The Immunosuppressive Effect of CTLA4Ig Monotherapy Depends On the Presence of Tregs Only at Suboptimally Low Doses
1Dept. of Surgery, Medical University of Vienna, Vienna, Austria
2Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
Meeting: 2015 American Transplant Congress
Abstract number: D10
Keywords: Co-stimulation, T cells
Session Information
Session Name: Poster Session D: Costimulation and Signaling in Lymphocytes
Session Type: Poster Session
Date: Tuesday, May 5, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Background: CTLA4Ig/belatacept has been recently approved for immunosuppression after renal transplantation. Concerns persist, however, that a paradoxical dose-response relationship might exist for CTLA4Ig in which inhibitory mechanisms and pathways are abrogated at higher doses. Thus, we investigated the immunosuppressive effect of CTLA4Ig monotherapy and its relationship with Tregs in murine heart transplantation (HTX).
Methods: Fully mismatched (Balb/C into B6) cervical HTX was performed with the following dosing regimens of CTLA4Ig which was injected on days 0,4,14,28,56,84,112: low dose (LD): 0.25mg/mouse (10mg/kg BW); high dose (HD): 1.25mg (50mg/kg); very high dose (VHD):6.25mg (250mg/kg). Anti-CD25 (PC61) was administered 0.25mg on days -6 and -1 (early Treg depletion) or d31 and d36 (late Treg depletion) in selected groups of mice. Grafts were graded according to the ISHLT rejection score. Donor specific antibodies were assessed by flow cytometry.
Results: Chronic CTLA4Ig treatment prolongs allograft survival in a dose-dependent manner (LD vs. untreated mice (median survival time [MST] 60 days vs. 8, p<0.001; n=9). Both HD (n=11) and VHD (n=5) CTLA4Ig regimen further improved graft survival compared to the LD treated mice (MST >100days each; p<0.001). Furthermore, histology revealed excellent scores in HD and VHD treated mice, respectively (median ISHLT score 0.5 vs. 1, p=0.239). Cessation of CTLA4Ig therapy after 100 days in HD treated mice led to prompt rejection of all grafts (mean survival of 56.3 days from the last CTLA4Ig dose), whereas mice with continuous therapy showed preserved graft function and low histology scores at 200 days (p=0.025) (median ISHLT score 4 vs. 2, p<0.001). Treg depletion with antiCD25 led to significantly reduced allograft survival when combined with CTLA4Ig LD therapy (n=6, MST: 21.5 days; p=0.012 vs LD without depletion), whereas neither early (n=5) nor late Treg depletion (n=6) under CTLA4Ig HD therapy impacted graft survival (MST >100days; p=0.312).
Conclusion: The immunosuppressive effect of CTLA4Ig monotherapy displays a conventional dose-response relationship. The negative impact of Treg depletion on graft survival is seen only at low, suboptimal doses of CTLA4Ig monotherapy, but not at higher doses effective in maintaining long-term graft survival.
To cite this abstract in AMA style:
Schwarz C, Unger L, Mahr B, Aumayr K, Pilat N, Hock K, Farkas A, Kristo I, Wekerle T. The Immunosuppressive Effect of CTLA4Ig Monotherapy Depends On the Presence of Tregs Only at Suboptimally Low Doses [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/the-immunosuppressive-effect-of-ctla4ig-monotherapy-depends-on-the-presence-of-tregs-only-at-suboptimally-low-doses/. Accessed May 9, 2025.« Back to 2015 American Transplant Congress