Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft.

Abstract

BACKGROUND: Blocking leukocyte function-associated antigen (LFA)-1 in organ transplant recipients prolongs allograft survival. However, the precise mechanisms underlying the therapeutic potential of LFA-1 blockade in preventing chronic rejection are not fully elucidated. Cardiac allograft vasculopathy (CAV) is the preeminent cause of late cardiac allograft failure characterized histologically by concentric intimal hyperplasia. METHODS: Anti-LFA-1 monoclonal antibody was used in a multiple minor antigen-mismatched, BALB.B (H-2B) to C57BL/6 (H-2B), cardiac allograft model. Endogenous donor-specific CD8 T cells were tracked down using major histocompatibility complex multimers against the immunodominant H4, H7, H13, H28, and H60 minor Ags. RESULTS: The LFA-1 blockade prevented acute rejection and preserved palpable beating quality with reduced CD8 T-cell graft infiltration. Interestingly, less CD8 T cell infiltration was secondary to reduction of T-cell expansion rather than less trafficking. The LFA-1 blockade significantly suppressed the clonal expansion of minor histocompatibility antigen-specific CD8 T cells during the expansion and contraction phase. The CAV development was evaluated with morphometric analysis at postoperation day 100. The LFA-1 blockade profoundly attenuated neointimal hyperplasia (61.6 vs 23.8%; P < 0.05), CAV-affected vessel number (55.3 vs 15.9%; P < 0.05), and myocardial fibrosis (grade 3.29 vs 1.8; P < 0.05). Finally, short-term LFA-1 blockade promoted long-term donor-specific regulation, which resulted in attenuated transplant arteriosclerosis. CONCLUSIONS: Taken together, LFA-1 blockade inhibits initial endogenous alloreactive T-cell expansion and induces more regulation. Such a mechanism supports a pulse tolerance induction strategy with anti-LFA-1 rather than long-term treatment.

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Citation

Published Version (Please cite this version)

10.1097/TP.0000000000000805

Publication Info

Kwun, Jean, Alton B Farris, Hyunjin Song, William T Mahle, William J Burlingham and Stuart J Knechtle (2015). Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft. Transplantation, 99(12). pp. 2485–2493. 10.1097/TP.0000000000000805 Retrieved from https://hdl.handle.net/10161/10236.

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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.

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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