Four Stages and Lack of Stable Accommodation in Chronic Alloantibody Mediated Renal Allograft Rejection in Cynomolgus Monkeys

Smith, Rex Neal; Kawai, Tatsuo; Bosković, S; Nadazdin, O.; Sachs, David H.; Cosimi, A. Benedict; Colvin, Robert B.

doi:10.1097/01.tp.0000331971.33455.7b

Cited by 30 publications

(48 citation statements)

References 48 publications

(65 reference statements)

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“…As opposed to acute AMR, CAMR is a long-term process which develops in sequential steps over months to years (35). Diagnostic features of CAMR can include the presence of DSA, TG, PTC basement membrane multilayering and the presence of C4d.…”

Section: Chronic Amrmentioning

confidence: 99%

Summary of FDA Antibody-Mediated Rejection Workshop

Archdeacon

Chan

Neuland

et al. 2011

American Journal of Transplantation

163

118

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The Food and Drug Administration (FDA) held an open public workshop in June 2010 to discuss the current state of science related to antibody-mediated rejection (AMR) in kidney transplantation. Desensitization, acute AMR and chronic AMR (CAMR) were considered in the context of clinical trial design. Participants discussed experiences with HLA antibody detection and quantitation and the utility of monitoring donorspecific antibodies (DSAs) to inform the management of patients with AMR. The role for animal models was discussed. Diagnostic and prognostic features of histology were presented, followed by discussion of sensitivity and specificity of various criteria. The published literature on treatment of acute AMR was summarized, which consisted of case series and limited data from controlled clinical trials. Considerations for future clinical trials were presented, including endpoints and statistical evaluations of outcome. Although many issues need further consideration, the meeting enabled an important exchange of ideas between experts in the field.

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Section: Chronic Amrmentioning

confidence: 99%

Summary of FDA Antibody-Mediated Rejection Workshop

Archdeacon

Chan

Neuland

et al. 2011

American Journal of Transplantation

163

118

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“…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)(8)(9)(10) and clinical data (11)(12)(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.…”

Section: Introductionmentioning

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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“…1,4,5 Experimental studies have shed light on the natural history of AMR. 6,7 The sequence starts with the generation of antibodies directed against the graft. Although highly polymorphic mismatched HLA molecules represent the most documented targets for DSAs, it is clear that DSAs can also be directed against other kinds of molecular targets, including polymorphic minor histocompatibility antigens and after a breakdown of B cell tolerance, 8 nonpolymorphic autoantigens.…”

mentioning

confidence: 99%

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Thaunat

Koenig

Leibler³

et al. 2016

JASN

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The negative effect of donor-specific antibodies on the success of solid transplant is now clearly established. However, the lack of effective treatment to prevent the development of antibody-mediated lesions deepens the need for clinicians to focus on primary prevention of de novo humoral allosensitization. Among the factors associated with the risk of developing de novo donor-specific antibodies, therapeutic immunosuppression is the most obvious parameter in which improvement is possible. Beyond compliance and the overall depth of immunosuppression, it is likely that the nature of the drugs is also crucial. Here, we provide an overview of the molecular effect of the various immunosuppressive drugs on B cell biology. Clinical data related to the effect of these drugs on de novo humoral allosensitization are also examined, providing a platform from which clinicians can optimize immunosuppression for prevention of de novo donor-specific antibody generation at the individual level.

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Four Stages and Lack of Stable Accommodation in Chronic Alloantibody Mediated Renal Allograft Rejection in Cynomolgus Monkeys

Cited by 30 publications

References 48 publications

Summary of FDA Antibody-Mediated Rejection Workshop

Summary of FDA Antibody-Mediated Rejection Workshop

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

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

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