HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival

Ashwin Ajith, Vera Portik-Dobos, Anh Thu Nguyen, Christine Callaway, Daniel D. Horuzsko, Rajan Kapoor, Carlos F Zayas Montalvo, Katsumi Maenaka, Laura L Mulloy, Anatolij Horuzsko

Research output: Contribution to journalArticle

Abstract

Human leukocyte antigen G (HLA-G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA-G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA-G dimer level was not affected by demographic status. One of the potential mechanisms in tissue-organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8+ cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T-cell–mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig-like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA-G dimer, we demonstrated a novel mechanism by which HLA-G dimer inhibits activation and cytotoxic capabilities of human CD8+ T cells. This mechanism implicated the down-regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA-G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.

Original languageEnglish (US)
Pages (from-to)5220-5236
Number of pages17
JournalFASEB Journal
Volume33
Issue number4
DOIs
StatePublished - Jan 1 2019

Fingerprint

Granzymes
HLA Antigens
Dimers
Allografts
Kidney
Transplants
T-cells
Leukocytes
Tissue
Perforin
Molecules
Cytotoxic T-Lymphocytes
Graft Survival
Genomics
Grafts
Transgenic Mice
Fetus
Down-Regulation
Chemical activation
Maintenance

Keywords

  • HLA-G
  • Human kidney transplantation
  • Humanized mouse

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival. / Ajith, Ashwin; Portik-Dobos, Vera; Nguyen, Anh Thu; Callaway, Christine; Horuzsko, Daniel D.; Kapoor, Rajan; Zayas Montalvo, Carlos F; Maenaka, Katsumi; Mulloy, Laura L; Horuzsko, Anatolij.

In: FASEB Journal, Vol. 33, No. 4, 01.01.2019, p. 5220-5236.

Research output: Contribution to journalArticle

Ajith, Ashwin ; Portik-Dobos, Vera ; Nguyen, Anh Thu ; Callaway, Christine ; Horuzsko, Daniel D. ; Kapoor, Rajan ; Zayas Montalvo, Carlos F ; Maenaka, Katsumi ; Mulloy, Laura L ; Horuzsko, Anatolij. / HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival. In: FASEB Journal. 2019 ; Vol. 33, No. 4. pp. 5220-5236.
@article{c2aa7624ce1b4792b30897534a65780d,
title = "HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival",
abstract = "Human leukocyte antigen G (HLA-G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA-G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA-G dimer level was not affected by demographic status. One of the potential mechanisms in tissue-organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8+ cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T-cell–mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig-like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA-G dimer, we demonstrated a novel mechanism by which HLA-G dimer inhibits activation and cytotoxic capabilities of human CD8+ T cells. This mechanism implicated the down-regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA-G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.",
keywords = "HLA-G, Human kidney transplantation, Humanized mouse",
author = "Ashwin Ajith and Vera Portik-Dobos and Nguyen, {Anh Thu} and Christine Callaway and Horuzsko, {Daniel D.} and Rajan Kapoor and {Zayas Montalvo}, {Carlos F} and Katsumi Maenaka and Mulloy, {Laura L} and Anatolij Horuzsko",
year = "2019",
month = "1",
day = "1",
doi = "10.1096/fj.201802017R",
language = "English (US)",
volume = "33",
pages = "5220--5236",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "4",

}

TY - JOUR

T1 - HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival

AU - Ajith, Ashwin

AU - Portik-Dobos, Vera

AU - Nguyen, Anh Thu

AU - Callaway, Christine

AU - Horuzsko, Daniel D.

AU - Kapoor, Rajan

AU - Zayas Montalvo, Carlos F

AU - Maenaka, Katsumi

AU - Mulloy, Laura L

AU - Horuzsko, Anatolij

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Human leukocyte antigen G (HLA-G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA-G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA-G dimer level was not affected by demographic status. One of the potential mechanisms in tissue-organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8+ cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T-cell–mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig-like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA-G dimer, we demonstrated a novel mechanism by which HLA-G dimer inhibits activation and cytotoxic capabilities of human CD8+ T cells. This mechanism implicated the down-regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA-G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.

AB - Human leukocyte antigen G (HLA-G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA-G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA-G dimer level was not affected by demographic status. One of the potential mechanisms in tissue-organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8+ cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T-cell–mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig-like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA-G dimer, we demonstrated a novel mechanism by which HLA-G dimer inhibits activation and cytotoxic capabilities of human CD8+ T cells. This mechanism implicated the down-regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA-G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.

KW - HLA-G

KW - Human kidney transplantation

KW - Humanized mouse

UR - http://www.scopus.com/inward/record.url?scp=85064135864&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064135864&partnerID=8YFLogxK

U2 - 10.1096/fj.201802017R

DO - 10.1096/fj.201802017R

M3 - Article

C2 - 30620626

AN - SCOPUS:85064135864

VL - 33

SP - 5220

EP - 5236

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 4

ER -