The role of B cells in solid organ transplantation

Kwun, Jean; Bulut, Pinar; Kim, Eugenia; Dar, Wasim; Oh, Byoungchol; Ruhil, R.; Iwakoshi, Neal N.; Knechtle, Stuart J.

doi:10.1016/j.smim.2011.08.022

Cited by 34 publications

(20 citation statements)

References 159 publications

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“…In previously reported CR models, alloantibody or B cells contributed little if any to CR (11,27). Such CR models are “acute rejection-driven” (28). Although posttransplant T cell responses may be effectively controlled by current immunosuppresants, the ineffectiveness of the same agents against B cell responses has become apparent.…”

Section: Discussionmentioning

confidence: 99%

Patterns of De Novo Allo B Cells and Antibody Formation in Chronic Cardiac Allograft Rejection After Alemtuzumab Treatment

Kwun

Gibby

et al. 2012

American Journal of Transplantation

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Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection.

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Section: Discussionmentioning

confidence: 99%

Patterns of De Novo Allo B Cells and Antibody Formation in Chronic Cardiac Allograft Rejection After Alemtuzumab Treatment

Kwun

Gibby

et al. 2012

American Journal of Transplantation

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“…For that reason, lymphodepletion has become a common immunosuppressive strategy at the time of solid organ transplantation (Kwun et al 2012a). Although this strategy has helped improve early graft survival, long-term outcomes after depletion are still afflicted with challenges.…”

Section: Lymphodepletion In Mouse Modelsmentioning

confidence: 99%

“…Several B-cell-targeting therapeutics have emerged over the last decade, as our understanding of the impact of B cells on allograft rejection as well as transplant tolerance has increased (Redfield et al 2011;Kwun et al 2012a). These strategies may be of particular interest in the setting of T-cell depletion in which humoral immunity is often up-regulated.…”

Section: B-cell Depletionmentioning

confidence: 99%

Lymphodepletional Strategies in Transplantation

Page

Kwun

et al. 2013

Cold Spring Harbor Perspectives in Medicine

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Because lymphocytes were shown to mediate transplant rejection, their depletion has been studied as a mechanism of preventing rejection and perhaps inducing immunologic tolerance. Agents that profoundly deplete lymphocytes have included monoclonal antibodies, cytotoxic drugs, and radiation. We have studied several such agents but focused on antibodies that deplete not only peripheral blood lymphocytes, but also lymph node lymphocytes. Depletion of lymph node T lymphocytes appears to permit peripheral tolerance at least for T cells in animal models. Nevertheless, B-cell responses may be resistant to such approaches, and T memory cells are likewise relatively resistant to depleting antibodies. We review the experimental and clinical approaches to depletion strategies and outline some of the pitfalls of depletion, such as limitations of currently available agents, duration of tolerance, infection, and malignancy. It is notable that most tolerogenic strategies that have been attempted experimentally and clinically include depleting agents even when they are not named as the underlying strategy. Thus, there is an implicitly acknowledged role for reducing the precursor frequency of donor antigen-specific lymphocytes when approaching the daunting goal of transplant tolerance.

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“…Unwanted humoral immune responses to protein antigens are responsible for numerous medical conditions in the areas of autoimmunity (1), transplantation (2), allergies (3), and biotherapeutics (4). Current treatment options largely rely on immunosuppressive drugs or immunodepletion therapy, but these approaches can compromise immunity (5,6).…”

Section: Introductionmentioning

confidence: 99%

Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis

Macauley

Pfrengle²,

Rademacher³

et al. 2013

J. Clin. Invest.

198

245

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Antibodies confer humoral immunity but can also be harmful when they target an autoantigen, alloantigen, allergen, or biotherapeutic. New strategies are needed for antigen-specific suppression of undesired antibody responses, particularly to T cell-dependent protein antigens, because they elicit T cell help. Here we show that liposomal nanoparticles, displaying both antigen and glycan ligands of the inhibitory coreceptor CD22, induce a tolerogenic program that selectively causes apoptosis in mouse and human B cells. These SIGLEC-engaging tolerance-inducing antigenic liposomes (STALs, where SIGLEC is defined as sialic acid-binding Ig-like lectin) induced robust antigen-specific tolerance to protein antigens in mice, preventing subsequent immune response to challenge with the same antigen. Since development of inhibitory antibodies to FVIII is a serious problem in treatment of hemophilia A patients, we investigated the potential of this approach for inducing tolerance to FVIII in a hemophilia mouse model. STALs prevented formation of inhibitory FVIII antibodies, allowing for effective administration of FVIII to hemophilia mice to prevent bleeding. These findings suggest that STALs could be used to eliminate or prevent harmful B cell-mediated immune responses.

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The role of B cells in solid organ transplantation

Cited by 34 publications

References 159 publications

Patterns of De Novo Allo B Cells and Antibody Formation in Chronic Cardiac Allograft Rejection After Alemtuzumab Treatment

Patterns of De Novo Allo B Cells and Antibody Formation in Chronic Cardiac Allograft Rejection After Alemtuzumab Treatment

Lymphodepletional Strategies in Transplantation

Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis

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