A P2X7R Mutation with Hypermetabolic T Cells, Th1/Th17 Skewing and Reduced Cardiac Allograft Survival.

F. D'Addio,^1,2 A. Vergani,³ L. Potena,⁴ A. Maestroni,² S. Tezza,¹ M. Ben Nasr,¹ V. Usuelli,² M. Sbolli,¹ L. Borgese,⁴ A. Iacovoni,⁵ D. Corradi,⁶ R. Abdi,⁷ A. Secchi,² R. Starling,⁸ M. Sayegh,^7,9 W. Harmon,¹ D. Briscoe,¹ P. Heeger,¹⁰ A. Chandraker,⁷ F. Grigioni,⁴ P. Fiorina.^1,2

¹Boston Children's Hospital, Boston, MA
²Ospedale San Raffaele, Milan, Italy
³Dompe Research, Milan, Italy
⁴University of Bologna, Bologna, Italy
⁵Ospedale Papa Giovanni XXIII, Bergamo, Italy
⁶University of Parma, Parma, Italy
⁷Brigham and Women's Hospital, Boston
⁸Cleveland Clinic, Cleveland
⁹American University of Beirut, Lebanon, Lebanon
¹⁰Icahn School of Medicine at Mount Sinai, New York.

Meeting: 2016 American Transplant Congress

Abstract number: 242

Keywords: Allorecognition, Rejection, T cell activation, T cells

Session Information

Session Name: Concurrent Session: Molecular and Bio-Markers in Hearts and VADs - A New Hope

Session Type: Concurrent Session

Date: Monday, June 13, 2016

Session Time: 2:30pm-4:00pm

Presentation Time: 2:42pm-2:54pm

Location: Room 102

Background. The purinergic receptor-7 (P2X7R), primarily expressed on lymphocytes, senses ATP released extracellularly during cell damage and regulates T cell activation.

Methods. In 640 heart transplant recipients from 3 international independent observational studies, the CTOT-05 (n=102), the NIT (n=187) and the AIRT (n=351), we evaluated the effect of the p.Glu496Ala/c.1513A>C (rs3751143) P2X7R loss-of-function mutation on major transplant outcomes (1-year cardiac allograft vasculopathy, CAV, through IVUS; 1-year biopsy-proven acute rejection, AR; 10-year major cardiac adverse events clinical analysis, MACE).

Results. Carrying the allele (C), as compared to non-carrying (NC), was associated with an increased risk of: (i) CAV development in the CTOT-05 (Maximal Intimal Thickness >5mm [OR=2.8, p=0.045]); (ii) AR in the NIT (OR=1.8, p=0.047); (iii) long-term MACE in the AIRT (OR=2.3, p=0.039), with a cumulative increased risk of graft loss (OR=1.9, p=0.0007). Analysis of T cell function at 3 and 5 years post-transplant showed an increase in Th1/Th17 cells (Th1/Th17: C=18.0±1.8/11.7±0.8 vs. NC=9.8±0.5/5.5±0.8, p<0.001) and skewed Th1/Th17 polarization in vitro in C as compared to NC. Mechanistic observations suggest maladaptive signaling by the mutant P2X7R intracellular domain, with abrogation of the NLRP3-mediated Th2 transcriptional program. In cardiac-transplanted mice (bm12 into B6 model), reduced graft survival, with severe CAV, hypermetabolic T cells and abnormal Th1/Th17 skewing, was evident in P2X7R^-/- mice. Th17 blockade rescued graft survival in P2X7R^-/- mice and normalized murine T cell phenotype.

Conclusion. Loss-of-function P2X7R mutation causes hypermetabolic T cell syndrome with Th1/Th17 skewing and reduced graft survival. (NCT02082821).

CITATION INFORMATION: D'Addio F, Vergani A, Potena L, Maestroni A, Tezza S, Ben Nasr M, Usuelli V, Sbolli M, Borgese L, Iacovoni A, Corradi D, Abdi R, Secchi A, Starling R, Sayegh M, Harmon W, Briscoe D, Heeger P, Chandraker A, Grigioni F, Fiorina P. A P2X7R Mutation with Hypermetabolic T Cells, Th1/Th17 Skewing and Reduced Cardiac Allograft Survival. Am J Transplant. 2016;16 (suppl 3).

To cite this abstract in AMA style:

D'Addio F, Vergani A, Potena L, Maestroni A, Tezza S, Nasr MBen, Usuelli V, Sbolli M, Borgese L, Iacovoni A, Corradi D, Abdi R, Secchi A, Starling R, Sayegh M, Harmon W, Briscoe D, Heeger P, Chandraker A, Grigioni F, Fiorina P. A P2X7R Mutation with Hypermetabolic T Cells, Th1/Th17 Skewing and Reduced Cardiac Allograft Survival. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/a-p2x7r-mutation-with-hypermetabolic-t-cells-th1th17-skewing-and-reduced-cardiac-allograft-survival/. Accessed November 22, 2024.

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