Review
Humoral immunity in chronic allograft rejection: Puzzle pieces come together

https://doi.org/10.1016/j.trim.2011.11.003Get rights and content

Abstract

Modern immunosuppressive armamentarium inadequately controls the humoral arm of recipient immune response, which in turn plays a central role in the pathogenesis of chronic rejection, a major cause of late allograft failure.

A consensus sequence has progressively emerged from the integration of both experimental and clinical data, in which the binding of circulating donor-specific antibodies to mismatched HLA molecules expressed by graft microvasculature leads to chronic inflammation and progressive tissue destruction.

Recent data suggest however that beyond their role in antibody production, B cells are also endowed with critical, yet overlooked, antibody-independent functions. Their abilities to present antigens and drive lymphoid neogenesis within rejected organ place them at the center of immune regulation with the power to enhance or inhibit antigraft immunity.

The key challenges for the next few years will be to learn how these conceptual progresses can be translated into innovative B cell-targeting therapies to improve long-term allograft outcome.

Highlights

► Humoral response plays a central role in the pathogenesis of chronic rejection. ► Alloantibody binding to graft microvasculature leads to microvascular inflammation. ► B cells present alloantigens to T cells within the graft, which amplifies rejection. ► A local humoral response develops in intragraft tertiary lymphoid tissue. ► B cells can participate in allograft tolerance.

Introduction

Progresses achieved over the last two decades have only marginally improved the long-term outcome of transplanted organs, as demonstrated by the stagnation of graft attrition rate beyond the first year post-transplantation [1], [2].

Among the main cause of late allograft failure is chronic rejection, which results from the inadequate control of the recipient immune response. Indeed, unlike T cells, which have progressively come under pharmacologic control, the humoral arm of recipient immune response remains insufficiently tamed by modern immunosuppressive armamentarium. As a result, B cells and alloantibodies are increasingly acknowledged as crucial mediators of chronic allograft injury.

The present article aims at connecting the concepts that recently emerged in the field of humoral alloimmunity. Putting these puzzle pieces together, the picture of chronic rejection pathogenesis begins to come into play.

Section snippets

The "humoral theory" of chronic rejection

Seminal clinical observations, made in the 1970s, have suggested a link between the presence of circulating donor-specific antibodies (DSA) and chronic rejection [3]. This hypothesis has then been substantiated by several experimental works [4], [5], notably the demonstration that immunodeficient scid mice given repeated doses of anti-MHC class I alloantibody develop fibrous intimal thickening of coronary arteries in cardiac allografts [6].

Finally, a recent large-scale prospective trial,

B cells as intragraft antigen-presenting cells

Binding of cognate antigen to B cell receptor (BCR) triggers membrane reorganisation, which results in the formation of an immunologic synapse that functions as a platform for internalization of the BCR-antigen complex [59]. Internalized antigen is degraded and subsequently exposed on the B-cell surface in association with major histocompatibility complex molecules for presentation to T cells. Of note, B cells are endowed with unique properties as antigen-presenting cells because i) they have

Conclusion

Chronic rejection represents currently the main obstacle to long-term survival of solid allografts. Accumulating evidence indicates that B cells are key players in chronic rejection pathophysiology. Beyond their widely acknowledged role in antibody production (following their differentiation in plasma cell), B cells are also endowed with critical, yet overlooked, antibody-independent functions, which place them at the center of immune regulation with the power to enhance or inhibit antigraft

Disclosures

The author has no conflicts of interest to disclose.

Acknowledgements

OT is supported by the CENTAURE Transplantation Research Network, the Hospices Civils de Lyon, the Societe de Nephrologie, the Societe Francophone de Transplantation, and the Fondation pour la Recherche Medicale.

References (88)

  • O. Thaunat et al.

    Chronic humoral rejection mediated by anti-HLA-DP alloantibodies: insights into the role of epitope sharing in donor-specific and non-donor specific alloantibodies generation

    Transpl Immunol

    (2009)
  • Q. Zhang et al.

    Non-MHC antigenic targets of the humoral immune response in transplantation

    Curr Opin Immunol

    (2010)
  • F.M. Heinemann et al.

    Immunoglobulin isotype-specific characterization of anti-human leukocyte antigen antibodies eluted from explanted renal allografts

    Hum Immunol

    (2007)
  • M. Wahrmann et al.

    Pivotal role of complement-fixing HLA alloantibodies in presensitized kidney allograft recipients

    Am J Transplant

    (2006)
  • T.S. Raju

    Terminal sugars of Fc glycans influence antibody effector functions of IgGs

    Curr Opin Immunol

    (2008)
  • A. Loupy et al.

    Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies

    Am J Transplant

    (2009)
  • S. Rahimi et al.

    Non-complement- and complement-activating antibodies synergize to cause rejection of cardiac allografts

    Am J Transplant

    (2004)
  • H.E. Feucht et al.

    Capillary deposition of C4d complement fragment and early renal graft loss

    Kidney Int

    (1993)
  • B. Sis et al.

    Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining

    Am J Transplant

    (2009)
  • T. Hirohashi et al.

    Complement independent antibody-mediated endarteritis and transplant arteriopathy in mice

    Am J Transplant

    (2010)
  • F. Li et al.

    Human leukocyte antigen antibodies in chronic transplant vasculopathy-mechanisms and pathways

    Curr Opin Immunol

    (2009)
  • F.A. Arosa et al.

    Open conformers: the hidden face of MHC-I molecules

    Trends Immunol

    (2007)
  • J.L. Platt et al.

    Transplantation of discordant xenografts: a review of progress

    Immunol Today

    (1990)
  • A.H. Tang et al.

    Accommodation of grafts: implications for health and disease

    Hum Immunol

    (2007)
  • H. Kohler et al.

    Superantibody activities: new players in innate and adaptive immune responses

    Immunol Today

    (1998)
  • H. Holschermann et al.

    In situ detection of tissue factor within the coronary intima in rat cardiac allograft vasculopathy

    Am J Pathol

    (1999)
  • V. Zarkhin et al.

    Characterization of intra-graft B cells during renal allograft rejection

    Kidney Int

    (2008)
  • F.K. Baddoura et al.

    Lymphoid neogenesis in murine cardiac allografts undergoing chronic rejection

    Am J Transplant

    (2005)
  • O. Thaunat et al.

    Is defective lymphatic drainage a trigger for lymphoid neogenesis?

    Trends Immunol

    (2006)
  • L. Le Texier et al.

    Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile

    Am J Transplant

    (2011)
  • T. Shimamura et al.

    Feedback suppression of the immune response in vivo. I. Immune B cells induce antigen-specific suppressor T cells

    Cell Immunol

    (1982)
  • O. Thaunat et al.

    Am"B"valent: anti-CD20 antibodies unravel the dual role of B cells in immunopathogenesis

    Blood

    (2010)
  • P.A. Blair et al.

    CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients

    Immunity

    (2010)
  • A. Pallier 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)
  • M. Jeannet et al.

    Humoral antibodies in renal allotransplantation in man

    N Engl J Med

    (1970)
  • C. Shi et al.

    Immunologic basis of transplant-associated arteriosclerosis

    Proc Natl Acad Sci U S A

    (1996)
  • O. Thaunat et al.

    Direct and indirect effects of alloantibodies link neointimal and medial remodeling in graft arteriosclerosis

    Arterioscler Thromb Vasc Biol

    (2006)
  • P.S. Russell et al.

    Alloantibody- and T cell-mediated immunity in the pathogenesis of transplant arteriosclerosis: lack of progression to sclerotic lesions in B cell-deficient mice

    Transplantation

    (1997)
  • D.J. Steele et al.

    Two levels of help for B cell alloantibody production

    J Exp Med

    (1996)
  • J.P. Vella et al.

    Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction

    Transplantation

    (1997)
  • F.G. Lakkis et al.

    Immunologic 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue

    Nat Med

    (2000)
  • N. Issa et al.

    Transplant glomerulopathy: risk and prognosis related to anti-human leukocyte antigen class II antibody levels

    Transplantation

    (2008)
  • J.L. Platt

    Antibodies in transplantation

    Discov Med

    (2010)
  • Z.V. Collins et al.

    A naturally occurring monospecific anti-HL-A8 isoantibody

    Tissue Antigens

    (1973)
  • Cited by (0)

    View full text