Year: 2017
Type: article
Abstract: Despite recent evidence of improved graft outcomes and safety, the high incidence of early acute cellular rejection with belatacept, a high-affinity CTLA4-Ig, has limited its use in clinical transplantation. Here we define how the incomplete control of endogenous donor-reactive memory T cells results in belatacept-resistant rejection in an experimental model of BALB/c.2W-OVA donor heart transplantation into C57BL/6 recipients presensitized to donor splenocytes. These sensitized mice harbored modestly elevated numbers of endogenous donor-specific memory T cells and alloantibodies compared with naive recipients. Continuous CTLA4-Ig treatment was unexpectedly efficacious at inhibiting endogenous graft-reactive T cell expansion but was unable to inhibit late CD4+ and CD8+ T cell infiltration into the allografts, and rejection was observed in 50% of recipients by day 35 after transplantation. When CTLA4-Ig was combined with the sphingosine 1-phosphate receptor-1 (S1PR1) functional antagonist FTY720, alloantibody production was inhibited and donor-specific IFN-γ-producing T cells were reduced to levels approaching nonsensitized tolerant recipients. Late T cell recruitment into the graft was also restrained, and graft survival improved with this combination therapy. These observations suggest that a rational strategy consisting of inhibiting memory T cell expansion and trafficking into the allograft with CTLA4-Ig and FTY720 can promote allograft survival in allosensitized recipients.
Source: JCI Insight
Institutions: University of Chicago, University of California, Davis
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Howard Hughes Medical Institute, American Heart Association, American Society of Transplantation, Teva Pharmaceutical Industries, University of Chicago, Second Military Medical University, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases
Awards: Mechanistic studies on Listeria infection and inhibition of allograft tolerance, G1459655681, G2340152788, Reduced avidity endogenous graft-specific T cells in transplantation tolerance, G3488383117, G5289408919, G529657565, G6212863132, The role of endogenous, antigen-specific, auto- and alloreactive Tregs in transplantation tolerance, G9000005519, G9000072622, Infections and the Stability of Transplantation Tolerance, G972191158
OpenAlex ID: W2611627387