Differential Modulation of Donor-Specific Antibodies After B-Cell Depleting Therapies to Cure Chronic Antibody Mediated Rejection Maxime Touzot, 1,2,7 Gre´goireCouvrat-Desvergnes, 1,2 Ste´phanieCastagnet, 3 Anne Cesbron, 3 Karine Renaudin, 4,5 Diego Cantarovich, 1,2 and Magali Giral 1,2,6 Background. Donor-specific antibodies (DSA) are considered as reliable biomarkers for antibody-mediated rejection (ABMR) diagnosis. However, it is unclear whether DSA monitoring is necessary and could predict graft outcome after antirejection treatment. Methods. We analyzed 28 non-sensitized kidney transplant patients with ABMR associated with de novo antiYhuman leukocyte antigen (HLA) DSA. Donor-specific antibody levels were measured by single antigen bead assays 12 months after antirejection therapy onset. Patients were placed in three groups according to their antirejection treatment: group I (n=10), plasma exchange-Rituximab; group II (n=8), Bortezomib; and group III (n=10), optimization of maintenance immunosuppression. Half of the patients in group I demonstrated concomitant acute cellular rejection (ACR+). Results. De novo DSA were mainly anti-DQ (60%). AntiYclass I and antiYDR DSA disappeared after treatment in group I and remained negative during follow-up, whereas antiYDQ DSA persisted without any modulation. In contrast, class I-II HLA-DSA mean fluorescence intensity remained unchanged in groups II and III. Graft loss was observed in 80% and 20% of patients from group I (ACR+) and group III, respectively. One year after the ABMR treatment, a 16-mL/min decline in estimated glomerular filtration rate was observed in patients from group I (ACRj) and group III. Group II showed better outcomes with a mean estimated glomerular filtration rate decline of 6.4 mL/min. Conclusion. Modulation of DSA at and after treatment of ABMR did not correlate with graft outcome over a 12-month period. Keywords: Antibody-mediated rejection, Donor-specific antibody, Immunosuppression, Rituximab, Bortezomib. (Transplantation 2014;00: 00Y00) D iagnosis of acute antibody mediated rejection is defined by specific histopathologic features (inflammation of mi- crocirculation, arterial-transmural inflammation, acute tubular necrosis), the presence of C4d deposits in the peritubular capillaritis and recently, by the identification of circulating antiYmajor histocompatibility complex (MHC) donor-specific antibodies (DSA) (1, 2). Because of newer and sensitive techniques of antibody detection (i.e., single antigen assays (LABScreen; One Lambda Inc., Canoga Park, CA), DSA are now considered as reliable biomarkers for antibody- mediated rejection (ABMR) diagnosis. In fact C4d deposits, may be absent in approximately half of confirmed cases of ABMR (3Y5). Moreover, the ability of DSA to bind the C1q fraction of the complement may additionally further discrim- inate clinical outcome (6). It is known that the presence of DSA, preformed (before Tx) or de novo (after Tx), represents a risk factor for the de- velopment of ABMR (mainly preformed DSA) in not only the kidney but also in liver, pancreas, and thoracic transplanta- tions (7Y11). Therapies focused on DSA elimination, such as plasma exchange (PE), anti-CD20 monoclonal antibodies, the CLINICAL AND TRANSLATIONAL RESEARCH Transplantation & Volume 00, Number 00, Month, 2014 www.transplantjournal.com 1 The authors declare no funding or conflicts of interest. 1 Institut National de la Sante Et de la Recherche Medicale INSERM U1064, Nantes, France. 2 Institut de Transplantation Urologie Ne ´phrologie du Centre Hospitalier Universitaire Ho ˆtel Dieu, Nantes, France. 3 Etablissement Franc ¸ais du Sang (EFS), Laboratoire HLA, Nantes, France. 4 Service D’anatomie Pathologique, Centre Hospitalier Universitaire Ho ˆtel Dieu, Nantes, France. 5 Faculte ´ De Me ´decine, Universite ´ de Nantes, Nantes, France. 6 CIC Biotherapy, Centre Hospitalier Universitaire Ho ˆtel Dieu, Nantes, France. 7 Address correspondence to: Maxime Touzot, M.D., Ph.D., Institut de Trans- plantation Urologie et ne ´phrologie du Centre Hospitalier Universitaire Ho ˆ tel Dieu, Nantes, France. E-mail: mtouzot@gmail.com G.C.-D., S.C., D.C., and M.G. contributed equally. M.T. participated in analyzing and interpreting data, performing computa- tional analysis, and in drafting the article. G.C. participated in collecting data. S.C. participated in collecting and analyzing data. A.C. participated in performing critical revision of the article. K.R. participated in performing critical revision of the article. M.G. participated in creating the concept and design and performing critical revision of the article. D.C. participated in making the concept and design and performing critical revision of the article. Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com). Received 7 February 2014. Revision requested 10 March 2014. Accepted 1 May 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/0000-00 DOI: 10.1097/TP.0000000000000285 Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.