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

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 - 2019

Keywords

  • HLA-G
  • Human kidney transplantation
  • Humanized mouse

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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