  CAS  PubMed  Google Scholar 

  118. Fedrigo M, Feltrin G, Poli F, Frigo AC, Benazzi E, Gambino A, et al. Intravascular macrophages in cardiac allograft biopsies for diagnosis of early and late antibody-mediated rejection. J Heart Lung Transplant. 2013;32(4):404–9.

    Article  PubMed  Google Scholar 

  119. Burns AM, Chong AS. Alloantibodies prevent the induction of transplantation tolerance by enhancing alloreactive T cell priming. J Immunol. 2011;186(1):214–21.

    Article  CAS  PubMed  Google Scholar 

  120. Hippen BE, DeMattos A, Cook WJ, Kew 2nd CE, Gaston RS. Association of CD20+ infiltrates with poorer clinical outcomes in acute cellular rejection of renal allografts. Am J Transplant. 2005;5(9):2248–52.

    Article  PubMed  Google Scholar 

  121. Tsai EW, Rianthavorn P, Gjertson DW, Wallace WD, Reed EF, Ettenger RB. CD20+ lymphocytes in renal allografts are associated with poor graft survival in pediatric patients. Transplantation. 2006;82(12):1769–73.

    Article  PubMed  Google Scholar 

  122. Noorchashm H, Reed AJ, Rostami SY, Mozaffari R, Zekavat G, Koeberlein B, et al. B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J Immunol. 2006;177(11):7715–22.

    Article  CAS  PubMed  Google Scholar 

  123. Heller F, Lindenmeyer MT, Cohen CD, Brandt U, Draganovici D, Fischereder M, et al. The contribution of B cells to renal interstitial inflammation. Am J Pathol. 2007;170(2):457–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343(1):227–35.

    Article  CAS  PubMed  Google Scholar 

  125. Mold C, Gewurz H, Du Clos TW. Regulation of complement activation by C-reactive protein. Immunopharmacology. 1999;42(1-3):23–30.

    Article  CAS  PubMed  Google Scholar 

  126. Ying SC, Gewurz AT, Jiang H, Gewurz H. Human serum amyloid P component oligomers bind and activate the classical complement pathway via residues 14-26 and 76-92 of the A chain collagen-like region of C1q. J Immunol. 1993;150(1):169–76.

    CAS  PubMed  Google Scholar 

  127. Sacks SH, Zhou W. The role of complement in the early immune response to transplantation. Nat Rev Immunol. 2012;12(6):431–42.

    Article  CAS  PubMed  Google Scholar 

  128. Farrar CA, Zhou W, Lin T, Sacks SH. Local extravascular pool of C3 is a determinant of postischemic acute renal failure. FASEB J. 2006;20(2):217–26.

    Article  CAS  PubMed  Google Scholar 

  129. Naesens M, Li L, Ying L, Sansanwal P, Sigdel TK, Hsieh SC, et al. Expression of complement components differs between kidney allografts from living and deceased donors. J Am Soc Nephrol. 2009;20(8):1839–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med. 2002;8(6):582–7.

    Article  CAS  PubMed  Google Scholar 

  131. Pavlov V, Raedler H, Yuan S, Leisman S, Kwan WH, Lalli PN, et al. Donor deficiency of decay-accelerating factor accelerates murine T cell-mediated cardiac allograft rejection. J Immunol. 2008;181(7):4580–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Muller TF, Kraus M, Neumann C, Lange H. Detection of renal allograft rejection by complement components C5A and TCC in plasma and urine. J Lab Clin Med. 1997;129(1):62–71.

    Article  CAS  PubMed  Google Scholar 

  133. Keslar K, Rodriguez ER, Tan CD, Starling RC, Heeger PS. Complement gene expression in human cardiac allograft biopsies as a correlate of histologic grade of injury. Transplantation. 2008;86(9):1319–21.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Damman J, Seelen MA, Moers C, Daha MR, Rahmel A, Leuvenink HG, et al. Systemic complement activation in deceased donors is associated with acute rejection after renal transplantation in the recipient. Transplantation. 2011;92(2):163–9.

    Article  CAS  PubMed  Google Scholar 

  135. Massoud O, Heimbach J, Viker K, Krishnan A, Poterucha J, Sanchez W, et al. Noninvasive diagnosis of acute cellular rejection in liver transplant recipients: a proteomic signature validated by enzyme-linked immunosorbent assay. Liver Transpl. 2011;17(6):723–32.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Kemper C, Atkinson JP. T-cell regulation: with complements from innate immunity. Nat Rev Immunol. 2007;7(1):9–18.

    Article  CAS  PubMed  Google Scholar 

  137. Marsh JE, Farmer CK, Jurcevic S, Wang Y, Carroll MC, Sacks SH. The allogeneic T and B cell response is strongly dependent on complement components C3 and C4. Transplantation. 2001;72(7):1310–8.

    Article  CAS  PubMed  Google Scholar 

  138. Carroll MC. The complement system in B cell regulation. Mol Immunol. 2004;41(2-3):141–6.

    Article  CAS  PubMed  Google Scholar 

  139. Colvin RB, Smith RN. Antibody-mediated organ-allograft rejection. Nat Rev Immunol. 2005;5(10):807–17.

    Article  CAS  PubMed  Google Scholar 

  140. Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8(4):753–60.

    Article  CAS  PubMed  Google Scholar 

  141. Stewart S, Winters GL, Fishbein MC, Tazelaar HD, Kobashigawa J, Abrams J, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005;24(11):1710–20.

    Article  PubMed  Google Scholar 

  142. Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011;11(11):2405–13.

    Article  CAS  PubMed  Google Scholar 

  143. Chopek MW, Simmons RL, Platt JL. ABO-incompatible kidney transplantation: initial immunopathologic evaluation. Transplant Proc. 1987;19(6):4553–7.

    CAS  PubMed  Google Scholar 

  144. Park WD, Grande JP, Ninova D, Nath KA, Platt JL, Gloor JM, et al. Accommodation in ABO-incompatible kidney allografts, a novel mechanism of self-protection against antibody-mediated injury. Am J Transplant. 2003;3(8):952–60.

    Article  CAS  PubMed  Google Scholar 

  145. Lynch RJ, Platt JL. Accommodation in organ transplantation. Curr Opin Organ Transplant. 2008;13(2):165–70.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511.

    Article  CAS  PubMed  Google Scholar 

  147. Alegre ML, Goldstein DR, Chong AS. Toll-like receptor signaling in transplantation. Curr Opin Organ Transplant. 2008;13(4):358–65.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Arumugam TV, Okun E, Tang SC, Thundyil J, Taylor SM, Woodruff TM. Toll-like receptors in ischemia/reperfusion injury. Shock. 2009;32(1):4–16.

    Article  CAS  PubMed  Google Scholar 

  149. Kruger B, Krick S, Dhillon N, Lerner SM, Ames S, Bromberg JS, et al. Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc Natl Acad Sci U S A. 2009;106(9):3390–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Dhillon N, Walsh L, Kruger B, Ward SC, Godbold JH, Radwan M, et al. A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation. J Hepatol. 2010;53(1):67–72.

    Article  CAS  PubMed  Google Scholar 

  151. Thornley TB, Brehm MA, Markees TG, Shultz LD, Mordes JP, Welsh RM, et al. TLR agonists abrogate costimulation blockade-induced prolongation of skin allografts. J Immunol. 2006;176(3):1561–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chen L, Wang T, Zhou P, Ma L, Yin D, Shen J, et al. TLR engagement prevents transplantation tolerance. Am J Transplant. 2006;6(10):2282–91.

    Article  CAS  PubMed  Google Scholar 

  153. Walker WE, Nasr IW, Camirand G, Tesar BM, Booth CJ, Goldstein DR. Absence of innate MyD88 signaling promotes inducible allograft acceptance. J Immunol. 2006;177(8):5307–16.

    Article  CAS  PubMed  Google Scholar 

  154. Goldstein DR, Tesar BM, Akira S, Lakkis FG. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest. 2003;111(10):1571–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Tesar BM, Zhang J, Li Q, Goldstein DR. TH1 immune responses to fully MHC mismatched allografts are diminished in the absence of MyD88, a toll-like receptor signal adaptor protein. Am J Transplant. 2004;4(9):1429–39.

    Article  CAS  PubMed  Google Scholar 

  156. Testro AG, Visvanathan K, Skinner N, Markovska V, Crowley P, Angus PW, et al. Acute allograft rejection in human liver transplant recipients is associated with signaling through toll-like receptor 4. J Gastroenterol Hepatol. 2011;26(1):155–63.

    Article  CAS  PubMed  Google Scholar 

  157. Palmer SM, Burch LH, Trindade AJ, Davis RD, Herczyk WF, Reinsmoen NL, et al. Innate immunity influences long-term outcomes after human lung transplant. Am J Respir Crit Care Med. 2005;171(7):780–5.

    Article  PubMed  Google Scholar 

  158. Shi HZ. Eosinophils function as antigen-presenting cells. J Leukoc Biol. 2004;76(3):520–7.

    Article  CAS  PubMed  Google Scholar 

  159. Hogan SP, Rosenberg HF, Moqbel R, Phipps S, Foster PS, Lacy P, et al. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy. 2008;38(5):709–50.

    Article  CAS  PubMed  Google Scholar 

  160. Maddur MS, Kaveri SV, Bayry J. Basophils as antigen presenting cells. Trends Immunol. 2010;31(2):45–8.

    Article  CAS  PubMed  Google Scholar 

  161. Abi Abdallah DS, Egan CE, Butcher BA, Denkers EY. Mouse neutrophils are professional antigen-presenting cells programmed to instruct Th1 and Th17 T-cell differentiation. Int Immunol. 2011;23(5):317–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Chirumbolo S. State-of-the-art review about basophil research in immunology and allergy: is the time right to treat these cells with the respect they deserve? Blood Transfus. 2012;10(2):148–64.

    PubMed  PubMed Central  Google Scholar 

  163. Tecchio C, Cassatella MA. Neutrophil-derived cytokines: facts beyond expression [Mini Review]. Front Immunol. 2014;21:5.

    Google Scholar 

  164. Mayadas TN, Cullere X, Lowell CA. The multifaceted functions of neutrophils. Annu Rev Pathol. 2014;9:181–218.

    Article  CAS  PubMed  Google Scholar 

  165. Kreisel D, Nava RG, Li W, Zinselmeyer BH, Wang B, Lai J, et al. In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. Proc Natl Acad Sci U S A. 2010;107(42):18073–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Li W, Nava RG, Bribriesco AC, Zinselmeyer BH, Spahn JH, Gelman AE, et al. Intravital 2-photon imaging of leukocyte trafficking in beating heart. J Clin Invest. 2012;122(7):2499–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. DeNicola MM, Weigt SS, Belperio JA, Reed EF, Ross DJ, Wallace WD. Pathologic findings in lung allografts with anti-HLA antibodies. J Heart Lung Transplant. 2013;32(3):326–32.

    Article  PubMed  Google Scholar 

  168. Kreisel D, Sugimoto S, Zhu J, Nava R, Li W, Okazaki M, et al. Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance. Blood. 2011;118(23):6172–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Yamamoto S, Nava RG, Zhu J, Huang HJ, Ibrahim M, Mohanakumar T, et al. Cutting edge: Pseudomonas aeruginosa abolishes established lung transplant tolerance by stimulating B7 expression on neutrophils. J Immunol. 2012;189(9):4221–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S73–80.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Yousem SA. Graft eosinophilia in lung transplantation. Hum Pathol. 1992;23(10):1172–7.

    Article  CAS  PubMed  Google Scholar 

  172. Martinez OM, Ascher NL, Ferrell L, Villanueva J, Lake J, Roberts JP, et al. Evidence for a nonclassical pathway of graft rejection involving interleukin 5 and eosinophils. Transplantation. 1993;55(4):909–18.

    Article  CAS  PubMed  Google Scholar 

  173. Nolan CR, Saenz KP, Thomas 3rd CA, Murphy KD. Role of the eosinophil in chronic vascular rejection of renal allografts. Am J Kidney Dis. 1995;26(4):634–42.

    Article  CAS  PubMed  Google Scholar 

  174. Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature. 2006;442(7106):997–1002.

    Article  CAS  PubMed  Google Scholar 

  175. de Vries VC, Elgueta R, Lee DM, Noelle RJ. Mast cell protease 6 is required for allograft tolerance. Transplant Proc. 2010;42(7):2759–62.

    Article  PubMed  CAS  Google Scholar 

  176. de Vries VC, Wasiuk A, Bennett KA, Benson MJ, Elgueta R, Waldschmidt TJ, et al. Mast cell degranulation breaks peripheral tolerance. Am J Transplant. 2009;9(10):2270–80.

    Article  PubMed  CAS  Google Scholar 

  177. Serbina NV, Jia T, Hohl TM, Pamer EG. Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol. 2008;26:421–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Saha P, Geissmann F. Toward a functional characterization of blood monocytes. Immunol Cell Biol. 2011;89(1):2–4.

    Article  PubMed  Google Scholar 

  179. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.

    Article  CAS  PubMed  Google Scholar 

  180. Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116(16):e74–80.

    Article  CAS  PubMed  Google Scholar 

  181. Wong KL, Yeap WH, Tai JJ, Ong SM, Dang TM, Wong SC. The three human monocyte subsets: implications for health and disease. Immunol Res. 2012;53(1-3):41–57.

    Article  CAS  PubMed  Google Scholar 

  182. Zhang PL, Malek SK, Prichard JW, Lin F, Yahya TM, Schwartzman MS, et al. Acute cellular rejection predominated by monocytes is a severe form of rejection in human renal recipients with or without Campath-1H (alemtuzumab) induction therapy. Am J Transplant. 2005;5(3):604–7.

    Article  CAS  PubMed  Google Scholar 

  183. Girlanda R, Kleiner DE, Duan Z, Ford EA, Wright EC, Mannon RB, et al. Monocyte infiltration and kidney allograft dysfunction during acute rejection. Am J Transplant. 2008;8(3):600–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Fang YS, Zhu LM, Sun ZG, Yu LZ, Xu H. Tumor necrosis factor-alpha pathway plays a critical role in regulating interferon-gamma induced protein-10 production in initial allogeneic human monocyte-endothelial cell interactions. Transplant Proc. 2012;44(4):993–5.

    Article  CAS  PubMed  Google Scholar 

  185. Oberbarnscheidt MH, Zeng Q, Li Q, Dai H, Williams AL, Shlomchik WD, et al. Non-self recognition by monocytes initiates allograft rejection. J Clin Invest. 2014;124(8):3579–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Valenzuela NM, Mulder A, Reed EF. HLA class I antibodies trigger increased adherence of monocytes to endothelial cells by eliciting an increase in endothelial P-selectin, and depending on subclass, by engaging FcgammaRs. J Immunol. 2013;190(12):6635–50.

    Article  CAS  PubMed  Google Scholar 

  187. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11(11):723–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Mannon RB. Macrophages: contributors to allograft dysfunction, repair, or innocent bystanders? Curr Opin Organ Transplant. 2012;17(1):20–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Jiang X, Tian W, Sung YK, Qian J, Nicolls MR. Macrophages in solid organ transplantation. Vasc Cell. 2014;6(1):5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Merry HE, Phelan P, Doak MR, Zhao M, Hwang B, Mulligan MS. Role of toll-like receptor-4 in lung ischemia/reperfusion injury. Ann Thorac Surg. 2015;99(4):1193–9.

    Article  PubMed  Google Scholar 

  192. Wyburn KR, Jose MD, Wu H, Atkins RC, Chadban SJ. The role of macrophages in allograft rejection. Transplantation. 2005;80(12):1641–7.

    Article  PubMed  Google Scholar 

  193. Magil AB. Monocytes/macrophages in renal allograft rejection. Transplant Rev (Orlando). 2009;23(4):199–208.

    Article  Google Scholar 

  194. Fishbein GA, Fishbein MC. Morphologic and immunohistochemical findings in antibody-mediated rejection of the cardiac allograft. Hum Immunol. 2012;73(12):1213–7.

    Article  CAS  PubMed  Google Scholar 

  195. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Broichhausen C, Riquelme P, Geissler EK, Hutchinson JA. Regulatory macrophages as therapeutic targets and therapeutic agents in solid organ transplantation. Curr Opin Organ Transplant. 2012;17(4):332–42.

    CAS  PubMed  Google Scholar 

  197. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811.

    Article  CAS  PubMed  Google Scholar 

  198. Ueno H, Schmitt N, Klechevsky E, Pedroza-Gonzalez A, Matsui T, Zurawski G, et al. Harnessing human dendritic cell subsets for medicine. Immunol Rev. 2010;234(1):199–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013;31:563–604.

    Article  CAS  PubMed  Google Scholar 

  200. Coquerelle C, Moser M. DC subsets in positive and negative regulation of immunity. Immunol Rev. 2010;234(1):317–34.

    Article  CAS  PubMed  Google Scholar 

  201. Lechler R, Ng WF, Steinman RM. Dendritic cells in transplantation—friend or foe? Immunity. 2001;14(4):357–68.

    Article  CAS  PubMed  Google Scholar 

  202. Josien R, Heslan M, Brouard S, Soulillou JP, Cuturi MC. Critical requirement for graft passenger leukocytes in allograft tolerance induced by donor blood transfusion. Blood. 1998;92(12):4539–44.

    CAS  PubMed  Google Scholar 

  203. Ueno T, Tanaka K, Jurewicz M, Murayama T, Guleria I, Fiorina P, et al. Divergent role of donor dendritic cells in rejection versus tolerance of allografts. J Am Soc Nephrol. 2009;20(3):535–44.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Garrovillo M, Ali A, Oluwole SF. Indirect allorecognition in acquired thymic tolerance: induction of donor-specific tolerance to rat cardiac allografts by allopeptide-pulsed host dendritic cells. Transplantation. 1999;68(12):1827–34.

    Article  CAS  PubMed  Google Scholar 

  205. Beriou G, Peche H, Guillonneau C, Merieau E, Cuturi MC. Donor-specific allograft tolerance by administration of recipient-derived immature dendritic cells and suboptimal immunosuppression. Transplantation. 2005;79(8):969–72.

    Article  CAS  PubMed  Google Scholar 

  206. van Nierop K, de Groot C. Human follicular dendritic cells: function, origin and development. Semin Immunol. 2002;14(4):251–7.

    Article  PubMed  CAS  Google Scholar 

  207. Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22(11):633–40.

    Article  CAS  PubMed  Google Scholar 

  209. Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23:225–74.

    Article  CAS  PubMed  Google Scholar 

  210. Ito A, Shimura H, Nitahara A, Tomiyama K, Ito M, Kanekura T, et al. NK cells contribute to the skin graft rejection promoted by CD4+ T cells activated through the indirect allorecognition pathway. Int Immunol. 2008;20(10):1343–9.

    Article  CAS  PubMed  Google Scholar 

  211. Sorrentino C, Scarinci A, D’Antuono T, Piccirilli M, Di Nicola M, Pasquale M, et al. Endomyocardial infiltration by B and NK cells foreshadows the recurrence of cardiac allograft rejection. J Pathol. 2006;209(3):400–10.

    Article  CAS  PubMed  Google Scholar 

  212. Uehara S, Chase CM, Kitchens WH, Rose HS, Colvin RB, Russell PS, et al. NK cells can trigger allograft vasculopathy: the role of hybrid resistance in solid organ allografts. J Immunol. 2005;175(5):3424–30.

    Article  CAS  PubMed  Google Scholar 

  213. Fildes JE, Yonan N, Tunstall K, Walker AH, Griffiths-Davies L, Bishop P, et al. Natural killer cells in peripheral blood and lung tissue are associated with chronic rejection after lung transplantation. J Heart Lung Transplant. 2008;27(2):203–7.

    Article  PubMed  Google Scholar 

  214. Kroemer A, Xiao X, Degauque N, Edtinger K, Wei H, Demirci G, et al. The innate NK cells, allograft rejection, and a key role for IL-15. J Immunol. 2008;180(12):7818–26.

    Article  CAS  PubMed  Google Scholar 

  215. Kummer JA, Wever PC, Kamp AM, ten Berge IJ, Hack CE, Weening JJ. Expression of granzyme A and B proteins by cytotoxic lymphocytes involved in acute renal allograft rejection. Kidney Int. 1995;47(1):70–7.

    Article  CAS  PubMed  Google Scholar 

  216. Kondo T, Morita K, Watarai Y, Auerbach MB, Taub DD, Novick AC, et al. Early increased chemokine expression and production in murine allogeneic skin grafts is mediated by natural killer cells. Transplantation. 2000;69(5):969–77.

    Article  CAS  PubMed  Google Scholar 

  217. Obara H, Nagasaki K, Hsieh CL, Ogura Y, Esquivel CO, Martinez OM, et al. IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses. Am J Transplant. 2005;5(9):2094–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. McNerney ME, Lee KM, Zhou P, Molinero L, Mashayekhi M, Guzior D, et al. Role of natural killer cell subsets in cardiac allograft rejection. Am J Transplant. 2006;6(3):505–13.

    Article  CAS  PubMed  Google Scholar 

  219. Hirohashi T, Chase CM, Della Pelle P, Sebastian D, Alessandrini A, Madsen JC, et al. A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant. 2012;12(2):313–21.

    Article  CAS  PubMed  Google Scholar 

  220. Hidalgo LG, Sis B, Sellares J, Campbell PM, Mengel M, Einecke G, et al. 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. 2010;10(8):1812–22.

    Article  CAS  PubMed  Google Scholar 

  221. Yu G, Xu X, Vu MD, Kilpatrick ED, Li XC. NK cells promote transplant tolerance by killing donor antigen-presenting cells. J Exp Med. 2006;203(8):1851–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Laffont S, Seillet C, Ortaldo J, Coudert JD, Guery JC. Natural killer cells recruited into lymph nodes inhibit alloreactive T-cell activation through perforin-mediated killing of donor allogeneic dendritic cells. Blood. 2008;112(3):661–71.

    Article  CAS  PubMed  Google Scholar 

  223. Zecher D, Li Q, Oberbarnscheidt MH, Demetris AJ, Shlomchik WD, Rothstein DM, et al. NK cells delay allograft rejection in lymphopenic hosts by downregulating the homeostatic proliferation of CD8+ T cells. J Immunol. 2010;184(12):6649–57.

    Article  CAS  PubMed  Google Scholar 

  224. Deniz G, Erten G, Kucuksezer UC, Kocacik D, Karagiannidis C, Aktas E, et al. Regulatory NK cells suppress antigen-specific T cell responses. J Immunol. 2008;180(2):850–7.

    Article  CAS  PubMed  Google Scholar 

  225. Ahmed R, Gray D. Immunological memory and protective immunity: understanding their relation. Science. 1996;272(5258):54–60.

    Article  CAS  PubMed  Google Scholar 

  226. Netea MG. Training innate immunity: the changing concept of immunological memory in innate host defence. Eur J Clin Invest. 2013;43(8):881–4.

    Article  CAS  PubMed  Google Scholar 

  227. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63.

    Article  CAS  PubMed  Google Scholar 

  228. Schluns KS, Lefrancois L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol. 2003;3(4):269–79.

    Article  CAS  PubMed  Google Scholar 

  229. Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol. 2015;15(3):149–59.

    Article  CAS  PubMed  Google Scholar 

  230. Wu YC, Kipling D, Dunn-Walters DK. The relationship between CD27 negative and positive B cell populations in human peripheral blood. Front Immunol. 2011;2:81.

    Article  PubMed  PubMed Central  Google Scholar 

  231. Maruyama M, Lam KP, Rajewsky K. Memory B-cell persistence is independent of persisting immunizing antigen. Nature. 2000;407(6804):636–42.

    Article  CAS  PubMed  Google Scholar 

  232. Taylor DK, Neujahr D, Turka LA. Heterologous immunity and homeostatic proliferation as barriers to tolerance. Curr Opin Immunol. 2004;16(5):558–64.

    Article  CAS  PubMed  Google Scholar 

  233. Lakkis FG, Sayegh MH. Memory T cells: a hurdle to immunologic tolerance. J Am Soc Nephrol. 2003;14(9):2402–10.

    Article  PubMed  Google Scholar 

  234. Heeger PS, Greenspan NS, Kuhlenschmidt S, Dejelo C, Hricik DE, Schulak JA, et al. Pretransplant frequency of donor-specific, IFN-gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. J Immunol. 1999;163(4):2267–75.

    CAS  PubMed  Google Scholar 

  235. Chalasani G, Dai Z, Konieczny BT, Baddoura FK, Lakkis FG. Recall and propagation of allospecific memory T cells independent of secondary lymphoid organs. Proc Natl Acad Sci U S A. 2002;99(9):6175–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Burns JM, Cornell LD, Perry DK, Pollinger HS, Gloor JM, Kremers WK, et al. Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation. Am J Transplant. 2008;8(12):2684–94.

    Article  CAS  PubMed  Google Scholar 

  237. Chong AS, Sciammas R. Memory B cells in transplantation. Transplantation. 2015;99(1):21–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Page AJ, Ford ML, Kirk AD. Memory T-cell-specific therapeutics in organ transplantation. Curr Opin Organ Transplant. 2009;14(6):643–9.

    Article  PubMed  PubMed Central  Google Scholar 

  239. Clatworthy MR. Targeting B, cells and antibody in transplantation. Am J Transplant. 2011;11(7):1359–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Ball LM, Egeler RM. Acute GvHD: pathogenesis and classification. Bone Marrow Transplant. 2008;41 Suppl 2:S58–64.

    Article  CAS  PubMed  Google Scholar 

  241. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012;12(6):443–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000;95(9):2754–9.

    CAS  PubMed  Google Scholar 

  243. Couriel DR, Saliba RM, Giralt S, Khouri I, Andersson B, de Lima M, et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant. 2004;10(3):178–85.

    Article  PubMed  Google Scholar 

  244. Matte CC, Liu J, Cormier J, Anderson BE, Athanasiadis I, Jain D, et al. Donor APCs are required for maximal GvHD but not for GVL. Nat Med. 2004;10(9):987–92.

    Article  CAS  PubMed  Google Scholar 

  245. Duffner UA, Maeda Y, Cooke KR, Reddy P, Ordemann R, Liu C, et al. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. J Immunol. 2004;172(12):7393–8.

    Article  CAS  PubMed  Google Scholar 

  246. Koyama M, Kuns RD, Olver SD, Raffelt NC, Wilson YA, Don AL, et al. Recipient nonhematopoietic antigen-presenting cells are sufficient to induce lethal acute graft-versus-host disease. Nat Med. 2012;18(1):135–42.

    Article  CAS  Google Scholar 

  247. Schmaltz C, Alpdogan O, Horndasch KJ, Muriglan SJ, Kappel BJ, Teshima T, et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood. 2001;97(9):2886–95.

    Article  CAS  PubMed  Google Scholar 

  248. Wasem C, Frutschi C, Arnold D, Vallan C, Lin T, Green DR, et al. Accumulation and activation-induced release of preformed Fas (CD95) ligand during the pathogenesis of experimental graft-versus-host disease. J Immunol. 2001;167(5):2936–41.

    Article  CAS  PubMed  Google Scholar 

  249. Min CK. The pathophysiology of chronic graft-versus-host disease: the unveiling of an enigma. Korean J Hematol. 2011;46(2):80–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. De Wit D, Van Mechelen M, Zanin C, Doutrelepont JM, Velu T, Gerard C, et al. Preferential activation of Th2 cells in chronic graft-versus-host reaction. J Immunol. 1993;150(2):361–6.

    PubMed  Google Scholar 

  251. Imanguli MM, Swaim WD, League SC, Gress RE, Pavletic SZ, Hakim FT. Increased T-bet+ cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa. Blood. 2009;113(15):3620–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Jacobsohn DA, Schechter T, Seshadri R, Thormann K, Duerst R, Kletzel M. Eosinophilia correlates with the presence or development of chronic graft-versus-host disease in children. Transplantation. 2004;77(7):1096–100.

    Article  PubMed  Google Scholar 

  253. Patriarca F, Skert C, Sperotto A, Zaja F, Falleti E, Mestroni R, et al. The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery. Exp Hematol. 2006;34(3):389–96.

    Article  CAS  PubMed  Google Scholar 

  254. Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ, et al. High levels of B-cell activating factor in patients with active chronic graft-versus-host disease. Clin Cancer Res. 2007;13(20):6107–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Ratanatharathorn V, Ayash L, Lazarus HM, Fu J, Uberti JP. Chronic graft-versus-host disease: clinical manifestation and therapy. Bone Marrow Transplant. 2001;28(2):121–9.

    Article  CAS  PubMed  Google Scholar 

  256. Truitt RL, Atasoylu AA. Contribution of CD4+ and CD8+ T cells to graft-versus-host disease and graft-versus-leukemia reactivity after transplantation of MHC-compatible bone marrow. Bone Marrow Transplant. 1991;8(1):51–8.

    CAS  PubMed  Google Scholar 

  257. Chakraverty R, Eom HS, Sachs J, Buchli J, Cotter P, Hsu R, et al. Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood. 2006;108(6):2106–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Apperley JF, Mauro FR, Goldman JM, Gregory W, Arthur CK, Hows J, et al. Bone marrow transplantation for chronic myeloid leukaemia in first chronic phase: importance of a graft-versus-leukaemia effect. Br J Haematol. 1988;69(2):239–45.

    Article  CAS  PubMed  Google Scholar 

  259. Ringden O, Karlsson H, Olsson R, Omazic B, Uhlin M. The allogeneic graft-versus-cancer effect. Br J Haematol. 2009;147(5):614–33.

    Article  PubMed  Google Scholar 

  260. Parham P, McQueen KL. Alloreactive killer cells: hindrance and help for haematopoietic transplants. Nat Rev Immunol. 2003;3(2):108–22.

    Article  CAS  PubMed  Google Scholar 

  261. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295(5562):2097–100.

    Article  CAS  PubMed  Google Scholar 

  262. Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat Rev Immunol. 2005;5(10):772–82.

    Article  CAS  PubMed  Google Scholar 

  263. Pelanda R, Torres RM. Central B-cell tolerance: where selection begins. Cold Spring Harb Perspect Biol. 2012;4(4):a007146.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  264. Mueller DL. Mechanisms maintaining peripheral tolerance. Nat Immunol. 2010;11(1):21–7.

    Article  CAS  PubMed  Google Scholar 

  265. Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science. 1945;102(2651):400–1.

    Article  CAS  PubMed  Google Scholar 

  266. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. 1953;172(4379):603–6.

    Article  CAS  PubMed  Google Scholar 

  267. Brent L. The discovery of immunologic tolerance. Hum Immunol. 1997;52(2):75–81.

    Article  CAS  PubMed  Google Scholar 

  268. Roussey-Kesler G, Giral M, Moreau A, Subra JF, Legendre C, Noel C, et al. Clinical operational tolerance after kidney transplantation. Am J Transplant. 2006;6(4):736–46.

    Article  CAS  PubMed  Google Scholar 

  269. Orlando G, Soker S, Wood K. Operational tolerance after liver transplantation. J Hepatol. 2009;50(6):1247–57.

    Article  PubMed  Google Scholar 

  270. Orlando G, Hematti P, Stratta RJ, Burke 3rd GW, Di Cocco P, Pisani F, et al. Clinical operational tolerance after renal transplantation: current status and future challenges. Ann Surg. 2010;252(6):915–28.

    Article  PubMed  PubMed Central  Google Scholar 

  271. Fudaba Y, Spitzer TR, Shaffer J, Kawai T, Fehr T, Delmonico F, et al. Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: in vivo and in vitro analyses. Am J Transplant. 2006;6(9):2121–33.

    Article  CAS  PubMed  Google Scholar 

  272. Strober S, Dhillon M, Schubert M, Holm B, Engleman E, Benike C, et al. Acquired immune tolerance to cadaveric renal allografts. A study of three patients treated with total lymphoid irradiation. N Engl J Med. 1989;321(1):28–33.

    Article  CAS  PubMed  Google Scholar 

  273. Posselt AM, Barker CF, Tomaszewski JE, Markmann JF, Choti MA, Naji A. Induction of donor-specific unresponsiveness by intrathymic islet transplantation. Science. 1990;249(4974):1293–5.

    Article  CAS  PubMed  Google Scholar 

  274. Jones ND, Fluck NC, Roelen DL, Mellor AL, Morris PJ, Wood KJ. Deletion of alloantigen-reactive thymocytes as a mechanism of adult tolerance induction following intrathymic antigen administration. Eur J Immunol. 1997;27(7):1591–600.

    Article  CAS  PubMed  Google Scholar 

  275. Tomita Y, Khan A, Sykes M. Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantation in mice conditioned with a nonmyeloablative regimen. J Immunol. 1994;153(3):1087–98.

    CAS  PubMed  Google Scholar 

  276. Manilay JO, Pearson DA, Sergio JJ, Swenson KG, Sykes M. Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning regimen. Transplantation. 1998;66(1):96–102.

    Article  CAS  PubMed  Google Scholar 

  277. Wells AD, Li XC, Strom TB, Turka LA. The role of peripheral T-cell deletion in transplantation tolerance. Philos Trans R Soc Lond B Biol Sci. 2001;356(1409):617–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Yang YG, deGoma E, Ohdan H, Bracy JL, Xu Y, Iacomini J, et al. Tolerization of anti-Galalpha1-3Gal natural antibody-forming B cells by induction of mixed chimerism. J Exp Med. 1998;187(8):1335–42.

    Google Scholar 

  279. Fan X, Ang A, Pollock-Barziv SM, Dipchand AI, Ruiz P, Wilson G, et al. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nat Med. 2004;10(11):1227–33.

    Article  CAS  PubMed  Google Scholar 

  280. Wood KJ, Bushell A, Hester J. Regulatory immune cells in transplantation. Nat Rev Immunol. 2012;12(6):417–30.

    Article  CAS  PubMed  Google Scholar 

  281. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.

    Article  CAS  PubMed  Google Scholar 

  282. Rudensky AY. Regulatory T, cells and Foxp3. Immunol Rev. 2011;241(1):260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Lio CW, Hsieh CS. Becoming self-aware: the thymic education of regulatory T cells. Curr Opin Immunol. 2011;23(2):213–9.

    Article  CAS  PubMed  Google Scholar 

  284. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8(7):523–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Gorantla VS, Schneeberger S, Brandacher G, Sucher R, Zhang D, Lee WP, et al. T regulatory cells and transplantation tolerance. Transplant Rev (Orlando). 2010;24(3):147–59.

    Article  Google Scholar 

  286. Joffre O, Santolaria T, Calise D, Al Saati T, Hudrisier D, Romagnoli P, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med. 2008;14(1):88–92.

    Article  CAS  PubMed  Google Scholar 

  287. Trenado A, Charlotte F, Fisson S, Yagello M, Klatzmann D, Salomon BL, et al. Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest. 2003;112(11):1688–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Dijke IE, Weimar W, Baan CC. The control of anti-donor immune responses by regulatory T cells in organ transplant patients. Transplant Proc. 2008;40(5):1249–52.

    Article  CAS  PubMed  Google Scholar 

  289. Dijke IE, Weimar W, Baan CC. Regulatory T cells after organ transplantation: where does their action take place? Hum Immunol. 2008;69(7):389–98.

    Article  CAS  PubMed  Google Scholar 

  290. Muthukumar T, Dadhania D, Ding R, Snopkowski C, Naqvi R, Lee JB, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med. 2005;353(22):2342–51.

    Article  CAS  PubMed  Google Scholar 

  291. Yang J, Brook MO, Carvalho-Gaspar M, Zhang J, Ramon HE, Sayegh MH, et al. Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci U S A. 2007;104(50):19954–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol. 2007;25:297–336.

    Article  CAS  PubMed  Google Scholar 

  293. Yasunami Y, Kojo S, Kitamura H, Toyofuku A, Satoh M, Nakano M, et al. Valpha14 NK T cell-triggered IFN-gamma production by Gr-1+CD11b+ cells mediates early graft loss of syngeneic transplanted islets. J Exp Med. 2005;202(7):913–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Toyofuku A, Yasunami Y, Nabeyama K, Nakano M, Satoh M, Matsuoka N, et al. Natural killer T-cells participate in rejection of islet allografts in the liver of mice. Diabetes. 2006;55(1):34–9.

    Article  CAS  PubMed  Google Scholar 

  295. Ikehara Y, Yasunami Y, Kodama S, Maki T, Nakano M, Nakayama T, et al. CD4(+) Valpha14 natural killer T cells are essential for acceptance of rat islet xenografts in mice. J Clin Invest. 2000;105(12):1761–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Seino KI, Fukao K, Muramoto K, Yanagisawa K, Takada Y, Kakuta S, et al. Requirement for natural killer T (NKT) cells in the induction of allograft tolerance. Proc Natl Acad Sci U S A. 2001;98(5):2577–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Sonoda KH, Taniguchi M, Stein-Streilein J. Long-term survival of corneal allografts is dependent on intact CD1d-reactive NKT cells. J Immunol. 2002;168(4):2028–34.

    Article  CAS  PubMed  Google Scholar 

  298. Jiang X, Kojo S, Harada M, Ohkohchi N, Taniguchi M, Seino KI. Mechanism of NKT cell-mediated transplant tolerance. Am J Transplant. 2007;7(6):1482–90.

    Article  CAS  PubMed  Google Scholar 

  299. Chesneau M, Michel L, Degauque N, Brouard S. Regulatory B cells and tolerance in transplantation: from animal models to human. Front Immunol. 2013;4:497.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  300. Yan Y, van der Putten K, Bowen DG, Painter DM, Kohar J, Sharland AF, et al. Postoperative administration of donor B cells induces rat kidney allograft acceptance: lack of association with Th2 cytokine expression in long-term accepted grafts. Transplantation. 2002;73(7):1123–30.

    Article  CAS  PubMed  Google Scholar 

  301. Deng S, Moore DJ, Huang X, Lian MM, Mohiuddin M, Velededeoglu E, et al. Cutting edge: transplant tolerance induced by anti-CD45RB requires B lymphocytes. J Immunol. 2007;178(10):6028–32.

    Article  CAS  PubMed  Google Scholar 

  302. Lee KM, Kim JI, Stott R, Soohoo J, O’Connor MR, Yeh H, et al. Anti-CD45RB/anti-TIM-1-induced tolerance requires regulatory B cells. Am J Transplant. 2012;12(8):2072–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H, et al. Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest. 2011;121(9):3645–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Pallier A, Hillion S, Danger R, Giral M, Racape M, Degauque N, et al. Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype. Kidney Int. 2010;78(5):503–13.

    Article  CAS  PubMed  Google Scholar 

  305. Sagoo P, Perucha E, Sawitzki B, Tomiuk S, Stephens DA, Miqueu P, et al. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest. 2010;120(6):1848–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest. 2010;120(6):1836–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  307. Chesneau M, Pallier A, Braza F, Lacombe G, Le Gallou S, Baron D, et al. Unique B cell differentiation profile in tolerant kidney transplant patients. Am J Transplant. 2014;14(1):144–55.

    Article  CAS  PubMed  Google Scholar 

  308. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A. 2007;104(49):19446–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  309. Wong SC, Puaux AL, Chittezhath M, Shalova I, Kajiji TS, Wang X, et al. Macrophage polarization to a unique phenotype driven by B cells. Eur J Immunol. 2010;40(8):2296–307.

    Article  CAS  PubMed  Google Scholar 

  310. Hutchinson JA, Riquelme P, Sawitzki B, Tomiuk S, Miqueu P, Zuhayra M, et al. Cutting edge: immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol. 2011;187(5):2072–8.

    Article  CAS  PubMed  Google Scholar 

  311. Rastellini C, Lu L, Ricordi C, Starzl TE, Rao AS, Thomson AW. Granulocyte/macrophage colony-stimulating factor-stimulated hepatic dendritic cell progenitors prolong pancreatic islet allograft survival. Transplantation. 1995;60(11):1366–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  312. Fu F, Li Y, Qian S, Lu L, Chambers F, Starzl TE, et al. Costimulatory molecule-deficient dendritic cell progenitors (MHC class II+, CD80dim, CD86-) prolong cardiac allograft survival in nonimmunosuppressed recipients. Transplantation. 1996;62(5):659–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  313. Peche H, Trinite B, Martinet B, Cuturi MC. Prolongation of heart allograft survival by immature dendritic cells generated from recipient type bone marrow progenitors. Am J Transplant. 2005;5(2):255–67.

    Article  PubMed  Google Scholar 

  314. Lutz MB, Suri RM, Niimi M, Ogilvie AL, Kukutsch NA, Rossner S, et al. Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo. Eur J Immunol. 2000;30(7):1813–22.

    Article  CAS  PubMed  Google Scholar 

  315. Taner T, Hackstein H, Wang Z, Morelli AE, Thomson AW. Rapamycin-treated, alloantigen-pulsed host dendritic cells induce Ag-specific T cell regulation and prolong graft survival. Am J Transplant. 2005;5(2):228–36.

    Article  CAS  PubMed  Google Scholar 

  316. O’Flynn L, Treacy O, Ryan AE, Morcos M, Cregg M, Gerlach J, et al. Donor bone marrow-derived dendritic cells prolong corneal allograft survival and promote an intragraft immunoregulatory milieu. Mol Ther. 2013;21(11):2102–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  317. Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E, et al. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol. 2000;164(9):4443–51.

    Article  CAS  PubMed  Google Scholar 

  318. O’Connell PJ, Li W, Wang Z, Specht SM, Logar AJ, Thomson AW. Immature and mature CD8alpha+ dendritic cells prolong the survival of vascularized heart allografts. J Immunol. 2002;168(1):143–54.

    Article  PubMed  Google Scholar 

  319. Ezzelarab M, Thomson AW. Tolerogenic dendritic cells and their role in transplantation. Semin Immunol. 2011;23(4):252–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  320. Bjorck P, Coates PT, Wang Z, Duncan FJ, Thomson AW. Promotion of long-term heart allograft survival by combination of mobilized donor plasmacytoid dendritic cells and anti-CD154 monoclonal antibody. J Heart Lung Transplant. 2005;24(8):1118–20.

    Article  CAS  PubMed  Google Scholar 

  321. Abe M, Wang Z, de Creus A, Thomson AW. Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival. Am J Transplant. 2005;5(8):1808–19.

    Article  CAS  PubMed  Google Scholar 

  322. Ochando JC, Homma C, Yang Y, Hidalgo A, Garin A, Tacke F, et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol. 2006;7(6):652–62.

    Article  CAS  PubMed  Google Scholar 

  323. Mazariegos GV, Zahorchak AF, Reyes J, Ostrowski L, Flynn B, Zeevi A, et al. Dendritic cell subset ratio in peripheral blood correlates with successful withdrawal of immunosuppression in liver transplant patients. Am J Transplant. 2003;3(6):689–96.

    Article  PubMed  Google Scholar 

  324. Tokita D, Mazariegos GV, Zahorchak AF, Chien N, Abe M, Raimondi G, et al. High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance. Transplantation. 2008;85(3):369–77.

    Article  PubMed  Google Scholar 

  325. Moreau A, Varey E, Bouchet-Delbos L, Cuturi MC. Cell therapy using tolerogenic dendritic cells in transplantation. Transplant Res. 2012;1(1):13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  326. Boros P, Ochando JC, Chen SH, Bromberg JS. Myeloid-derived suppressor cells: natural regulators for transplant tolerance. Hum Immunol. 2010;71(11):1061–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  327. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 2006;66(2):1123–31.

    Article  CAS  PubMed  Google Scholar 

  328. Centuori SM, Trad M, LaCasse CJ, Alizadeh D, Larmonier CB, Hanke NT, et al. Myeloid-derived suppressor cells from tumor-bearing mice impair TGF-beta-induced differentiation of CD4+CD25+FoxP3+ Tregs from CD4+CD25-FoxP3- T cells. J Leukoc Biol. 2012;92(5):987–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  329. Dugast AS, Haudebourg T, Coulon F, Heslan M, Haspot F, Poirier N, et al. Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J Immunol. 2008;180(12):7898–906.

    Article  CAS  PubMed  Google Scholar 

  330. Garcia MR, Ledgerwood L, Yang Y, Xu J, Lal G, Burrell B, et al. Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice. J Clin Invest. 2010;120(7):2486–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The author wishes to thank Dr. Bruce Motyka, Dr. Luis Hidalgo, Dr. Tereza Martinu, Anne Halpin, and Henno van Gemeren for critical reading and editing of this chapter and Dr. Lori West for her support. IED is supported by the Canadian Institutes of Health Research (CIHR) through the Canadian National Transplant Research Program.

Author information

Authors and Affiliations

  1. Department of Pediatrics/Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada

    I. Esme Dijke Ph.D.

Authors
  1. I. Esme Dijke Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. Esme Dijke Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Pathology, McGill University and McGill University Health Center, Montreal, Québec, Canada

    René P. Michel

  2. Department of Pathology, Stanford University Medical Center, Stanford, California, USA

    Gerald J. Berry

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Dijke, I.E. (2016). Immunobiology of Transplantation. In: Michel, R., Berry, G. (eds) Pathology of Transplantation. Springer, Cham. https://doi.org/10.1007/978-3-319-29683-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-29683-8_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-29681-4

  • Online ISBN: 978-3-319-29683-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation