Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation

Fan, Xiaohu; Ang, A.; Pollock-BarZiv, Stacey M.; Dipchand, Anne I.; Ruiz, Phillip; Wilson, Gregory J.; Platt, Jeffrey L.; West, Lori J.

doi:10.1038/nm1126

Cited by 199 publications

(193 citation statements)

References 42 publications

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“…In a recent review of ABO-incompatible organ transplantation, Warner et al [76] postulate that survival of grafts by accommodation may be a multi-step process, initially facilitated by cytoprotective factors and later by decreases in TNF-α, TGFβ and SMAD5; and increases in Muc1 and GFRA1. This concept of accommodation changing over time is quite compatible with the observations of Lin et al [77] and Ogawa et al [78] in rodents and West et al [79] in human subjects that what begins as accommodation can become some different process, perhaps including tolerance.…”

Section: Discussionsupporting

confidence: 88%

Accommodation of grafts: Implications for health and disease

Tang

Platt

2007

Human Immunology

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Accommodation refers to the acquired resistance of a graft to immune-mediated injury. It is typically observed after antibodies that would cause rejection of a graft are removed from a recipient and then return. Besides being a condition so induced, accommodation can occur spontaneously, without the depleting of antibodies. Indeed, we postulate that spontaneous accommodation may be the most common outcome of clinical organ transplantation. This communication will review the current understanding of accommodation, emphasizing recent advances and important questions. Among the recent advances are the discoveries of potentially broader relevance of accommodation for biology and immunology and pathways by which accommodation may be achieved. To investigate these pathways and to understand how accommodation begins and how it evolves, clinical organ transplants might offer a useful and incisive model.

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Section: Discussionsupporting

confidence: 88%

Accommodation of grafts: Implications for health and disease

Tang

Platt

2007

Human Immunology

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“…Of note, ABO-incompatible heart transplantation, and possibly other organ transplantation, is feasible in infants before the development of significant anti-ABO antibody titers (113). Transplanted infants in fact acquire tolerance to the incompatible ABO antigen, providing firm proof that human B cells are prone to tolerance if challenged while the immune system is still relatively immature (114).…”

Section: Role In Renal Transplantationmentioning

confidence: 99%

B Cells, Antibodies, and More

Hoffman¹,

Lakkis

Chalasani

2016

Clinical Journal of the American Society of Nephrology

384

268

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B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by secreting cytokines that inhibit disease onset and/or progression. B cell-targeted approaches for treating immune diseases of the kidney and other organs have gained significant momentum. However, much remains to be understood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic response to B cell-targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers and regulators of immunity with relevance to kidney disease and transplantation.

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“…This result may be particularly favored if the waves of B cell precursors that repopulate B cell niches from the bone marrow mature in the context of an immunologically quiescent (uninflamed) host, as exists months after the transplant procedure. Deletional tolerance and even "desensitization" to ABO carbohydrate antigens has been observed in a series of pediatric heart allograft recipients treated with conventional immunosuppression (52) and in adult recipients of other ABOincompatible organ allografts treated with rituximab (53)(54)(55)(56)(57). The conditions under which responses to immunodominant transplant protein antigens may be durably regulated remain to be determined, as do the relative contribution of deletional, anergic, and immunomodulatory mechanisms.…”

Section: Figurementioning

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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Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation

Cited by 199 publications

References 42 publications

Accommodation of grafts: Implications for health and disease

Accommodation of grafts: Implications for health and disease

B Cells, Antibodies, and More

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

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