Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft. Issue 12 (December 2015)

• Record Type: Journal Article
• Authors: Kwun, Jean; Farris, Alton B.; Song, Hyunjin; Mahle, William T.; Burlingham, William J.; Knechtle, Stuart J.
• Is Part Of: Transplantation. Volume 99:Issue 12(2015)
• Publication Date: 2015-12
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000000805
• Languages: English
• ISSNs: 0041-1337

Abstract

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-2 b ) to C57BL/6 (H-2 b ), 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. Abstract : The authors investigate the inhibitory role of LFA-1 blockade on endogenous alloreactive T cell expansion in a mouse cardiac allograft model. The short-term LFA-1 blockade promotes long-term donor-specific regulation and attenuated transplant arteriosclerosis. Supplemental digital content is available in the text.