Overcoming Chronic Rejection—Can it B?

Kwun, Jean; Knechtle, Stuart J.

doi:10.1097/tp.0b013e3181b96646

Cited by 40 publications

(26 citation statements)

References 111 publications

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“…Elaboration of anti-donor antibody (25)(26)(27)(28)(29) and appearance of B cell-rich tertiary lymphoid structures (30)(31)(32) and expression of B cell genes in the graft (33,34) are all closely associated with chronic rejection of the heart and other organ allografts in rodents, nonhuman primates, and human recipients. Our observations in the current study, that alloantibody detection, complement deposition, and CAV severity correlate closely with each other, add further compelling support for the generally accepted hypothesis that alloantibody contributes to the pathogenesis of CAV.…”

Section: Discussionmentioning

confidence: 99%

Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys

Kelishadi¹,

Azimzadeh²,

Zhang³

et al. 2010

J. Clin. Invest.

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Chronic rejection currently limits the long-term efficacy of clinical transplantation. Although B cells have recently been shown to play a pivotal role in the induction of alloimmunity and are being targeted in other transplant contexts, the efficacy of preemptive B cell depletion to modulate alloimmunity or attenuate cardiac allograft vasculopathy (CAV) (classic chronic rejection lesions found in transplanted hearts) in a translational model has not previously been described. We report here that the CD20-specific antibody (αCD20) rituximab depleted CD20 + B cells in peripheral blood, secondary lymphoid organs, and the graft in cynomolgus monkey recipients of heterotopic cardiac allografts. Furthermore, CD20 + B cell depletion therapy combined with the calcineurin inhibitor cyclosporine A (CsA) prolonged median primary graft survival relative to treatment with αCD20 or CsA alone. In animals treated with both αCD20 and CsA that achieved efficient B cell depletion, alloantibody production was substantially inhibited and the CAV severity score was markedly reduced. We conclude therefore that efficient preemptive depletion of CD20 + B cells is effective in a preclinical model to modulate pathogenic alloimmunity and to attenuate chronic rejection when used in conjunction with a conventional clinical immunosuppressant. This study suggests that use of this treatment combination may improve the efficacy of transplantation in the clinic. IntroductionThe majority of human allograft recipients develop clinically significant chronic rejection, with incidence and severity increasing steadily over time after transplant. For example, over 50% of human cardiac allograft recipients and 80% of lung recipients exhibit chronic rejection within 10 years. Recent additions to the clinical immunosuppressive armamentarium, such as blocking (1) or depleting antibodies (2) and pharmacologic inhibitors (3), have had little appreciable impact on this phenomenon (4-6).The causes of chronic rejection remain incompletely understood. The classic chronic rejection lesions found in heart (cardiac allograft vasculopathy [CAV]), lung (obliterative bronchiolitis), liver (vanishing bile duct syndrome), and renal (chronic allograft nephropathy) allografts are often temporally associated with detection of anti-donor antibodies, implicating alloantibody as an effector mechanism. Animal models (7-10) and clinical data (11-13) consistently implicate T cell-mediated immunity in the elicited alloantibody response. Thus the current consensus paradigm for chronic rejection holds that T cell-mediated adaptive immunity to alloantigens amplifies innate immune activation initiated by donor brain death and organ ischemia/reperfusion. Influenced in part by the intensity of innate immune activation, T cells propagate pathogenic vascular remodeling and sustain alloantigen-specific chronic inflammation in the transplanted organ. Under the influence

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Section: Discussionmentioning

confidence: 99%

Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys

Kelishadi¹,

Azimzadeh²,

Zhang³

et al. 2010

J. Clin. Invest.

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“…Increasingly, it is recognised that the role of B cells in transplantation is not restricted to their effector function, the humoral response, alone: antigen presentation of B cells also contributes to the optimal immune response 1 . Similarly, although graft rejection had been considered largely mediated by T cell effector function, there is growing evidence that B cells and their immunoglobulin products (alloantibody) may play a role in the process 2 . In this review, we wish to focus on crosstalk between T and B cells in antibody-mediated rejection (ABMR), following transplantation.…”

Section: General Introductionmentioning

confidence: 99%

Crosstalk Between T and B Cells in the Germinal Center After Transplantation

et al. 2017

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Cross-talk between B and T cells in transplantation is increasingly recognized as being important in the alloimmune response. T cell activation of B cells occurs by a 3-stage pathway, culminating with costimulation signals. We review the distinct T cell subtypes required for B cell activation, and discuss the formation of the Germinal Center (GC) after transplantation, with particular reference to the repopulation of the GC following depletional induction, and the subsequent effect of immunosuppressive manipulation of T-B cell interactions. Additionally, ectopic GCs are seen in transplantation, but their role is not fully understood. Therapeutic options to target T-B cell interactions are of considerable interest, both as immunosuppressive tools, and to aid further understanding of these important alloimmune mechanisms.

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“…The etiology of CR is often described as “multifactorial” and poorly understood (3,4). Pathologically, common features of CR include vasculopathy leading to ischemic injury, and fibrosis associated with replacement of normal tissue architecture by fibrous elements.…”

Section: Introductionmentioning

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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Overcoming Chronic Rejection—Can it B?

Cited by 40 publications

References 111 publications

Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys

Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys

Crosstalk Between T and B Cells in the Germinal Center After Transplantation

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

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