IL-21 Biased Alemtuzumab Induced Chronic Antibody-Mediated Rejection Is Reversed by LFA-1 Costimulation Blockade

• Authors: Jean Kwun, Duke University; Jaeberm Park, Duke University; John S. Yi, Duke University; Alton B Farris III, Emory University; Allan D. Kirk, Duke University; Stuart J. Knechtle, Duke University
• Journal Title: Frontiers in Immunology
• Volume: Volume 9, Number OCT
• Publisher: Frontiers Media | 2018-10-15, Pages 2323-2323
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3389/fimmu.2018.02323
• Subjects: Health Sciences, Medicine and Surgery; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology; IL-21; germinal center; follicular helper T cells; heart transplantation; antibody-mediated rejection; FOLLICULAR-HELPER-CELLS; KIDNEY-TRANSPLANT PATIENTS; GERMINAL CENTER FORMATION; T-CELLS; B-CELL; CARDIAC ALLOGRAFT; DE-NOVO; BRONCHIOLITIS OBLITERANS; RENAL-TRANSPLANTATION; ORGAN-TRANSPLANTATION

Abstract

Despite its excellent efficacy in controlling T cell mediated acute rejection, lymphocyte depletion may promote a humoral response. While T cell repopulation after depletion has been evaluated in many aspects, the B cell response has not been fully elucidated. We tested the hypothesis that the mechanisms also involve skewed T helper phenotype after lymphocytic depletion. Post-transplant immune response was measured from alemtuzumab treated hCD52Tg cardiac allograft recipients with or without anti-LFA-1 mAb. Alemtuzumab induction promoted serum DSA, allo-B cells, and CAV in humanized CD52 transgenic (hCD52Tg) mice after heterotopic heart transplantation. Additional anti-LFA-1 mAb treatment resulted in reduced DSA (Fold increase 4.75 ± 6.9 vs. 0.7 ± 0.5; p < 0.01), allo-specific B cells (0.07 ± 0.06 vs. 0.006 ± 0.002 %; p < 0.01), neo-intimal hyperplasia (56 ± 14% vs. 23 ± 13%; p < 0.05), arterial disease (77.8 ± 14.2 vs. 25.8 ± 20.1%; p < 0.05), and fibrosis (15 ± 23.3 vs. 4.3 ± 1.65%; p < 0.05) in this alemtuzumab-induced chronic antibody-mediated rejection (CAMR) model. Surprisingly, elevated serum IL-21 levels in alemtuzumab-treated mice was reduced with LFA-1 blockade. In accordance with the increased serum IL-21 level, alemtuzumab treated mice showed hyperplastic germinal center (GC) development, while the supplemental anti-LFA-1 mAb significantly reduced the GC frequency and size. We report that the incomplete T cell depletion inside of the GC leads to a systemic IL-21 dominant milieu with hyperplastic GC formation and CAMR. Conventional immunosuppression, such as tacrolimus and rapamycin, failed to reverse AMR, while co-stimulation blockade with LFA-1 corrected the GC hyperplastic response. The identification of IL-21 driven chronic AMR elucidates a novel mechanism that suggests a therapeutic approach with cytolytic induction.