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Medline ® Abstracts for References 3-7

of 'Evaluation and treatment of antibody-mediated lung transplant rejection'

3
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Acute rejection and humoral sensitization in lung transplant recipients.
AU
Martinu T, Chen DF, Palmer SM
SO
Proc Am Thorac Soc. 2009;6(1):54.
 
Despite the recent introduction of many improved immunosuppressive agents for use in transplantation, acute rejection affects up to 55% of lung transplant recipients within the first year after transplant. Acute lung allograft rejection is defined as perivascular or peribronchiolar mononuclear inflammation. Although histopathologic signs of rejection often resolve with treatment, the frequency and severity of acute rejections represent the most important risk factor for the subsequent development of bronchiolitis obliterans syndrome (BOS), a condition of progressive airflow obstruction that limits survival to only 50% at 5 years after lung transplantation. Recent evidence demonstrates that peribronchiolar mononuclear inflammation (also known as lymphocytic bronchiolitis) or even a single episode of minimal perivascular inflammation significantly increase the risk for BOS. We comprehensively review the clinical presentation, diagnosis, histopathologic features, and mechanisms of acute cellular lung rejection. In addition, we consider emerging evidence that humoral rejection occurs in lung transplantation, characterized by local complement activation or the presence of antibody to donor human leukocyte antigens (HLA). We discuss in detail methods for HLA antibody detection as well as the clinical relevance, the mechanisms, and the pathologic hallmarks of humoral injury. Treatment options for cellularrejection include high-dose methylprednisolone, antithymocyte globulin, or alemtuzumab. Treatment options for humoral rejection include intravenous immunoglobulin, plasmapheresis, or rituximab. A greater mechanistic understanding of cellular and humoral forms of rejection and their role in the pathogenesis of BOS is critical in developing therapies that extend long-term survival after lung transplantation.
AD
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina, USA.
PMID
4
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C4d staining of pulmonary allograft biopsies: an immunoperoxidase study.
AU
Wallace WD, Reed EF, Ross D, Lassman CR, Fishbein MC
SO
J Heart Lung Transplant. 2005;24(10):1565.
 
BACKGROUND: The role of antibody-mediated/humoral rejection in lung allografts is not fully elucidated. In other organ systems, deposition of a specific complement product, C4d, is a sensitive and specific marker for humoral rejection. C4d can be evaluated in tissue biopsies by immunofluorescence or light microscopic immunohistochemical staining techniques. Using immunohistochemical staining techniques we sought to determine whether there was any specific staining pattern for C4d in lung allograft biopsies with or without the diagnosis of acute or chronic cellular or humoral rejection.
METHODS: A total of 68 lung transplant biopsies, performed at UCLA Medical Center from January 2002 to August 2004, were collected and the paraffin blocks were re-cut and stained for C4d by an immunoperoxidase technique. The cases were separated by the presence or absence of features of acute and/or chronic rejection based on the International Society for Heart and Lung Transplantation working formulation for the classification of pulmonary allograft rejection, revised 1995. The pattern of staining for C4d was then systematically examined.
RESULTS: Positive staining in a variable, focal non-specific pattern was observed. There was no consistent staining pattern within the different diagnostic groups.
CONCLUSIONS: C4d staining of paraffin-embedded lung allograft biopsies, using currently available techniques, does not identify acute or chronic cellular or humoral rejection in lung allograft tissue.
AD
Division of Anatomic Pathology, David Geffen School of Medicine, University of California Los Angeles, California, USA.
PMID
5
TI
Antibody-mediated rejection in lung transplantation: myth or reality?
AU
Glanville AR
SO
J Heart Lung Transplant. 2010;29(4):395.
 
Whether antibody-mediated rejection after lung transplantation exists as an entity is debated by immunologists, histopathologists, and clinicians, without a strong consensus regarding diagnostic characteristics despite an increasing body of evidence that attests to a significant role in other solid organ transplant disciplines. Evidence for and against the protean manifestations of antibody-mediated rejection after lung transplantation is discussed, with special reference to hyperacute pulmonary allograft rejection as well as acute and chronic pulmonary allograft rejection, emphasizing the potential role of complement and antibodies to human leukocyte antigens and anti-endothelial antigens. A well-described clinical phenotype exists for hyperacute pulmonary allograft rejection with low-level evidence for efficacy of therapy with intravenous immunoglobulin, plasmapheresis, and anti-CD20 monoclonal antibodies plus supportive care, if instituted early in the evolution of the process. The clinical phenotype of acute antibody-mediated rejection is now better defined, if not widely diagnosed, and a similar treatment protocol appears effective. The role of antibody-mediated rejection in the development of chronic pulmonary allograft rejection remains an exciting area for further study based on some compelling preliminary work to date. Antibody-mediated rejection after lung transplantation remains a majorarea for research. In the clinical domain, experience suggests antibody-mediated rejection should be considered a potential cause of graft dysfunction, whether concomitant acute cellular rejection is diagnosed or not, and especially where resistance to corticosteroid therapy is encountered.
AD
Lung Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia. aglanville@stvincents.com.au<aglanville@stvincents.com.au>
PMID
6
TI
Acute antibody-mediated rejection after lung transplantation.
AU
Morrell MR, Patterson GA, Trulock EP, Hachem RR
SO
J Heart Lung Transplant. 2009;28(1):96. Epub 2008 Dec 4.
 
The role of humoral immunity after lung transplantation remains unclear. In this report, we describe the pathologic findings and clinical course of a case of acute antibody-mediated rejection (AMR) after lung transplantation. After an uncomplicated early course, a 31-year-old man with cystic fibrosis developed acute graft dysfunction 1 month after bilateral lung transplantation. Lung biopsies showed acute pneumonitis with capillary injury, neutrophilic infiltration and nuclear dust. Immunostaining for C4d demonstrated endothelial cell deposition, and circulating donor-specific human leukocyte antigen (HLA) antibodies were identified. Despite severe hypoxemic respiratory failure, he responded well to a regimen consisting of methylprednisolone, plasma exchange, intravenous immunoglobulin and rituximab therapy. He completely recovered clinically although donor-specific HLA antibodies have remained detectable. The incidence of acute AMR after lung transplantation is unknown, but this case fulfills all of the consensus diagnostic criteria, and we suggest that AMR could be an under-recognized cause of acute graft dysfunction.
AD
Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine/Barnes-Jewish Hospital, St. Louis, Missouri, USA. mmorrell@im.wustl.edu
PMID
7
TI
Increased erythrocyte C4D is associated with known alloantibody and autoantibody markers of antibody-mediated rejection in human lung transplant recipients.
AU
Golocheikine A, Nath DS, Basha HI, Saini D, Phelan D, Aloush A, Trulock EP, Hachem RR, Patterson GA, Ahearn JM, Mohanakumar T
SO
J Heart Lung Transplant. 2010;29(4):410.
 
BACKGROUND: Immune responses to mismatched donor human leukocyte antigens (HLA) are important in the pathogenesis of chronic rejection. This study evaluated whether erythrocyte-bound C4d (E-C4d) is associated with known alloimmune and autoimmune markers of antibody-mediated rejection after human lung transplantation (LTx).
METHODS: Flow cytometry was used to analyze 22 LTx recipients and 15 healthy individuals for E-C4d. Development of antibodies to donor-mismatched HLA (donor-specific antibody [DSA]) and antibodies to HLA were determined using the solid-phase method by Luminex. Development of antibodies to self-antigens, K-alpha-1-tubulin (KA1T) and collagen V (Col-V), were measured by enzyme-linked immunosorbent assay. C3d deposition in lung biopsy specimens was determined by immunohistochemical staining.
RESULTS: Percent E-C4d (%E-C4d) levels were 19.9% in LTx patients vs 3.7% in healthy individuals (p = 0.02). DSA+ patients had higher E-C4d levels than DSA- patients (34.1% vs 16.7%, p = 0.02). In 5 patients with preformed anti-HLA, E-C4d levels were not significantly different vs 13 patients without detectable anti-HLA (p = 0.1). E-C4d levels were higher in patients who developed antibodies to KA1T (p = 0.02) and Col-V (p = 0.03). Recipients with C3d-positive tissue deposition had higher E-C4d levels than patients with C3d-negative biopsy results (p = 0.01).
CONCLUSIONS: Increased %E-C4d levels are found in patients with positive DSA, high antibody titers to KA1T and Col-V, and have C3d+ lung biopsy findings. Therefore, %E-C4d can serve as a potential marker for antibody-mediated rejection after LTx.
AD
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
PMID