Ameliorating Progression of Allograft Vasculopathy by Targeting the T Follicular Helper Cell Subset.
Department of Surgery, University of Cambridge, Cambridge, United Kingdom.
Meeting: 2016 American Transplant Congress
Abstract number: 91
Keywords: Antibodies, Gene expression
Session Information
Date: Sunday, June 12, 2016
Session Name: Concurrent Session: Chronic Allograft Rejection: Animal Models
Session Time: 4:30pm-6:00pm
Presentation Time: 4:42pm-4:54pm
Location: Room 309
BACKGROUND
Development of long-lived alloantibody is closely linked with chronic rejection and graft failure. We examined in a murine model of antibody-mediated rejection (AMR) if targeting T follicular helper (Tfh) cell development prevents chronic rejection by blocking germinal centre (GC) activity.
METHODS
T-cell deficient CB57BL/6 recipients of a BALB/c heart were reconstituted with monoclonal TCR75 CD4 T cells (with indirect specificity to donor Class I H-2Kd) or with TCR75 CD4 T cells genetically deficient for the adaptor molecule SAP. SAP signalling is essential for Tfh development but does not influence extrafollicular antibody production.
RESULTS
Adoptive transfer of 103 TCR75 T cells generated persistent anti-H-2Kd antibody responses, characterised by Kd-binding GC B cells within the spleen, and long-lived anti-Kd-secreting plasma cells in the bone marrow. This was associated with endothelial complement deposition and activation; resulting in chronic allograft vasculopathy, and ultimately, graft rejection (median survival time (MST) = 50 d, n=10). In contrast, transfer of 103 SAP-deficient TCR75 T cells failed to initiate GC responses, with substantial reduction in anti-Kd IgG production. Grafts in this group survived indefinitely (n=5), without development of allograft vasculopathy. Transfer of large numbers (105) of SAP-deficient TCR75 T cells likewise did not initiate GC responses, but did provoke strong and immediate extrafollicular responses, which precipitated acute graft loss (MST=13 d, n=4), with histological hallmarks of acute AMR.
CONCLUSIONS
The demonstration that GC alloantibody responses are essential for allograft vasculopathy highlights the potential for targeting the Tfh subset for improving clinical transplant outcomes. High T helper cell precursor frequency may however provoke acute graft rejection through extrafollicular antibody production.
CITATION INFORMATION: Chhabra M, Ali J, Alsughayyir J, Qureshi S, Bradley J, Bolton E, Motallebzadeh R, Pettigrew G. Ameliorating Progression of Allograft Vasculopathy by Targeting the T Follicular Helper Cell Subset. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:
Chhabra M, Ali J, Alsughayyir J, Qureshi S, Bradley J, Bolton E, Motallebzadeh R, Pettigrew G. Ameliorating Progression of Allograft Vasculopathy by Targeting the T Follicular Helper Cell Subset. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/ameliorating-progression-of-allograft-vasculopathy-by-targeting-the-t-follicular-helper-cell-subset/. Accessed March 4, 2021.« Back to 2016 American Transplant Congress