Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.

Abstract

De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.

Department

Description

Provenance

Subjects

Antibody-mediated rejection, costimulation blockade, follicular helper T cells, germinal center reaction, Abatacept, Animals, Antibodies, B-Lymphocytes, CD4-Positive T-Lymphocytes, Germinal Center, Graft Rejection, Immunoconjugates, Kidney Transplantation, Lymph Nodes, Macaca mulatta, Male, Recombinant Fusion Proteins, T-Lymphocytes, Helper-Inducer, Tacrolimus

Citation

Published Version (Please cite this version)

10.1111/ajt.12526

Publication Info

Kim, EJ, J Kwun, AC Gibby, JJ Hong, AB Farris III, NN Iwakoshi, F Villinger, AD Kirk, et al. (2014). Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection. Am J Transplant, 14(1). pp. 59–69. 10.1111/ajt.12526 Retrieved from https://hdl.handle.net/10161/10063.

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Scholars@Duke

Kwun

Jean Kwun

Associate Professor in Surgery

Research interests include humoral tolerance to organ transplants in animal model and humans, developing a clinically relevant animal model to study the mechanisms of antibody-mediated rejection (AMR), and establishing a conceptual basis that will translate into therapeutic intervention of AMR.

Kirk

Allan Douglas Kirk

David C. Sabiston, Jr. Distinguished Professor of Surgery

I am a surgeon with interest in immune management of transplant recipients. I am particularly interested in therapies that influence T cell costimulation pathways and adjuvant therapies that facilitate costimulation blockade to prevent the rejection of transplanted organs without undue suppression of protective immunity. I am also interested in understanding how injury, such as that occurring during trauma or in elective surgery, influences immune responses and subsequent healing following injury.

Knechtle

Stuart Johnston Knechtle

William R. Kenan, Jr. Distinguished Professor

During my career as an academic surgeon, I have had the privilege of leading and/or participating in a diverse portfolio of hypothesis-driven research projects.  These projects have centered on the immunology of surgery and transplantation, including both cellular and antibody-mediated immune responses.  During my training I studied the response of hyper-sensitized recipients to allogeneic liver transplantation, and am currently studying means of reducing immunologic memory that might allow more successful transplantation in sensitized recipients.  This immune response involves pathways of coagulation, antibody-mediated rejection, and cellular rejection and current work in my lab involves these three pathways.  The other major focuses of my work have been co-stimulation blockade and immune cell depletion as approaches to immunologic unresponsiveness or tolerance.  My research group has been involved in translational and clinical research to develop these mechanistic tools for the benefit of human organ transplant recipients.

Recent Publications

Knechtle SJ, Shaw JM, Hering BJ, Kraemer K, Madsen JC. Translational impact of NIH-funded nonhuman primate research in transplantation. Sci Transl Med. 2019 Jul 10;11(500). pii: eaau0143. Reprint | Full Text


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