Acute Cellular Rejection with CD20-Positive Lymphoid Clusters in Kidney Transplant Patients Following Lymphocyte Depletion

Kayler, Liise K.; Lakkis, Fadi G.; Morgan, Charles W.; Basu, Amit; Blisard, Deanna; Tan, Henkie P.; McCauley, Jerry; Wu, Caiying; Shapiro, R; Randhawa, Parmjeet

doi:10.1111/j.1600-6143.2007.01737.x

Cited by 63 publications

(65 citation statements)

References 22 publications

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“…In at least one patient, immunohistochemistry revealed the presence of a dense B-cell, rather than T-cell, mononuclear infiltrate. Consistent with this observation, a recent report has described the presence of CD20 positive (B-cell) lymphoid clusters in kidney allografts undergoing allograft rejection following treatment with alemtuzumab therapy (19). Similarly, another report also describes a form of monocytic rejection in renal transplant recipients following alemtuzumab therapy (20).…”

Section: Reams Et Alsupporting

confidence: 66%

Alemtuzumab in the Treatment of Refractory Acute Rejection and Bronchiolitis Obliterans Syndrome After Human Lung Transplantation

Reams¹,

Musselwhite²,

Zaas³

et al. 2007

American Journal of Transplantation

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Despite substantial improvements in early survival after lung transplantation, refractory acute rejection (RAR) and bronchiolitis obliterans syndrome (BOS) remain major contributors to transplant-related morbidity and mortality. We have utilized alemtuzumab, a humanized anti-CD52 antibody which results in potent lymphocyte depletion, in consecutive patients with RAR (n = 12) or BOS (n = 10). All patients failed conventional treatment with methylprednisolone and antithymocyte globulin and received strict infection prophylaxis. Alemtuzumab significantly improved histological rejection scores in RAR. Total rejection grade/biopsy was 1.98 ± 0.25 preceding alemtuzumab versus 0.33 ± 0.14 posttreatment, p-value <0.0001 (with a similar number of biopsies/patient per respective time interval). Freedom from BOS was observed in 65% of RAR patients 2 years after alemtuzumab treatment. Although there was no statistically significant change in forced expiratory volume in 1 second (FEV1) before and after alemtuzumab treatment in patients with BOS, a stabilization or improvement in BOS grade occurred in 70% of patients. Patient survival 2 years after alemtuzumab for BOS was 69%. Despite a dramatic decline in CD4 counts in alemtuzumab-treated patients, only one patient developed a lethal infection. Thus, we provide the first evidence that alemtuzumab is a potentially useful therapy in lung transplant recipients with RAR or BOS.

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Section: Reams Et Alsupporting

confidence: 66%

Alemtuzumab in the Treatment of Refractory Acute Rejection and Bronchiolitis Obliterans Syndrome After Human Lung Transplantation

Reams¹,

Musselwhite²,

Zaas³

et al. 2007

American Journal of Transplantation

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“…Recently, CD20 infiltrates during acute cellular rejection have been shown to possibly represent a heterogeneous population that might not help to identify a graft at risk for failure. 30 Moreover, very recent data suggest an association between enhanced B cell levels and operational tolerance in kidney transplant patients (unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Molecular Phenotypes of Acute Rejection Predict Kidney Graft Prognosis

Viklický

Hřibová²,

Volk³

et al. 2010

Journal of the American Society of Nephrology

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Earlier detection of antibody-mediated rejection of kidney allografts may improve graft outcomes. Profiling of gene expression holds promise for the diagnosis and prognosis of antibody-mediated rejection. Here, we identified 730 patients who received kidney transplants during 2002-2005, including 21 patients (2.9%) who experienced early acute antibody-mediated rejection. We also identified a matched group of 43 patients with early acute T cell-mediated rejection to serve as controls. Compared with patients with T cell-mediated rejection, those with antibody-mediated rejection had significantly higher intrarenal mRNA expression of the cytoprotective heme oxygenase-1 but had lower expression of the regulatory T cell marker forkhead box P3 (FoxP3), the B cell marker CD20, and the chemokine regulated upon activation, normal T cell expressed and secreted (RANTES). T cell infiltration was similar in both groups of patients. Compared with grafts that had a favorable course, those that failed as a result of antibody-mediated rejection had expression profiles suggesting a lack of regulation (less FoxP3, TGF-␤1, RANTES, and CD20). Grafts that failed as a result of T cell-mediated rejection only revealed lower expression of CD20 mRNA. In summary, these data suggest that severe antibody-mediated rejection and T cell-mediated rejection result in graft loss by distinct mechanisms. Molecular phenotypes of early acute rejection might help to identify grafts with poor prognosis, allowing earlier application of additional therapies.

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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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Acute Cellular Rejection with CD20-Positive Lymphoid Clusters in Kidney Transplant Patients Following Lymphocyte Depletion

Cited by 63 publications

References 22 publications

Alemtuzumab in the Treatment of Refractory Acute Rejection and Bronchiolitis Obliterans Syndrome After Human Lung Transplantation

Alemtuzumab in the Treatment of Refractory Acute Rejection and Bronchiolitis Obliterans Syndrome After Human Lung Transplantation

Molecular Phenotypes of Acute Rejection Predict Kidney Graft Prognosis

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

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