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

Publication ,  Journal Article
Kwun, J; Farris, AB; Song, H; Mahle, WT; Burlingham, WJ; Knechtle, SJ
Published in: Transplantation
December 2015

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.

Duke Scholars

Published In

Transplantation

DOI

EISSN

1534-6080

Publication Date

December 2015

Volume

99

Issue

12

Start / End Page

2485 / 2493

Location

United States

Related Subject Headings

  • Transplantation, Homologous
  • Surgery
  • Minor Histocompatibility Antigens
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Lymphocyte Function-Associated Antigen-1
  • Heart Transplantation
  • Graft Survival
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kwun, J., Farris, A. B., Song, H., Mahle, W. T., Burlingham, W. J., & Knechtle, S. J. (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), 2485–2493. https://doi.org/10.1097/TP.0000000000000805
Kwun, Jean, Alton B. Farris, Hyunjin Song, William T. Mahle, William J. Burlingham, and Stuart J. Knechtle. “Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft.Transplantation 99, no. 12 (December 2015): 2485–93. https://doi.org/10.1097/TP.0000000000000805.
Kwun, Jean, et al. “Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft.Transplantation, vol. 99, no. 12, Dec. 2015, pp. 2485–93. Pubmed, doi:10.1097/TP.0000000000000805.

Published In

Transplantation

DOI

EISSN

1534-6080

Publication Date

December 2015

Volume

99

Issue

12

Start / End Page

2485 / 2493

Location

United States

Related Subject Headings

  • Transplantation, Homologous
  • Surgery
  • Minor Histocompatibility Antigens
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Lymphocyte Function-Associated Antigen-1
  • Heart Transplantation
  • Graft Survival