Article

National Conference to Assess Antibody-Mediated Rejection in Solid Organ Transplantation

Dumont Transplant Program & Immunogenetics Center, UCLA School of Medicine, UCLA, Los Angeles, CA, USA.
American Journal of Transplantation (Impact Factor: 6.19). 08/2004; 4(7):1033-41. DOI: 10.1111/j.1600-6143.2004.00500.x
Source: PubMed

ABSTRACT The process of humoral rejection is multifaceted and has different manifestations in the various types of organ transplants. Because this process is emerging as a leading cause of graft loss, a conference was held in April 2003 to comprehensively address issues regarding humoral rejection. Though humoral rejection may result from different factors, discussion focused on a paradigm caused by antibodies, typically against donor HLA antigens, leading to the term 'antibody-mediated rejection' (AMR). Conference deliberations were separated into four workgroups: The Profiling Workgroup evaluated strengths and limitations of different methods for detecting HLA reactive antibody, and created risk assessment guidelines for AMR; The Diagnosis Workgroup reviewed clinical, pathologic, and serologic criteria for assessing AMR in renal, heart and lung transplant recipients; The Treatment Workgroup discussed advantages, limitations and possible mechanisms of action for desensitization protocols that may reverse AMR; and The Basic Science Workgroup presented animal and human immunologic models for humoral rejection and proposed potential targets for future intervention. This work represents a comprehensive review with contributions from experts in the fields of Transplantation Surgery, Medicine, Pathology, Histocompatibility, Immunology, and clinical trial design. Immunologic barriers once considered insurmountable are now consistently overcome to enable more patients to undergo organ transplantation.

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Available from: Jerzy Kupiec-Weglinski, Jul 28, 2015
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    • "Chronic AMR, which is characteristically seen as transplant glomerulopathy in kidney biopsies, is characterized by glomerular mesangial expansion and capillary basement membrane duplication or splitting, interstitial fibrosis/tubular atrophy, and/or fibrous intimal thickening in arteries. Sometimes, peritubular capillary basement membrane multilayering is also observed on electron microscopy [7] [13] [14]. Due to donor-specific antibodies, AMR leads to the activation of the classical complement pathway, resulting in impaired graft function [15]. "
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    ABSTRACT: Antibody-mediated rejection (AMR) is highly detrimental to the prolonged survival of transplanted kidneys. C4d has been regarded as a footprint of AMR tissue damage, and the introduction of C4d staining in daily clinical practice aroused an ever-increasing interest in the role of antibody-mediated mechanisms in allograft rejection. Despite the general acceptance of the usefulness of C4d in the identification of acute AMR, the data for C4d staining in chronic AMR is variable. The presence of C4d in the majority of the biopsies with features of chronic antibody-mediated rejection is reported, but this rejection without C4d staining is observed as well, suggesting that C4d is specific but not sensitive. Further studies on AMR with positive C4d staining in biopsy specimens are really important, as well as the study of novel routine markers that may participate in the pathogenesis of this process.
    Clinical and Developmental Immunology 07/2013; 2013:678180. DOI:10.1155/2013/678180 · 2.93 Impact Factor
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    • "B cell involvement is in general characterized by intragraft B cell infiltration, C4d deposition and circulating donor-specific antibodies (Barnett et al., 2011). In humans, about 5–7% of the kidney transplant patients develop acute humoral rejection (Takemoto et al., 2004). Therefore, we had a closer look into the detection of complement factor deposits and the circulation of donor-specific antibodies. "
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    ABSTRACT: Mesenchymal stromal cells (MSC) have shown immunomodulatory and tissue repair potential including partial tolerance induction by pre-treatment of donor-specific cells in a rat heart transplantation model. Very recently, we could show that autologous MSC attenuated ischemia reperfusion injury in a highly mismatched donor-recipient rat kidney transplant model. Therefore, we investigated donor-specific MSC pre-treatment in this rat kidney transplantation model to study whether graft function could be improved, or if tolerance could be induced. Donor- and recipient-type MSC or phosphate buffered saline (PBS) as a control was injected i.v. 4 days before kidney transplantation. Mycophenolate mofetil immunosuppression (20mg/kg body weight) was applied for 7 days. Kidney grafts and spleens were harvested between days 8 and 10 and analyzed by quantitative RT-PCR and immunohistology. In addition, creatinine levels in the blood were measured and serum was screened for the presence of donor-specific antibodies. Surprisingly, application of both donor- and recipient-specific MSC resulted in enhanced humoral immune responses verified by intragraft B cell infiltration and complement factor C4d deposits. Moreover, signs of inflammation and rejection were generally enhanced in both MSC-treated groups relative to PBS control group. Additionally, pre-treatment with donor-specific MSC significantly enhanced the level of donor-specific antibody formation when compared with PBS- or recipient MSC-treated groups. Pre-treatment with both MSC types resulted in a higher degree of kidney cortex tissue damage and elevated creatinine levels at the time point of rejection. Thus, MSC pre-sensitization in this model impairs the allograft outcome. Our data from this pre-clinical kidney transplantation model indicate that pre-operative MSC administration may not be optimal in kidney transplantation and caution must be exerted before moving forward with clinical studies in order to avoid adverse effects.
    Frontiers in Immunology 07/2012; 3:202. DOI:10.3389/fimmu.2012.00202
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    • "Hence, antidonor antibodies detected after transplantation by the technologies mentioned above may really mark graft damage rather than initiation of a humoral immune response. The possibility that such " donor specific antibodies, " or DSA, represent late rather than early markers of rejection is important given the high level of interest in this diagnostic index (Sis et al., 2010; Takemoto et al., 2004). Markers of humoral immunity other than antibodies might be needed to detect and treat antibody-mediated injury early in the course. "
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    ABSTRACT: Transplantation of cells, tissues, and organs from one individual to another can incite the production of antibodies specific for foreign antigens, especially major histocompatibility antigens, in the graft. Antibodies specific for a graft provide an index of immunity and a potential trigger for injury and rejection. However, the index of immunity can sometimes miss antibody-mediated rejection and besides causing injury the antibodies against a graft can also protect a graft from injury by blocking immune recognition, called enhancement, regulating activation of complement, and inducing changes in the graft that resist damage. Reviewed here are potential limitations in the use of antibodies as an index of immunity and the ways antibodies cause and/or prevent injury.
    Discovery medicine 08/2010; 10(51):125-33. · 3.50 Impact Factor
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