RESEARCH IN PROGRESS
Terasaki Innovation Center, Inc. salutes the transplant scientists from around the world who continue to move the legacy of Paul Terasaki forward with their cutting edge research in the role of antibodies
in transplant rejection.
This quarter our featured articles are:
Understanding and measuring human B-cell tolerance and its breakdown in autoimmune disease
Kevin S Cashman , Scott A Jenks. , Matthew C Woodruff , Deepak Tomar , Christopher M Tipton , Christopher D Scharer ,
F Eun-Hyung Lee , Jeremy M Boss , Iñaki Sanz
1. Department of Medicine, Division of Rheumatology, Emory University, Atlanta, GA, USA
2. Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
3. Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA
4. Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Emory University, Atlanta, GA, USA
The maintenance of immunological tolerance of B lymphocytes is a complex and critical process that must be implemented as to avoid the detrimental development of autoreactivity and possible autoimmunity. Murine models have been invaluable to elucidate many of the key components in B-cell tolerance; however, translation to human homeostatic and pathogenic immune states can be difficult to assess. Functional autoreactive, flow cytometric, and single-cell cloning assays have proven to be critical in deciphering breaks in B-cell tolerance within autoimmunity; however, newer approaches to assess human B-cell tolerance may prove to be vital in the further exploration of underlying tolerance defects. In this review, we supply a comprehensive overview of human immune tolerance checkpoints with associated mechanisms of enforcement, and highlight current and future methodologies which are likely to benefit future studies into the mechanisms that become defective in human autoimmune conditions.
Cashman KS, Jenks SA, Woodruff MC, et al. Understanding and measuring human B-cell tolerance and its breakdown in autoimmune disease. Immunol Rev. 2019;292:76–89. https ://doi.org/10.1111/imr.12820
Donor-specific B Cell Memory in Alloimmunized Kidney Transplant Recipients: First Clinical Application of a Novel Method
Caroline Wehmeier , Gonca E Karahan , Juliette Krop , Yvonne de Vaal , Janneke Langerak-Langerak , Isabelle Binet ,
Stefan Schaub , Dave L Roelen , Frans H J Claas , Sebastiaan Heidt , Swiss Transplant Cohort Study
1. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
2. Department of Nephrology and Transplantation Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland.
3. Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
HLA-specific memory B cells may contribute to the serum HLA antibody pool upon antigen reexposure. The aim of this pilot study was to investigate the presence of concurrent donor-specific memory B cell-derived HLA antibodies (DSA-M) in renal allograft recipients with pretransplant donor-specific HLA antibodies (DSA) and its association with occurrence of antibody-mediated rejection (AMR) using a recently developed method.
Twenty patients with Luminex single antigen bead (SAB) assay-defined DSA but negative complement-dependent cytotoxicity crossmatches were enrolled. Plasma samples and peripheral blood mononuclear cells were collected at 3 timepoints (pretransplant, mo 6, mo 12). We analyzed IgG-purified and concentrated culture supernatants from polyclonally activated peripheral blood mononuclear cells using SAB assays and compared HLA antibody profiles with same day plasma results.
Plasma SAB analysis revealed 35 DSA in 20 patients pretransplant. DSA-M were detected in 9 of 20 (45%) patients and for 10 of 35 specificities (29%). While median mean fluorescence intensity values of DSA with concurrent DSA-M (5877) were higher than those of DSA without DSA-M (1476), 3 of 6 patients with AMR and low mean fluorescence intensity DSA (<3000) had DSA-M. Overall, pretransplant DSA/DSA-Mpos allograft recipients showed a higher incidence of biopsy-proven (sub)clinical AMR (P = 0.032) and a higher extent (g≥1 + ptc≥1) of microvascular inflammation (67% vs 9%, P = 0.02). In 17 patients (28 DSA) with posttransplant analyses, persisting DSA posttransplant had more often DSA-M (6/12; 50%) than nonpersisting DSA (2/16; 13%).
Assessment of DSA-M might be a novel tool to supplement serum HLA antibody analysis for pretransplant risk stratification in patients with DSA.
Wehmeier C, Karahan G, Krop J, et al. Donor-specific B Cell Memory in Alloimmunized Kidney Transplant Recipients: First Clinical Application of a Novel Method. Transplantation. 2020 May;104(5):1026-1032.doi: 10.1097/TP.0000000000002909.