Humoral Immunity to Vimentin Is Associated with Cardiac Allograft Injury in Nonhuman Primates

Azimzadeh, Agnes M.; Pfeiffer, Steffen; Wu, Guosheng; Schröder, Carsten; Zhou, Hui; Zorn, George L.; Kehry, Marilyn R.; Miller, Geraldine G.; Rose, Marlene L.; Pierson, Richard N.

doi:10.1111/j.1600-6143.2005.01022.x

Cited by 70 publications

(55 citation statements)

References 38 publications

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“…Our results thus highlight the novel concept that passenger donor CD4 T cells within a cardiac allograft can contribute to its rejection. Autoimmune responses are increasingly described in recipients of solid organ transplants, 8 -10,15,32-34 but their contribution to graft damage is unclear, because although associated with poor outcome, 15,16,32 this may simply indicate nonpathogenic bystander activation that is triggered by a particularly aggressive (and consequently damaging) alloimmune response. Rodent studies have highlighted the contribution of T-cell autoimmunity to graft rejection, 9 -11 but the only convincing evidence of an effector role for autoantibody is the beneficial response to the depletion of autoantibody in renal transplant patients with vascular rejection associated with antiangiotensin receptor autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

Donor CD4 T Cells Contribute to Cardiac Allograft Vasculopathy by Providing Help for Autoantibody Production

Win

Rehakova

Negus

et al. 2009

Circ: Heart Failure

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Background-The development of autoantibody after heart transplantation is increasingly associated with poor graftoutcome, but what triggers its development and whether it has a direct causative role in graft rejection is not clear. Here, we study the development of antinuclear autoantibody in an established mouse model of heart allograft vasculopathy. Methods and Results-Humoral vascular changes, including endothelial complement staining, were present in bm12 heart grafts, explanted 50 days after transplantation. Alloantibody was not detectable, but long-lasting autoantibody responses developed in C57BL/6 recipients from the third week after transplantation. No autoantibody was generated if donor CD4 T cells were depleted before heart graft retrieval or in recipients that lacked B-cell major histocompatibility complex class II expression, indicating that humoral autoimmunity is a consequence of donor CD4 T-cell allorecognition of the major histocompatibility complex class II complex on recipient autoreactive B cells. An effector role for autoantibody in graft rejection was confirmed by abrogation of humoral vascular rejection, and attenuation of vasculopathy, in B-cell deficient recipients and by development of vascular obliteration and accelerated rejection in recipients primed for autoantibody before transplantation. Conclusions-Passenger CD4 T cells within heart transplants can contribute to allograft vasculopathy by providing help to recipient B cells for autoantibody generation. (Circ Heart Fail. 2009;2:361-369.)

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Section: Discussionmentioning

confidence: 99%

Donor CD4 T Cells Contribute to Cardiac Allograft Vasculopathy by Providing Help for Autoantibody Production

Win

Rehakova

Negus

et al. 2009

Circ: Heart Failure

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“…Alloantibodies were measured retrospectively by flow cytometry using archived frozen donor splenocytes and recipient serum as described previously (10,63). Antibody binding was revealed using PE-labeled goat anti-human IgM (Fcμ specific) antibodies (Biosource) or biotin-labeled goat anti-monkey IgG (Fcγ specific) antibodies (Nordic) followed by PE-labeled streptavidin (BD BiosciencesPharmingen).…”

Section: Figurementioning

confidence: 99%

“…Tissue deposits of C4d were assayed using double-fluorescence immunochemistry on OCT frozen tissue sections as previously described (63). The presence of C4d was scored by 2 investigators (A.M. Azimzadeh and R.N.…”

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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“…Alloantibodies were measured retrospectively by flow cytometry using frozen donor splenocytes as described previously (32). Results were expressed as the percentage of positive T cells (defined as CD3 ϩ DR Ϫ ) as compared with recipient pretransplant serum.…”

Section: Alloantibody Assaymentioning

confidence: 99%

CCR5 Blockade Modulates Inflammation and Alloimmunity in Primates

Schröder

Pierson

Nguyen

et al. 2007

The Journal of Immunology

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Pharmacologic antagonism of CCR5, a chemokine receptor expressed on macrophages and activated T cells, is an effective antiviral therapy in patients with macrophage-tropic HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this regard, the recruitment of CCR5-bearing cells into clinical allografts is a hallmark of acute rejection and may anticipate chronic rejection, whereas conventionally immunosuppressed renal transplant patients homozygous for a nonfunctional Δ32 CCR5 receptor rarely exhibit late graft loss. Therefore, we explored the effects of a potent, highly selective CCR5 antagonist, Merck’s compound 167 (CMPD 167), in an established cynomolgus monkey cardiac allograft model. Although perioperative stress responses (fever, diminished activity) and the recruitment of CCR5-bearing leukocytes into the graft were markedly attenuated, anti-CCR5 monotherapy only marginally prolonged allograft survival. In contrast, relative to cyclosporine A monotherapy, CMPD 167 with cyclosporine A delayed alloantibody production, suppressed cardiac allograft vasculopathy, and tended to further prolong graft survival. CCR5 therefore represents an attractive therapeutic target for attenuating postsurgical stress responses and favorably modulating pathogenic alloimmunity in primates, including man.

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Humoral Immunity to Vimentin Is Associated with Cardiac Allograft Injury in Nonhuman Primates

Cited by 70 publications

References 38 publications

Donor CD4 T Cells Contribute to Cardiac Allograft Vasculopathy by Providing Help for Autoantibody Production

Donor CD4 T Cells Contribute to Cardiac Allograft Vasculopathy by Providing Help for Autoantibody Production

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

CCR5 Blockade Modulates Inflammation and Alloimmunity in Primates

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