[R01] Regulation of Alloimmunity by Intragraft Endothelial Cells
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2031-07-31
Importo max: 847.299 EUR
Paese: US
Descrizione
Project Summary/Abstract
Allograft rejection is characterized by effector CD4+ T cell activation, leukocyte recruitment and an intense
cellular and humoral attack on the graft. The functional interplay between infiltrating effector leukocytes and
graft microvascular endothelial cells (EC) within an allograft is well established to create a local
microenvironment that both initiates and sustains the progression of rejection. However, recent studies
indicate that under select conditions, immunoevasive and immunoregulatory genes may be expressed by
graft EC, and there is evidence to suggest that they suppress local alloimmune Teffector responses and
rejection. While little is known about the expression of immunomodulatory genes within allografts or their
mechanism of induction, it is an important mechanism underlying immune evasion in tumors, where it has
resulted in the clinical development of novel anti-tumor therapeutics. Nevertheless, in-depth profiling of the
temporal patterns of expression of immunoregulatory and immunoevasive gene signatures over time post-
transplantation has not been performed. Furthermore, the mechanisms that result in their induction and
regulation in vivo within allografts is not known. In preliminary studies, we developed a murine model of graft-
dependent immunomodulation and find that EC within these allografts have, a high level of MHC class I and
II expression, reduced PI3K/mTOR and cytokine signaling activity and an associated co-expression of both
coinhibitory and costimulatory molecules. Since intragraft EC also express DEPTOR, which modulates mTOR
and cytokine-induced signals, we speculate that it may regulate immunomodulatory events in subsets of
intragraft EC. Our objectives in this R01 are to precisely discover the temporal patterns of expression and
function of immunomodulatory genes within allograft EC in established murine models of transplantation as
well as in human allograft biopsies. We will test the hypothesis that intragraft subpopulation(s) of EC facilitate
immunomodulation following transplantation, and that immunoregulatory EC activation is dependent on cell
intrinsic inhibition of mTOR signaling and/or DEPTOR-dependent interactions. We propose two specific aims
in which we will: 1) comprehensively map the expression of immunoevasive and immunomodulatory genes
within allograft endothelial cells and define heterogeneity in signatures in the course of transplantation, and
2) mechanistically evaluate the function of intragraft endothelial cell DEPTOR in the development of local
immunoregulation and determine its association with long-term graft survival. Collectively, these innovative
studies have broad scientific, biological and clinical implications.
Istituzione: BOSTON CHILDREN'S HOSPITAL
PI: David M. Briscoe
Progetto: 1R01AI192982-01A1
Settori: National Institute of Allergy and Infectious Diseases
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