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

dc.contributor.author

Kwun, Jean

dc.contributor.author

Farris, Alton B

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Song, Hyunjin

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Mahle, William T

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Burlingham, William J

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Knechtle, Stuart J

dc.coverage.spatial

United States

dc.date.accessioned

2015-06-26T17:34:12Z

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2015-12

dc.description.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.

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/26102611

dc.identifier.eissn

1534-6080

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https://hdl.handle.net/10161/10236

dc.language

eng

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Ovid Technologies (Wolters Kluwer Health)

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Transplantation

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10.1097/TP.0000000000000805

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Allografts

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Animals

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Antibodies, Monoclonal

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CD8-Positive T-Lymphocytes

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Disease Models, Animal

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Graft Rejection

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Graft Survival

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Heart Transplantation

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Lymphocyte Function-Associated Antigen-1

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Male

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Mice

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Mice, Inbred BALB C

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Mice, Inbred C57BL

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Minor Histocompatibility Antigens

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Transplantation, Homologous

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Kwun, Jean|0000-0002-8563-5472

duke.contributor.orcid

Knechtle, Stuart J|0000-0002-1625-385X

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/26102611

pubs.begin-page

2485

pubs.end-page

2493

pubs.issue

12

pubs.organisational-group

Clinical Science Departments

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Duke

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Duke Clinical Research Institute

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Institutes and Centers

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School of Medicine

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Surgery

pubs.organisational-group

Surgery, Abdominal Transplant Surgery

pubs.publication-status

Published

pubs.volume

99

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